Full Download Multifunctional and Targeted Theranostic Nanomedicines Formulation Design and Applications Keerti Jain PDF

Full download test bank at ebookmeta.
com
Multifunctional And Targeted Theranostic

Nanomedicines Formulation Design And Applications
Keerti Jain
For dowload this book click LINK or Button below
https://ebookmeta.com/product/multifunctional-and-
targeted-theranostic-nanomedicines-formulation-
design-and-applications-keerti-jain/
OR CLICK BUTTON
DOWLOAD EBOOK
Download More ebooks from https://ebookmeta.com

More products digital (pdf, epub, mobi) instant
download maybe you interests ...
Advanced Multifunctional Lightweight Design Development

and Implementation 1st Edition Kamran Behdinan
https://ebookmeta.com/product/advanced-multifunctional-
lightweight-design-development-and-implementation-1st-edition-
kamran-behdinan/
Herbal Product Development : Formulation and

Applications 1st Edition Anil K Sharma
https://ebookmeta.com/product/herbal-product-development-
formulation-and-applications-1st-edition-anil-k-sharma/
Molecular Imaging and Targeted Therapy:

Radiopharmaceuticals and Clinical Applications, 2nd 2nd
Edition Shankar Vallabhajosula
https://ebookmeta.com/product/molecular-imaging-and-targeted-
therapy-radiopharmaceuticals-and-clinical-applications-2nd-2nd-
edition-shankar-vallabhajosula/
Building Offline Applications with Angular: Develop

Reliable, Performant Web Applications for Desktop and
Mobile Platforms 1st Edition Venkata Keerti Kotaru
https://ebookmeta.com/product/building-offline-applications-with-
angular-develop-reliable-performant-web-applications-for-desktop-
and-mobile-platforms-1st-edition-venkata-keerti-kotaru/
Building Offline Applications with Angular: Develop
Reliable, Performant Web Applications for Desktop and
Mobile Platforms 1st Edition Venkata Keerti Kotaru
https://ebookmeta.com/product/building-offline-applications-with-
angular-develop-reliable-performant-web-applications-for-desktop-
and-mobile-platforms-1st-edition-venkata-keerti-kotaru-2/
Digitization in Dentistry: Clinical Applications

Priyanka Jain
https://ebookmeta.com/product/digitization-in-dentistry-clinical-
applications-priyanka-jain/
Cognitive Computing Systems: Applications and

Technological Advancements 1st Edition Vishal Jain
(Editor)
https://ebookmeta.com/product/cognitive-computing-systems-
applications-and-technological-advancements-1st-edition-vishal-
jain-editor/
Angular for Material Design: Leverage Angular Material

and TypeScript to Build a Rich User Interface for Web
Apps 1st Edition Venkata Keerti Kotaru
https://ebookmeta.com/product/angular-for-material-design-
leverage-angular-material-and-typescript-to-build-a-rich-user-
interface-for-web-apps-1st-edition-venkata-keerti-kotaru/
Fundamentals and Properties of Multifunctional

Nanomaterials 1st Edition Sabu Thomas (Editor)
https://ebookmeta.com/product/fundamentals-and-properties-of-
multifunctional-nanomaterials-1st-edition-sabu-thomas-editor/
Editors
Keerti Jain and N. K. Jain
Multifunctional And Targeted

Theranostic Nanomedicines
Formulation, Design And Applications
Editors
Keerti Jain
Department of Pharmaceutics, National Institute of Pharmaceutical
Education and Research (NIPER) – Raebareli, Lucknow, India
N. K. Jain
Department of Pharmaceutical Sciences, Dr. Hari Singh Gour University,
Sagar, Madhya Pradesh, India
ISBN 978-981-99-0537-9 e-ISBN 978-981-99-0538-6

https://doi.org/10.1007/978-981-99-0538-6
© The Editor(s) (if applicable) and The Author(s), under exclusive

license to Springer Nature Singapore Pte Ltd. 2023
This work is subject to copyright. All rights are solely and exclusively
licensed by the Publisher, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of
illustrations, recitation, broadcasting, reproduction on microfilms or in
any other physical way, and transmission or information storage and
retrieval, electronic adaptation, computer software, or by similar or
dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks,

service marks, etc. in this publication does not imply, even in the
absence of a specific statement, that such names are exempt from the
relevant protective laws and regulations and therefore free for general
use.
The publisher, the authors, and the editors are safe to assume that the
advice and information in this book are believed to be true and accurate
at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, expressed or implied, with respect to the
material contained herein or for any errors or omissions that may have
been made. The publisher remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
This Springer imprint is published by the registered company Springer

Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04
Gateway East, Singapore 189721, Singapore
Preface
Nanotechnology-based therapeutic systems are extensively being
explored for targeted delivery of drugs as well as for diagnostic
purposes. At present, nanotechnology-based therapeutic approaches
are being explored in pharmaceutical, biomedical, and biotechnological
research and innovation to design unique nanomedicines with different
ability to treat and diagnose the diseases like cancer, autoimmune
disorders, AIDS, and other deadly infectious as well as non-infectious
diseases. Further, various multifunctional nanomedicines,
functionalized with different ligands or targeting agents or some other
active moiety to make it versatile carrier with different beneficial
abilities including targeted delivery, gene delivery, immunotherapy,
diagnosis/imaging/sensing, theranostic applications, etc., are also
being explored extensively by researchers.
Currently, nanotechnology-based products are rapidly growing and
multifunctional nanomedicines are emerging as multifunctional nano-
sized engineered nanomaterials useful in the simultaneous targeted
delivery of various biotherapeutics as well as diagnostic and imaging
agents. Although customizing, designing, optimization, formulation,
pilot scale-up, and validation of nano-formulations are considered
major obstacles in delivering safe and efficacious products in the
market, yet ample of nano-formulations exist for the treatment of
multiple diseases and disorders. Functionalization of these
formulations aids in delivering these nanomaterials to the target sites
in the right amount while minimizing the dose and adverse effects.
This book titled Multifunctional and Targeted Theranostic
Nanomedicines ―Formulation, Design and Applications, covers various
aspects of multifunctional nanomedicines for theranostic applications
such as methods of functionalization, characterization, applications,
and regulatory aspects. Chapters 1 and 2 deal with introductory
knowledge on nanomedicines, theranostics, functionalization, and
design of functionalized theranostic nanomedicines. The safety and
toxicity aspects along with regulatory perspectives of functionalized
theranostic nanomaterials are also discussed in Chap. 1. Chapters 3−6
provide advanced information on vesicular, polymeric, metallic, and
lipid-based nanomedicines for theranostic applications and their
functionalization. Chapters 7−10 discuss the engineering,
functionalization, and theranostic applications of nanoemulsions,
dendrimers, carbon-based nanomaterials, and quantum dots. Chapters
11−14 deal with different multifunctional nanomaterials including
nanogels, exosomes, polymeric micelles, and nanocrystals in
theranostic applications. Chapters 15 and 16 are focused on magnetic
and mesoporous silica nanoparticles and their functionalization for
theranostic applications. This book is a compilation of vivid chapters
contributed by renowned formulators, researchers, and academicians
across the world with their specialized area of interest in the field of
chemistry, biology, pharmacy, diagnosis, and nanomedicine.
We firmly believe that this book, Multifunctional and Targeted
Theranostic Nanomedicines―Formulation, Design and Applications, will
be useful for the postgraduate students, doctorate, and postdoctoral
research fellows, while scientists, researchers, and academicians
working in nanomedicines, pharmaceutical nanotechnology, and
theranostics can enrich and upgrade their knowledge. It will be equally
insightful for industrial, scientific, and academic purposes and will also
assist formulation scientists and academicians working in the field of
pharmaceutical product development to upgrade and enhance their
knowledge on the nanotechnology-driven product development. This
book should primarily address the challenges in realizing the
simultaneous therapeutic and diagnostic benefits of optimized
pharmaceutical delivery systems, exceeding the boundaries of “magic
bullet” concept.
We express our sincere thanks to all the authors for their
contributions. We are also extremely grateful to our respective
institutions, colleagues, students, and family members for their support
during the compilation of this book. We also acknowledge our gratitude
to Springer Nature team and all those concerned, for their untiring
efforts in bringing this book to the publication and in the market.
Keerti Jain
N. K. Jain
Lucknow, Uttar Pradesh, India
Sagar, Madhya Pradesh, India
Contents
1 Functionalized Targeted Theranostic Nanomedicines
Mohammad Zaki Ahmad, Kalyani Pathak, Javed Ahmad,
Mohammad Aslam, Archana Bagre, Parth Patel and Keerti Jain
2 Designing of Smartly Functionalized Theranostic Nanomedicines
Dheeraj Pandey, Parth Patel, Keerti Jain and Abha Sharma
3 Theranostic Applications of Functionalized Vesicular Carriers
Mohammed Asadullah Jahangir, Dibyalochan Mohanty,
Amarendranath Choudhury and Syed Sarim Imam
4 Theranostic Applications of Functionalized Polymeric
Nanoparticles
Syed Sarim Imam, Ameeduzzafar Zafar, Keerti Jain and
Sultan Alshehri
5 Functionalized Metallic Nanoparticles:Theranostic Applications
Kapil D. Patel, Anup Kumar Patel, Prasad Sawadkar, Bineta Singh
and Adam W. Perriman
6 Functionalized Lipidic Nanoparticles:Smartly Engineered
Lipidic Theragnostic Nanomedicines
Namrata Gautam, Harish Vishkarma, Debopriya Dutta,
Muskan Goyal, Lubna Siddiqui and Sushama Talegaonkar
7 Functionalized Nanoemulsions:Could Be a Promising Approach
for Theranostic Applications
Mohammed Aslam, Georgeos Deeb, Mohammad Zaki Ahmad,
Keerti Jain and Javed Ahmad
8 Functionalized Dendrimers:Promising Nanocarriers for
Theranostic Applications
Anchal Pathak, Saba Naqvi and Keerti Jain
9 Functionalized Carbon Nanotubes, Graphene Oxide, Fullerenes,
and Nanodiamonds:Emerging Theranostic Nanomedicines
Satish Shilpi, Anamika Sahu Gulbake, Sandhya Chouhan and
Pramod Kumar
10 Quantum Dots:Functionalization and Theranostic Applications
Stanzin Sonam, Parth Patel, Dheeraj Pandey, Abha Sharma and
Keerti Jain
11 Functional Nanogels and Hydrogels:A Multipronged
Nanotherapy in Drug Delivery and Imaging
Prashant Sahu, Sushil K. Kashaw, Varsha Kashaw and Arun K. Iyer
12 Theranostic Applications of Functionalized Exosomes
Ayesha Waheed, Abdul Ahad, Dipak Kumar Gupta, Asad Ali,
Mohd. Aqil, Yasmin Sultana, Fahad I. Al-Jenoobi and Abdullah M. Al-
Mohizea
13 Theranostic Applications of Functionalized Polymeric Micelles
Bhakti S. Aiwale, Monika S. Deore, Keerti Jain and Saba Naqvi
14 Functionalized Nanocrystals and Theranostic Applications
Dipak Kumar Gupta, Asad Ali, Abdul Ahad, Ayesha Waheed,
Mohd. Aqil, Fahad I. Al-Jenoobi and Abdullah M. Al-Mohizea
15 Theranostics Applications of Functionalized Magnetic
Nanoparticles
Ruchi Tiwari, Gaurav Tiwari and Poonam Parashar
16 Functionalized Mesoporous Silica-Based Nanoparticles for
Theranostic Applications
Ujwala Ramteke, Vinay Kumar, Sanya Batheja, Ganesh Phulmogare
and Umesh Gupta
© The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023
K. Jain, N. K. Jain (eds.), Multifunctional And Targeted Theranostic Nanomedicines
https://doi.org/10.1007/978-981-99-0538-6_1
1. Functionalized Targeted Theranostic

Nanomedicines
Mohammad Zaki Ahmad1 , Kalyani Pathak2, Javed Ahmad1, Mohammad Aslam3,
Archana Bagre4, Parth Patel5 and Keerti Jain5
(1) Department of Pharmaceutics, College of Pharmacy, Najran University, Najran,
Kingdom of Saudi Arabia
(2) Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh,
Assam, India
(3) Faculty of Pharmacy, Al Hawash Private University, Homs, Syria
(4) Department of Pharmaceutics, Truba Institute of Pharmacy, Bhopal, India
(5) Department of Pharmaceutics, National Institute of Pharmaceutical Education
and Research (NIPER) – Raebareli, Lucknow, India
Mohammad Zaki Ahmad (Corresponding author)

Email: zaki.manipal@gmail.com
Keerti Jain (Corresponding author)

Email: keertijain.02@niperraebareli.edu.in
Abstract
Nanotechnology has a substantial impact on the development of both therapeutic
and diagnostic agents in the health sector. Nanocarriers were widely explored for
therapeutic purpose by scientific community due to its unique ability to improve
the solubility, bioavailability, and cellular uptake of active pharmaceutical
ingredients. Nowadays, nanomedicines became more popular for its ability to serve
as carrier to get imaging of various biological systems or deliver the image-guided
treatment options in treatment of various life-threatening diseases. Clinically
effective formulations that combine treatment and diagnostics are widely attractive
at the nexus of these two paradigms: This notion, recently termed as
nanotheranostic, is significantly important for the ligand decorated nanocarriers,
which accumulated at diseased area more potentially and can give customized or
image-guided treatment. Numbers of theranostic nanoparticles with various
combination of imaging agents and therapeutic agents were thoroughly
investigated in past few years. These include, for example, liposomes; polymeric
nanoparticles; micelles; drug conjugates and complexes; dendrimers; vesicles;
micelles; core-shell particles; microbubbles; and carbon nanotubes. The current
chapter gives detailed overview of various imaging techniques that are usually
used in clinical setups along with recently explored theranostic nanocarriers and
regulatory obstacles behind its commercialization.
Keywords Nanomedicines – Theranostic nanoparticles – Imaging agents –

Quantum dots – Diagnostic techniques
Abbreviations
AuNPs Gold nanoparticles
GO Graphene oxide
MRI Magnetic imaging resonance
NIR Near infrared
PDT Photodynamic therapy
PEG Polyethylene glycol
PET Positron emission tomography
PLA Polylactic acid
PTT Photothermal therapy
SPIONs Superparamagnetic iron oxide nanoparticles
1.1 Introduction
There is a tremendous demand in clinical trials for addressing differences in drug
responsiveness induced by genetic diversity in large patient populations.
Therefore, as a result, tailored treatment is the current strategy for resolving this
issue (Moghimi et al. 2005). Hood invented the Predictive, Personalized,
Preventive, and Participatory (P4) approach to medicine. Personalized medicine is
predicated on collecting unique data from an individual’s cells or biomolecules
regarding their illness, health status, and therapeutic response (Hood 2013).
Personal medicine or precision medicine can be defined as, “a customized medical
care based on the detailed study of genomic, epigenetic changes and other data to
treat the disease in best possible way” (National Research Council (US) Committee
on A Framework for Developing a New Taxonomy of Disease 2011). The vast
pharmacokinetic diversity of drug has opened the doors for personalized medicine
in treatment of life-threatening diseases. Because of the unique characteristics of
personalized medicine, it has gained considerable attention (Kim and Nie 2005).
Numerous techniques, including genomics, proteomics, and metabolomics, can be
used to decode and collect data at the molecular level for a person. Over the last
few decades, the traditional Evidence-Based Medicine paradigm has transitioned
steadily toward an individualized or customized medicine system. In general, the
main objective behind the phase IV clinical trial was to optimize the medications
for a large group of population in conventional treatment strategy. But the newer
approaches focused on the individual’s genetic peculiarities, which not only
minimize the side effects associated with conventional medicines but also improve
the therapeutic outcome. Additionally, real-time monitoring of pharmacokinetics of
drug and pathological conditions will give insights for future planning of treatment
strategy. This provides chance to manage the dosage of medications so that
therapeutic response will get better and side effects will decrease (Lammers et al.
2012).
In the realm of medical science, nanotechnology has developed a distinct
position. Due to their unique physical and chemical attributes, nanomaterials
imparted the desired characteristics like large surface area for improving the
solubility of lipophilic drugs; ease of functionalization will provide better cell
uptake and side specific delivery of drug, high loading capacity, etc. This enables
them to be applied in a broad range of technological disciplines. Theranostics is a
term that refers to a method that combines diagnostic and therapeutic aspects. The
concept of tailored nanomedicine lies at the heart of nanotheranostic. In 2002,
Funkhouser coined the term “Theranostics,” which includes therapeutic as well as
imaging moieties in a single carrier to track the unwanted disposition of drug or its
carrier and side effects associated with it (Moghimi et al. 2005). After it is injected
into the body, the pharmacokinetics and pharmacodynamics can be tracked using
theranostic materials. There was an initial focus on cancer treatment, but it has
now been broadened to other life-threatening diseases as well, which include
autoimmune disorders such as type 1 diabetes, cardiovascular diseases,
inflammatory diseases, and many more (Gollavelli and Ling 2014). Figure 1.1
showed the various applications of theranostic nanocarrier system. It is possible to
perform both treatment and diagnosis simultaneously using tailored
multifunctional theranostic nanomaterials, such as magnetic resonance imaging
(MRI), computed tomography (CT), positron emission tomography (PET) scans, or
fluorescence imaging. Smart and new biomaterials will steadily improve the
theranostic efficacy of nanoparticles (Choi et al. 2011).
Fig. 1.1 Applications of theranostic nanomedicine formulations (Adapted with permission from
Lammers et al. (2011))
Therapy is the process of resolving a problem following its discovery. The
methods used will differ according to the patient’s condition. Effective treatments
strategy for cancer includes radiation therapy, immunotherapy, chemotherapy,
targeted therapy, stem cell therapy, and surgery. Conventional therapy approaches
have numerous disadvantages like toxicity to normal cells, lengthy processing
times, high dosage requirements including nonspecific targeting, etc. (Gollavelli
and Ling 2014). The major side effects associated with chemotherapy include
neurotoxicity, immune system suppression, hair loss, fatigue, muscle pain,
headache, etc. This showed the requirement of development of more precise and
effective dosage form, which significantly reduces the dose of anticancer agents by
lowering the unwanted disposition of drug and increasing the cellular uptake at
tumor site (Li et al. 2014). Nanotherapeutics have potential to precisely target the
infection location; they reduce undesirable side effects, increase effectiveness, and
improve patient compliance and prognosis. This chapter discussed in detail the
importance of theranostic nanocarrier and various imaging techniques along with
various therapeutic and imaging agents, along with novel nanocarrier explored to
get theranostic application in treatment of various life-threatening diseases.
1.2 Design of Nanotheranostic

Nanotheranostic is a term that referred as combination of nanotechnology,
diagnostics agent, and therapeutic moiety. Several scientific fields have put
significant efforts in developing theranostic nanomedicines during the past several
years. New and exciting applications for nanotheranostic-based nanomedicines are
the results of this collaboration (Akhter et al. 2013; Bukhari et al. 2021; Ahmed et
al. 2022). As shown in Fig. 1.2 theranostic is an interdisciplinary approach, which
required sincere involvement of a pharmacist, pharmacologists, a medicinal
chemist, and other technical personnel.
Fig. 1.2 Schematic representation of the highly interdisciplinary field of nanotheranostics

There are three primary components to nanotheranostic agents: a therapeutic
drug, an imaging agent, and a carrier that envelopes both. This theranostic system
is targeted explicitly by connecting the ligands to carrier molecule. Figure 1.3
depicts a straightforward schematic illustration of a nanotheranostic system.
Fig. 1.3 Schematic representation of nanotheranostic system
1.3 Therapy in Nanotheranostic

1.3.1 Drug Therapy
There are a lot of things that make it hard for drugs to get to the sites they need to
go, like anatomical barriers, cellular membranes, blood-brain barriers, nuclear
membranes, physiological barriers, and chemical and physical barriers (Lammers
et al. 2012; Bai et al. 2015). Nanotechnology plays an integral part in the rapidly
expanding field of personalized medicine by clubbing therapeutic and diagnostic
functions in a single system (Kim et al. 2013; Akhter et al. 2011). As nanocarrier-
based delivery systems have the ability to deliver the drug directly to the desired
site, thus reducing the dose and frequency of medication (Bai et al. 2015; Ahmad et
al. 2013, 2015). Additionally, cytotoxicity associated with the plain drug
also decreases significantly upon its entrapment inside ligand decorated
nanocarrier due to selective delivery to diseases site sparing normal cells. Cisplatin,
5-fluorouracil, carboplatin, bleomycin, dactinomycin, paclitaxel, topotecan,
vinblastine, doxorubicin, etoposide, mercaptopurine, and other chemotherapeutics
are commonly employed as therapeutic drugs in nanotheranostic system for
treatment of cancer (Ali et al. 2011).
1.3.2 Gene Delivery

Gene delivery includes transfer of specific gene to the infected cells of human body
to treat the specific disease. One such approach is RNA interference (RNAi), which
includes usage of siRNA (small-interfering RNA) or miRNA (micro-RNA) to reduce
the expression of physiologically overexpressed proteins. Circulating miRNA is an
important biomarker of cancer (Wan et al. 2012). Due to siRNA’s low stability and
inadequate distribution to target cells, its therapeutic potential is restricted.
Inhibition of overexpressed miRNA and its reconditioning were the two major
objectives behind the RNAi treatment (Muthiah et al. 2013). To overcome the
challenges affiliated with the in vivo delivery of genes, Kenny et al. developed
theranostic siRNA attached PEGylated nanoparticles. These magnetic resonance
sensitive nanoparticles were used in combination with fluorescent markers to get
the image-guided delivery of siRNA in tumor. In vivo administration of this
formulation in tumor-bearing mice resulted in a significant decrease in tumor
growth (Kenny et al. 2011). Overall, gene delivery is a novel approach to treat a
range of diseases, but its high cost and lack of stability limit its application in
clinical application.
1.3.3 Photodynamic Therapy

Historically from very ancient time phototherapy was used for treatment of various
skin and other diseases; for instance, vitiligo was treated by applying plant extract
of Ammi majus L., followed by exposing them to sunlight (Hö nigsmann 2012).
Nowadays, development of focusable carbon arc torch to cure the lupus vulgaris by
Danish physician Niels Finsen made the phototherapy popular, again (Gøtzsche
2011). Photodynamic therapy (PDT) can be used in the treatment of a wide range
of malignant as well as non-malignant disorders. Photosensitizers are used in PDT
to absorb light energy and transfer it to surrounding cells, resulting in the
formation of reactive oxygen species inside the cells, which can eventually lead to
cell death (Bai et al. 2015). In PDT, photosensitizing agents absorb lights at a
specific wavelength and convert molecular oxygen present inside the cytoplasm of
cells to singlet oxygen, which cause apoptosis of tumor cells (Paszko et al. 2011).
Examples of photosensitizing agents used in PDT include napthalocyanines,
photofrin, phorphine, phthalocyanine derivatives, and chlorins (Gollavelli and Ling
2014; Li et al. 2014; Allison et al. 2004). Figure 1.4 showed the photochemical
reaction as per Jablonski’s rule. In the case of a photosensitizer material, an excited
electron crosses over the other molecules instead of coming to its ground or low
energy state, which may produce hydrogen peroxide or superoxide as shown in Fig.
1.5. This hydrogen peroxide or superoxide was able to kill the tumor cells by
damaging nucleus or cell organelles like mitochondria, resulting in cell death
(Calzavara-Pinton et al. 2007). However, these types of photosensitizing agents
tended to stay in the human body for longer period of time, which made the
patients more susceptible to sunlight. To avoid any unwanted phototoxicity,
patients were advised to stay in a dark environment (Zhao and He 2014). The
ligand decorated theranostic nanocarriers can make the PDT safe as well as
effectively improving the cellular uptake in diseased cells.
Fig. 1.4 Schematic representation of photosensitizer associated ROS generation and its role in
causing apoptosis of cancer cells
Fig. 1.5 Schematic representation of PTT and PDT using nanotheranostic
1.3.4 Photothermal Therapy

Photothermal therapy (PTT) is also called heat ablation technique, which uses light
radiation to generate heat within the tissue (Gellci and Mehrmohammadi 2014).
Heat is a highly effective weapon for destroying tumor cells. However, inducing a
moderate temperature of 41–50 °C in the body for a brief period (5–10 min)
without damaging normal tissue is a challenging task. PTT uses the near infrared
(NIR) light waves to get the better tissue penetration and a photosensitive agent
with good light absorbing capacity. PTT can selectively kill the pathologic cell upon
excitation of photosensitizing agent by NIR light by converting the resonance
energy of electromagnetic rays into heat production as shown in Fig. 1.5. This heat
causes the irreversible changes in tumor cells by cellular mutilation (Gellci and
Mehrmohammadi 2014). However, use of PTT in clinical practice is very limited
due to its no specificity in identification between malignant and non-malignant
cells. Clear demarcation between diseased and non-diseased cell is important to
protect the normal body cells. To overcome this problem, ligand decorated
nanotheranostic agents were explored in recent years. Due to its ability to
significantly improve the cellular uptake at diseased tissue, side effect associated
with unwanted disposition of photosensitizing agents was reduced significantly,
and its therapeutic potential will improve (Huang et al. 2021; Liu et al. 2020;
Dheyab et al. 2021). Such types of nanomaterials along with suitable targeting
ligands were preferable for the clinical application of PTT.
Many interesting theranostic nanomaterials are made from noble metals such
as gold. Gold nanoparticles (AuNPs) were widely explored for the PTT due to its
low toxicity and easy renal clearance (Akhter et al. 2012). Gold has been the most
extensively studied PTT agent, which showed promising results in treatment of
various cancers in many research articles.
1.4 Nanotheranostic for Imaging

Theranostic agents must contain some imaging agents to provide in vivo diagnosis.
Many approaches are being investigated to meet these goals using various
materials. Nanotheranostic can be imaged using a variety of techniques such as
optical imaging, nuclear imaging, CT, MRI, PET, and ultrasound (Fig. 1.6) (Debbage
and Jaschke 2008; Janib et al. 2010). Each technique has its own advantages and
disadvantages, which are discussed in the following subsections.
Fig. 1.6 Typical molecular imaging instruments
1.4.1 Optical Imaging

Optical imaging is the cost-effective and most widely used imaging technique in
preclinical studies. It has proven helpful for non-invasive, sensitive, real-time
molecular recognition and imaging investigations. Photons generated by
bioluminescent or fluorescent probes are used in optical imaging (Janib et al. 2010;
Sarbadhikary et al. 2021; Jain and Zhong 2022). It offers advantages over other
imaging modalities in that it is relatively inexpensive to detect low-energy photons;
also, the visible to near-infrared (NIR) light spectrum gives excellent spatial
resolution without the use of ionizing radiation (Janib et al. 2010). To get the better
resolution optical imaging can be integrated with other imaging agents such as PET
or MRI. Bioluminescence and fluorescence imaging are the two most commonly
explored technique in tumor diagnosis and image-guided surgery, in vivo (Lim et al.
2020). Metal nanoparticles can also be used in nanotheranostic to provide
anticancer therapy with fluorescence imaging. For example, silver nanoparticles
with strong metal enhanced fluorescence are helpful for cell imaging (Li et al.
2015a). Unfortunately, this modality has limited application in biological system
due to poor tissue penetration. Additionally, fluorescence imaging is sensitive to
noise due to heme groups (λmax 560 nm), protein (257–280 nm), and even water
(around 900 nm) (Debbage and Jaschke 2008). However NIR probe due to its
identical structural properties could improve the efficiency due to good tissue
penetration capacity.
1.4.2 Magnetic Resonance Imaging

The precession movement given by hydrogen nuclei of water within the applied
magnetic field is the basis for the MRI signal (Janib et al. 2010; Richard et al. 2008).
This modality produced a high-quality cross-sectional image of the body in any
plane using radiofrequency pulses and a controlled magnetic field (Anani et al.
2021; Zhou et al. 2021). All hydrogen atoms align and become excited along the
applied external magnetic field after the application of radiofrequency. The wire
coils in the MRI unit will capture the energy released by the excited atoms, and
with the aid of a computer system, the MRI mapping will be performed. The
relaxation process, which takes place when the nuclei return to their initial aligned
condition, can be used to produce an image (Li et al. 2015a). MRI contrast agents
helped in reducing the relaxation parameters to increase the tissue differentiation.
MRI contrast agents can be divided as paramagnetic agents, such as manganese or
gadolinium, and superparamagnetic agents like iron core or manganese core
polymeric matrix, which were considered as better MRI contrast agents (Avasthi et
al. 2020; Bonnet and Tó th 2021; Xiao et al. 2016).
Due to its great spatial resolution and sensitivity, MRI is frequently used to
diagnose solid and brain tumors, which is regarded as the most efficient and non-
invasive imaging technology. It has superior spatial resolution when compared to
other imaging techniques. However, it has low sensitivity. To compensate, relatively
large contrast agent concentrations are needed to provide a discernible signal.
Concerns about accumulation and toxicity have arisen due to the use of high
dosages of these contrast agents, which has become a substantial issue for Gd (III)
complexes. While Gd (III) provides more excellent contrast for tumor and vascular
imaging, sluggish excretion and toxicity from long-term accumulation may limit its
clinical application.
1.4.3 Computed Tomography

A CT scan employs computer processing to build cross-sectional images from a
series of X-ray images obtained from various angles around the body. The capacity
of CT to differentiate tissues is dependent on the degrees of X-ray attenuation, and
the attenuation coefficient depended on the electron density and atomic number of
the tissues. Absorption differences between identification of air, fat, and bone
depended on the absorption differences, and produced high contrast images of
anatomical components (Janib et al. 2010; Weissleder 2002). The CT contrast
agents that are currently available have a low molecular weight and exhibit quick
extravasation as well as clearance. However, macromolecular and nanoparticulate
agents may be more suited for vascular CT imaging because of their long-lasting
presence in the blood (Janib et al. 2010). Most CT contrast research is focused on
solid nanoparticles or liposomes containing iodinated molecules since these
ingredients are required in high concentrations (Cormode et al. 2009).
1.4.4 Ultrasound Imaging

In ultrasound imaging, a transducer (probe) is used to convert the electrical energy
into mechanical energy based on the piezoelectric effect. A thin layer of gel was
applied over the skin to transmit the ultrasound waves generated by transducer
(Janib et al. 2010). This ultrasound imaging approach is well established, non-
invasive, adaptable, and commonly utilized in human clinical imaging modalities as
a diagnostic tool (Janib et al. 2010; Zhou et al. 2020). Because of the advantages of
real time, portable, non-ionizing, and deep tissue-penetrating abilities, Ultrasound
has already become a widely demanded approach for tumor diagnosis due to
advantages like portable machinery, real time imaging and deep tissue imaging
abilities (Zhou et al. 2020; Frinking et al. 2000).
Furthermore, the advent of US contrast agents has accelerated its use in
diagnosis and treatment of various diseases (Campbell 2006). Microbubble-based
ultrasound imaging offers good contrast effect, which is the need for in vivo
imaging. Additionally, it can function as an efficient delivery mediator of genes and
medications for treating tumors by affecting cellular membranes and vascular
endothelial integrity in the case of an excessive collapse of microbubbles at high-
pressure amplitude (Papachristodoulou et al. 2019; Xu et al. 2017). Furthermore,
these gas-filled microbubbles have poor stability and a short half-life due to the
materials used and the process used to produce them (Zhou et al. 2020).
Nanotheranostic agents have some eye touching features like ultrasmall size and
ability to bind specific receptors to target cells or tumor microenvironments with
prolonged circulation time and high stability (Ahmad et al. 2013, 2020, 2021;
Akhter et al. 2012). Tremendous possibilities available behind the development of
novel theranostic agents to treat life-threatening diseases attract lots of scientists
to research in this particular area (Bajwa et al. 2015; Jain et al. 2015a). Such
nanotheranostics carriers are discussed in the following sections.
1.5 Different Types of Nanotheranostics

The “theranostics” word is referred to systems that can be both applied as
therapeutics and imaging agents. Ideally, a nanotheranostic should be designed in
such a way that it could circulate for a longer duration in the biological system,
depict desired release as per the requirement, have target specificity and ability to
deliver the drug and theranostic agent in desired concentration at target site, and
have imaging ability and a larger target to background ratio.
Based on nanoplatform used in design of nanotheranostics, nanotheranostics
could be classified into two categories. One is inorganic theranostic, where
inorganic materials are used as theranostics like superparamagnetic iron oxide,
gold, carbon nanomaterials, graphene oxide, quantum dots, etc. Another category is
organic nanotheranostics in which organic materials like polymeric nanoparticles,
polymeric micelles, liposome, lipids, etc. are used. We have shown different
nanotheranostic systems graphically in Fig. 1.7 along with their three main
biomedical applications, i.e., therapeutic delivery, diagnostic/imaging applications,
and targeted delivery of bioactive if we modify or engineer the nanotheranostics
with targeting ligands/moieties also depicted in Fig. 1.7. Additionally, the summary
of recently researched nanotheranostic agents is showcased in Table 1.1.
Fig. 1.7 Types and applications of nanotheranostics
Table 1.1 Summary of few nanotheranostic agents explored for biomedical applications
S. Types Functionalization Targeted disease Imaging References

no. technique
1. Superparamagnetic SPIONs-aptamer Cancer MRI Jalalian et
iron oxide bioconjugates al. (2013)
no. technique
nanoparticles
(SPIONs)
2. SPIONs Chitosan-coated Cancer Ultrasound/MRI Sun et al.
SPION (2019)
3. SPIONs Chondroitin Cancer MRI Mallick et
sulfate-capped al. (2016)
SPIONs
4. Ultrasmall SPIONs Phenothiazine- Alzheimer’s disease NIR Cai et al.
based near- (2020)
infrared (NIR)
fluorescent dye
5. Ultrasmall SPIONs Epirubicin (EPI)- Cancer MRI Yoon et al.
loaded ultrasmall (2017)
SPIONs with poly
(aspartic acid)
graft copolymer
6. Gold antennas Cetuximab loaded Tumor Raman Ló pez-
in gold spectroscopy Lorente
nanoantenna (2021)
7. Hollow gold Ac-Glu-Glu-Cys- Cancer NIR Xiong et al.
nanocages NH 2 tripeptide- (2018)
linked AuNPs
loaded with
cisplatin Pt (II)
8. Carbon Functionalized Cancer MRI Li et al.
nanomaterials fullerene with (2015b)
cytokine
interleukin-13
encapsulated
9. Nanodiamonds Human serum Brain targeting Fluorescent dye Moscariello
albumin-based et al. (2019)
biopolymer
(polyethylene
glycol) coating
(dcHSA-PEG)
10. Polymeric Poly (vanillin Hepatic H 2O 2 Kang et al.
nanoparticles oxalate) ischemia/reperfusion (2016)
nanoparticles (I/R) injury
11. Polymeric Autofluorescence Angiogenesis and Polymer with Shao et al.
nanotheranostics polymer tumor cell growth NIR dye (2019)
polyethylene
no. technique
imine-polylactide
(PEI-PLA)
12. Liposome PEG-coated and Cancer 159Gd Siafaka et
folate-PEG-coated al. (2021)
Inorganic nanocarriers have offered wide range of benefits due to their
properties like diverse surface chemistry, controllable structures, large surface
area, and tunable optical characteristics in delivery of therapeutic and diagnostic
agents. Furthermore, research work published in last decade proved the efficiency
of inorganic nanoparticles as theranostic agents (Feliu et al. 2016).
1.5.1 Superparamagnetic Iron Oxide Nanoparticles

SPIONs are the particles of submicron size, consisting of iron oxide core, which
imparts them magnetic properties under influence of external magnetic field. The
colloidal stability of SPIONs is improved by either surface functionalization or
surface coating with suitable polymeric or non-polymeric capping agents such as
carboxymethyl cellulose, chondroitin sulfate, starch, chitosan, etc. (Sun et al. 2019;
Mallick et al. 2015, 2016). SPIONs can be used as efficient multimodal
nanotheranostics carrier due to its small size, good biocompatibility, ability of
surface functionalization, sensitivity, and their capacity to be used as multimodal
contrast agent (Cai et al. 2020). The FDA authorized “Ferumoxides,” the first
SPION-derived MRI contrast agent, in 1996. Several iron oxide nanoparticles,
notably “Feridex” and “Feraheme,” have so far obtained confirmation for use in
clinical settings (Wahsner et al. 2019). Iron oxide nanoparticles capped with
specific polymers have shown ability to serve as efficient contrast agents in
ultrasound/MRI (Sun et al. 2019).
SPIONs are used as multimodal MRI contrast agent for imaging of brain cells,
liver cells, lung cells, heart cells, etc. (Yoon et al. 2017; Reczyń ska et al. 2020; Dao et
al. 2017). Conjugation of SPIONs with aptamers has been explored for colorectal
and prostate cancer therapy and imaging. High-intensity MRI signals were
observed from tumor area upon intravenous administration of aptamer conjugated
SPIONs. Scientists have also observed that SPIONs were metabolized into non-toxic
iron ions in in vivo experiments (Jalalian et al. 2013; Wang et al. 2008). Cai et al.
developed ultrasmall SPIONs coupled with phenothiazine-based NIR fluorescent
dye and evaluated for Alzheimer’s disease. The SPION coupled with novel
theranostic agents showed strong binding with Aβ species as well as an
enhancement of fluorescence in the NIR window. They were highly stable in bovine
serum with low cytotoxic effect toward human neuroblastoma cells. The in vivo
NIR fluorescence and MRI images showed a big difference between double
transgenic mice and wild-type control mice. Histological staining in slices of brain
confirmed the specific binding of nanoparticles to Aβ plaque. The SPION coupled
with novel theranostic agents blocked the seeding-mediated aggregation with an
IC50 of 11.7–32.1 ng/mL, which is much better than observed in phenothiazine-
based small molecules (Cai et al. 2020). Also, the research published in last few
years confirmed that conjugation of SPIONs with antibodies, ligands, polymers,
folic acid, PEG, or peptide gave promising results of radiosensitivity in ovarian
cancer, cervical cancer, and breast cancer (Fakhimikabir et al. 2018; Zhang et al.
2016; Song et al. 2018; Pan et al. 2018).
Excellent blood–brain barrier permeability of SPIONs without disturbing other
brain cells under low radio radiofrequency field is an important feature in brain
imaging. Phenothiazine-based and PEGylated ultrasmall SPIONs worked as novel
theranostics agents for amyloid plaques in Alzheimer’s disease (Dao et al. 2017;
Yallapu et al. 2010). Next generation SPIONs act as a Trojan horse (administered
intravenously) for the delivery of therapeutic drugs to cancers. Recently, ultrasmall
SPIONs working as a multimodal contrast agent have been recognized as a
promising material for development of nanotheranostic carriers due to its good
biocompatibility and high sensitivity (Chen et al. 2022). SPIONs have tremendous
potential to study the in vivo behavior of nanocarriers, as they are inherently
holding the MRI contrast agents.
1.5.2 Gold
AuNPs have been widely explored for applications as imaging agents, drug delivery
carrier, for targeted delivery, theranostics, etc., because they are capable of
conjugating and delivering drugs and bioactive molecules (ligands) to targeted
cells. AuNPs were an attractive alternative amidst various inorganic systems
exploited by research community due to their high surface-area-to-volume ratio,
unique and tunable optical properties, as well as easy surface functionalization
along with high loading capacity of biomolecules. When AuNPs are in contact with
a biological medium, they may rapidly be coated with nonspecific serum proteins.
This process has been known as the corona effect. To diminish corona effect AuNPs
were frequently coated with PEG (Albertini et al. 2019; Groysbeck et al. 2019) or
multilayer coating of albumins (Achilli et al. 2022).
In addition to this, AuNPs can be explored for the PDT, PTT, and photoacoustic
treatments. Therefore, we can use AuNPs in various fields, e.g., bioimaging
(Demiral et al. 2021; Nicholls et al. 2016), targeted delivery of therapeutics (García
et al. 2022; Li et al. 2018), and plasmonic PTT (Ali et al. 2022; Taylor et al. 2022).
Demiral et al. formulated PEGylated AuNPs by attaching cell penetration enhancer
D-α-Tocopherol succinate to detect and treat drug-resistant micro tumors through
PTT by using verteporfin as photosensitizer. The theranostic system was not only
used for drug delivery and imaging in vitro/vivo, but it can also be used for other
fluorescence-based biological and medical purposes. Covalent attachment of ligand
and imaging agent to the system makes the theranostic agent work better against
tumors, and observed to be the most promising candidate, causing 4 times as many
cells to die. The cell studies showed that the theranostic agent improves the
apoptosis process in 61% of the cells (Demiral et al. 2021).
Gold nanocarriers involved in diagnosis, therapeutic, and theranostic
application showed different morphology such as spherical, nanorods, nano shells,
hollow nanocages, nanoantenna, nanoplates, nano prisms, etc. (Ló pez-Lorente
2021; Xiong et al. 2018; Vines et al. 2019; Gharatape and Salehi 2017). Gold-based
nanotherapeutics can be remodeled for tumor microenvironment for targeting by
changing unfavorable therapeutic conditions into therapeutically accessible by
imparting them different external (temperature, laser, or ultrasound) and internal
(pH, enzymes, and glutathione) stimuli responsive drug release mechanisms
(Mohapatra et al. 2021; Rajendrakumar et al. 2018). AuNPs have inherent property
to provide catenate sites for coating or conjugation of various active
pharmaceutical ingredients, ligands, proteins, and imaging agents, which provide
immense potential to use AuNPs as nanocarrier in biological system.
1.5.3 Carbon Nanomaterials

Carbon allotropes such as nanodiamonds, carbon nanoparticles, fullerenes, carbon
nanotubes, graphene, etc., have tremendous potential to serve as delivery carrier
due to their unique physiochemical properties, chemical nature, handy fabrication,
facile surface modification, thermal stability, optical properties, great mechanical
strength, and electrical conductivity (Kaur et al. 2016). Researchers already
explored carbon-based nanomaterials as theranostics nanocarrier in image-guided
treatment of cardiovascular diseases and cancer (Alagarsamy et al. 2021; Gao et al.
2019).
Nanodiamonds have an octahedral architecture (size 5–50 nm), known for its
unique properties like low toxicity, stable fluorescence, easy functionalization, and
intrinsic biocompatibility (Qin et al. 2021). Similarly, carbon nanotubes have a
unique architectural form of fullerene (cylindrical fullerene) broadly classified into
single-walled carbon nanotubes and multi-walled carbon nanotubes. They are
highly ordered, pseudo-one-dimensional carbon allotropes that can easily
penetrate various cells to deliver the drugs or bioactive molecules (Augustine et al.
2017).
Fullerenes have lots of free active groups on its surface, which provide them
immense potential for functionalization (Shi et al. 2014). Li et al. formulated
surface functionalized fullerene with cytokine interleukin-13, and encapsulated
Gadolinium, to increase the intracellular uptake of anticancer agent. When this
fullerene was attached to an interleukin-13 peptide, this hydrophilic nanoparticle
showed a better uptake in human brain cell lines (U-251 GBM). These results
support the idea that the positively charged (amino)-I nanoparticle has a stronger
charge attraction for human brain cellular endocytosis on the metallofullerene cage
surface (Li et al. 2015b).
A wide range of carbon-based materials provide good fluorescence and less
toxicity compared to the organic dyes, although their cytotoxicity-related concerns
and poor knowledge regarding pharmacokinetic behavior limit their commercial
application.
1.5.4 Graphene Oxide

Graphene oxide (GO) is a form of graphene that has been oxidized, widely explored
in biotechnology and medicine field to treat cancer, drug delivery, and easy
penetration through cells. GO also has many physical and chemical properties, such
as a nanoscale size, a large surface area, and an electrical charge (Esmaeili et al.
2020). GO is more hydrophilic compared to graphene, hence showed more
solubility and colloidal stability in aqueous media. GO-based nanocarriers can also
be explored as antimicrobial agents due to their dose-dependent cytotoxicity and
bactericidal activity. Although GO was toxic to living cells and organs, which makes
it hard to use in the biomedical field, surface functionalization of GO decreases the
toxicity significantly. Two graphene-based materials, GO and reduced GO
nanosheets, which significantly inhibited the E. coli bacterial growth were reported
by Kumar and co-workers (Kumar et al. 2019).
GO nanoparticles were explored for the non-invasive bio-imaging and targeted
therapy (Syama and Mohanan 2019) due to their unique advantages such as low
cytotoxicity, tunable optical properties, high photostability, brightly emissive for
high-contrast imaging, and facile surface functionalization for specific targeting
(Dong et al. 2018). GO as fluorescence probe is highly suitable for fluorescent
probe, due to its advantages like biological compatibility, resistance to
photobleaching, and efficient light emission (Esmaeili et al. 2020). More
advancement in GO nanoparticles was performed to improve its hydrophilicity and
subsequently the in vivo circulation time by attaching the low molecular weight
PEG. Results of the in vivo study showed improved blood circulation time and
lowered cytotoxicity (Ghosh and Chatterjee 2020). To make the most of the
benefits of nanotechnology and to reduce the risks to human health, it is important
to figure out the molecular targets involved in toxicity and to weigh the pros and
cons of GO.
Nanomedicine can be formulated using varieties of organic materials, which
majorly include carbohydrates, proteins, lipids, and synthetic or semi-synthetic
polymers. The commonly used nanoparticles are discussed in the following
subsections.
1.5.5 Polymeric Nanoparticles

Polymeric nanoparticles are widely explored due to their easy availability, cost
effectiveness, sustained type drug release pattern, and inertness. Commonly used
polymers for formulating theranostics nanoparticles are chitosan, gelatin, albumin,
sodium alginate, poly (lactic-co-glycolic acid), PLA, poly-glutamic acid, etc., used
very promisingly for delivering the drug to cardiovascular and central nervous
systems (Kang et al. 2016). Shao and co-workers formulated the triple-
collaborative nanotheranostics nanocarrier for combining the therapeutic benefits
of anti-angiogenesis, RNA interference, and PTT using PLA as polymer. In vitro cell
line study showed self-fluorescence activity and significant increase in cellular
uptake (Shao et al. 2019). Chio et al. made chlorin e6, a second-generation
photosensitizer and camptothecin-loaded polymeric nanoparticles that were
decorated with hyaluronic acid-grafted monomethoxy PEG for imaging and treating
triple negative breast cancer. In vitro cell line studies with MDA-MB-231 cells
showed that hyaluronic acid-grafted monomethoxy PEG-based nanoparticles were
taken up much more rapidly than nanoparticles without a coating. The therapeutic
effectiveness was measured by putting free and camptothecin-loaded nanoparticles
into MDA-MB-231 cells for 6 h and then emitting a 670 nm laser on them. The
results showed that nanoparticles killed 28% of the cells while same concentration
of camptothecin has killed 12% of cells (Choi et al. 2015). Polymeric nanoparticles
have been explored widely for theranostic application, and due to the inertness of
polymers, it provided stable nanoparticles for treatment of various diseases.
1.5.6 Polymeric Micelles

Polymeric micelles are self-assembled aggregated colloidal nano-constructs of
amphiphilic polymers with a core-shell structure. These have been used as
versatile carriers for delivery of diagnostic agents and drugs. They have gained
immense popularity due to their unique features such as smaller size, good
solubilization properties, easy surface functionalization, biocompatibility,
longevity, enhanced permeation and retention effect, good encapsulation efficiency,
high stability (in vitro and in vivo), and the ability to accumulate into tumor
through compromised vasculature. The core of the micelles are formed by various
amphiphilic copolymers including di-block, triblock, as well as graft copolymers of
PEG, poly-l-aspartic acid, poly(2-hydroxyethyl-l-aspartamide), etc. (Kang et al.
2016). Gregoriou and his team used a single emulsification-based approach to
make resveratrol-loaded micelles from pluronic F127 block copolymer and D—
tocopheryl PEG succinate. This was done to improve cellular uptake and get more
desirable pharmacokinetics for breast cancer treatment. Cellular uptake studies
were performed on MCF-7 and MDA-MB-231 cells; 4 h cellular uptake data showed
significantly higher cellular uptake by MDA-MB-231 cells compared to MCF-7 cells
(Gregoriou et al. 2021). Micelles were widely explored for their simplicity and easy
modification capacity. Results published regarding the theranostics micelles in
scientific literature have potential to give therapeutic and image-guided treatment
to patients.
1.5.7 Liposome
Liposomes are one of the widely accepted, biocompatible, biodegradable lipidic
nanocarriers and first approved nanocarrier by FDA. Easy preparation, feasibility
to scale up, biocompatibility, ability to load hydrophilic, as well as hydrophobic
drugs and easy surface functionalization (PEG or vitamins) established it as a
superior nanocarrier. Recently, liposome was explored for various applications of in
vivo imaging through optical, MRI, PET, CT, PDT and PTT, etc., by scientific
community (Lee and Im 2019).
Skupin-Mrugalska et al. formulated liposomes by using lipid derivatives of
gadolinium (III) diethylenetriaminepentaacetic acid salt, which can also serve as
MRI contrasting agent and a photosensitizer agent zinc phthalocyanine. This hybrid
nanocarrier was capable to kill cancer cells by PTT as well as diagnosis through
MRI. Confocal microscopy images showed the internalization of nanohybrid inside
the fibroblast cells (Skupin-Mrugalska et al. 2018). Lozano et al. made a
nanotheranostic system for TNBC using doxorubicin and indocyanine green loaded
monoclonal antibody decorated PEGylated liposomes that target the mucin1
receptor. In vivo monitoring of this antibody-coated nanotheranostic formulation
showed that the liposomes quickly gathered in a tumor model, unlike the non-
targeted formulation (Lozano et al. 2015).
There are numbers of liposomal products currently in the market as well as in
clinical trials, which impart them immense value to develop as novel commercial
product. But clinical application of theranostic liposomes or other nanocarriers
requires detailed clinical studies regarding their behavior in biological system,
metabolism profile, toxicological studies, and many more. Although few
theranostic-based nanocarriers are currently under clinical trials, outcomes of such
clinical studies will guide researchers in the future.
1.6 Regulatory Aspects

Nanomedicine has been a massively explored research area worldwide, due to its
ability to improve therapeutic outcome of active pharmaceutical ingredients by
transforming polymers, lipids, carbohydrates, etc., into nanocarriers, ligand
decorated nanocarriers, inorganic nanoparticles, dendrimers, and quantum dots
(Jain et al. 2015b; Ojha et al. 2021). However, most of the regulatory authorities do
not have clear regulatory guideline for the marketing approval of nanomedicine,
which restricts the easy translation of nanomedicine and creates a lack of clarity
for research institutes and manufacturer in development of novel nanocarriers
(Sainz et al. 2015).
There are lots of challenges in preparation of clear regulatory guidelines for
nanomedicines. For instance, (1) at physiological level nanomedicine demonstrated
contrasting pharmacokinetic behavior compared to small drug molecules, (2)
unavailability of clear evidence regarding its penetration through blood-brain
barrier due to its small size, which may compromise the normal brain function;
(3) another problem was associated with nanomaterial is explanation of the
accumulation of nanoparticles in high blood perfusion containing organs upon
systemic administration, and (4) lack of standard nanotoxicology tests
cumulatively limits the translation of nanomedicine from bench to bed (Hejmady et
al. 2020). Furthermore, insufficient and ununified regulatory guidelines (like
different interpretations of definition and classification of nanomedicine in
different countries) made regulatory approval of nanomedicine more stringent and
time-consuming. One of the major concerns was scale up of laboratory batches at
commercial level, and stability throughout its shelf life also created muddle in
regulatory approval. Genotoxicity and environment-related concerns have further
aggregated, which required separate guideline and analytical tests for regulatory
clearance (Foulkes et al. 2020).
Besides all these regulatory-related problems, more than 50 nanomedicines
were already deployed in the market till date, and this number raises steadily
(Sarwal et al. 2019). Most of the regulatory authorities do not consider
nanomedicine harmful but choose to evaluate and provide approval on case-to-case
bases. In recent time many regulatory authorities have created committee or
declared some sort of guidelines to make the regulatory approval process easy. For
example, the US Food and Drug Administration has formed a task force and a
“Nanotechnology Interest Group.” The task force noticed that the current
regulatory guidelines were broad enough to ensure the safe production of
nanomedicines, which can go to the preclinical and clinical trials. But no specific
points were discussed about the clinical evaluations (Nanotechnology Task Force
2022). Similarly, the European Union and the healthcare product authority of the
United Kingdom have established a European nanomedicine characterization
laboratory for providing constantly refined intellectual results in preclinical studies
of nanomedicine to manufacturers and regulatory authorities. Furthermore, few of
the health-related government agencies of the United States and European
Commission have introduced a project titled “REFINE” to set the criteria for
regulatory approval of nanomedicine with their objective “Development and
validation of new analytical or experimental methods.” To set the definite criteria
for manufacturing of nanomedicine, the Department of Science and Technology,
Government of India, has also prepared a draft. This contained the three-tier
governance framework to regulate the nanomedicine (Foulkes et al. 2020).
It was now clear toward the regulatory authorities present worldwide that a
proper set of guidelines is a must for smooth approval of nanomedicine and for
guiding the manufacturers as well as health workers for development of new
nanomedicines. Academicians, clinicians, manufacturers, and regulatory personnel
should combinedly form a defined set of criteria, which will make approval process
for nanomedicine easy.
1.7 Conclusion
The current chapter discussed in detail the various ligand decorated
nanotheranostic drug delivery carrier. Various imaging techniques like
fluorescence, PET, CT, MRI, etc., used for in vivo imaging were also explored. The
novel techniques like PTT and PDT have opened the new door for the treatment of
various life-threatening diseases like cancer. Also, the numerous research articles
published by scientific community proved the efficiency of ligand decorated
theranostic nanocarrier for the treatment of cancer, infectious diseases, and
neurodegenerative diseases. Some of the ligand decorated nanocarriers have also
entered the initial stage of clinical trials, which proved the importance and
feasibility of this type of nanocarriers in clinical applications.
Acknowledgments
The authors (Parth Patel and Keerti Jain) are grateful to the Department of
Pharmaceuticals, Ministry of Chemicals and Fertilizers, Government of India, for
providing facilities for writing this chapter. The NIPER Raebareli communication
number for this publication is NIPER-R/Communication/387.
References
Achilli E, Flores CY, Temprana CF, del Alonso S, Radrizzani M, Grasselli M (2022) Enhanced gold
nanoparticle-tumor cell recognition by albumin multilayer coating. OpenNano 6:100033
Ahmad MZ, Akhter S, Rahman Z, Akhter S, Anwar M, Mallik N et al (2013) Nanometric gold in
cancer nanotechnology: current status and future prospect. J Pharm Pharmacol 65(5):634–651
[PubMed]
Ahmad MZ, Alkahtani SA, Akhter S, Ahmad FJ, Ahmad J, Akhtar MS et al (2015) Progress in
nanotechnology-based drug carrier in designing of curcumin nanomedicines for cancer therapy:
current state-of-the-art. J Drug Target 24(4):273–293
[PubMed]
Ahmad MZ, Ahmad J, Haque A, Alasmary MY, Abdel-Wahab BA, Akhter S (2020) Emerging advances
in synthetic cancer nano-vaccines: opportunities and challenges. Expert Rev Vaccines
19(11):1053–1071
[PubMed]
Ahmad MZ, Ahmad J, Alasmary MY, Abdel-Wahab BA, Warsi MH, Haque A et al (2021) Emerging
advances in cationic liposomal cancer nanovaccines: opportunities and challenges.
Immunotherapy 13(6):491–507
[PubMed]
Ahmed F, Khan MA, Haider N, Ahmad MZ, Ahmad J (2022) Recent advances in theranostic
applications of nanomaterials in cancer. Curr Pharm Des 28(2):133–150
[PubMed]
Akhter S, Zaki Ahmad M, Singh A, Ahmad I, Rahman M, Anwar M et al (2011) Cancer targeted
metallic nanoparticle: targeting overview, recent advancement and toxicity concern. Curr Pharm
Des 17(18):1834–1850
[PubMed]
Akhter S, Ahmad MZ, Ahmad FJ, Storm G, Kok RJ (2012) Gold nanoparticles in theranostic
oncology: current state-of-the-art. Expert Opin Drug Deliv 9(10):1225–1243
[PubMed]
Akhter S, Ahmad I, Ahmad MZ, Ramazani F, Singh A, Rahman Z, et al (2013) Nanomedicines as

cancer therapeutics: current status. Curr Cancer Drug Targets 13(4):362–378
Alagarsamy KN, Mathan S, Yan W, Rafieerad A, Sekaran S, Manego H et al (2021) Carbon

nanomaterials for cardiovascular theranostics: promises and challenges. Bioact Mater 6(8):2261–
2280
[PubMed][PubMedCentral]
Albertini B, Mathieu V, Iraci N, van Woensel M, Schoubben A, Donnadio A et al (2019) Tumor

targeting by peptide-decorated gold nanoparticles. Mol Pharm 16(6):2430–2444
[PubMed]
Ali I, Rahis-Uddin SK, Rather M, Wani W, Haque A (2011) Advances in nano drugs for cancer
chemotherapy. Curr Cancer Drug Targets 11(2):135–146
[PubMed]
Ali MRK, Warner PE, Yu AM, Tong M, Han T, Tang Y (2022) Preventing metastasis using gold
nanorod-assisted plasmonic photothermal therapy in xenograft mice. Bioconjug Chem 33:2320
[PubMed]
Allison RR, Downie GH, Cuenca R, Hu XH, Childs CJH, Sibata CH (2004) Photosensitizers in clinical
PDT. Photodiagn Photodyn Ther 1(1):27–42
Anani T, Rahmati S, Sultana N, David AE (2021) MRI-traceable theranostic nanoparticles for

targeted cancer treatment. Theranostics 11(2):579–601
Augustine S, Singh J, Srivastava M, Sharma M, Das A, Malhotra BD (2017) Recent advances in carbon
based nanosystems for cancer theranostics. Biomater Sci 5(5):901–952
[PubMed]
Avasthi A, Caro C, Pozo-Torres E, Leal MP, García-Martín ML (2020) Magnetic nanoparticles as MRI
contrast agents. Top Curr Chem 378(3)
Bai RG, Muthoosamy K, Manickam S (2015) Nanomedicine in theranostics. Nanotechnology

applications for tissue engineering, pp 195–213
Bajwa N, Kumar Mehra N, Jain K, Kumar JN (2015) Targeted anticancer drug delivery through
anthracycline antibiotic bearing functionalized quantum dots. Artif Cells Nanomed Biotechnol
44(7):1774–1782
[PubMed]
Bonnet CS, Tó th É (2021) Metal-based environment-sensitive MRI contrast agents. Curr Opin Chem
Biol 61:154–169
[PubMed]
Bukhari SI, Imam SS, Ahmad MZ, Vuddanda PR, Alshehri S, Mahdi WA et al (2021) Recent progress
in lipid nanoparticles for cancer theranostics: opportunity and challenges. Pharmaceutics
13(6):840
Cai J, Dao P, Chen H, Yan L, Li YL, Zhang W et al (2020) Ultrasmall superparamagnetic iron oxide
nanoparticles-bound NIR dyes: novel theranostic agents for Alzheimer’s disease. Dyes Pigments
173:107968
Calzavara-Pinton PG, Venturini M, Sala R (2007) Photodynamic therapy: update 2006 part 2:
clinical results. J Eur Acad Dermatol Venereol 21(4):439–451
[PubMed]
Campbell RB (2006) Tumor physiology and delivery of nanopharmaceuticals. Anti Cancer Agents
Med Chem 6(6):503–512
Chen C, Ge J, Gao Y, Chen L, Cui J, Zeng J et al (2022) Ultrasmall superparamagnetic iron oxide
nanoparticles: a next generation contrast agent for magnetic resonance imaging. Wiley Interdiscip
Rev Nanomed Nanobiotechnol 14(1):e1740
[PubMed]
Choi J et al (2011) Gold nanostructures as photothermal therapy agent for cancer. Anti-Cancer
Agents in Med Chem 11(10):953–964
Choi J, Kim H, Choi Y (2015) Theranostic nanoparticles for enzyme-activatable fluorescence

imaging and photodynamic/chemo dual therapy of triple-negative breast cancer. Quant Imaging
Med Surg 5(5):656–65664
Cormode DP, Skajaa T, Fayad ZA, Mulder WJM (2009) Nanotechnology in medical imaging: probe
design and applications. Arterioscler Thromb Vasc Biol 29(7):992–1000
[PubMed]
Dao P, Ye F, Liu Y, Du ZY, Zhang K, Dong CZ et al (2017) Development of phenothiazine-based

theranostic compounds that act both as inhibitors of β-amyloid aggregation and as imaging probes
for amyloid plaques in Alzheimer’s disease. ACS Chem Neurosci 8(4):798–806
[PubMed]
Debbage P, Jaschke W (2008) Molecular imaging with nanoparticles: giant roles for dwarf actors.
Histochem Cell Biol 130(5):845–875
[PubMed]
Demiral A, Verimli N, Goralı Sİ, Yılmaz H, Çulha M, Erdem SS (2021) A rational design of multi-
functional nanoplatform: fluorescent-based “off-on” theranostic gold nanoparticles modified with
D-α-tocopherol succinate. J Photochem Photobiol B 222:112261
[PubMed]
Dheyab MA, Aziz AA, Khaniabadi PM, Jameel MS (2021) Potential of a sonochemical approach to
generate MRI-PPT theranostic agents for breast cancer. Photodiagn Photodyn Ther 33:102177
Dong J, Wang K, Sun L, Sun B, Yang M, Chen H et al (2018) Application of graphene quantum dots for
simultaneous fluorescence imaging and tumor-targeted drug delivery. Sens Actuators B Chem
256:616–623
Esmaeili Y, Zarrabi A, Mirahmadi-Zare SZ, Bidram E (2020) Hierarchical multifunctional graphene

oxide cancer nanotheranostics agent for synchronous switchable fluorescence imaging and
chemical therapy. Microchim Acta 187(10):553
Fakhimikabir H, Tavakoli MB, Zarrabi A, Amouheidari A, Rahgozar S (2018) The role of folic acid-
conjugated polyglycerol coated iron oxide nanoparticles on radiosensitivity with clinical electron
beam (6 MeV) on human cervical carcinoma cell line: in vitro study. J Photochem Photobiol B
182:71–76
[PubMed]
Feliu N, Docter D, Heine M, del Pino P, Ashraf S, Kolosnjaj-Tabi J et al (2016) In vivo degeneration
and the fate of inorganic nanoparticles. Chem Soc Rev 45(9):2440–2457
[PubMed]
Foulkes R, Man E, Thind J, Yeung S, Joy A, Hoskins C (2020) The regulation of nanomaterials and
nanomedicines for clinical application: current and future perspectives, vol 8. Biomater Sci R Soc
Chem, pp 4653–4664
Frinking PJA, Bouakaz A, Kirkhorn J, ten Cate FJ, de Jong N (2000) Ultrasound contrast imaging:
current and new potential methods. Ultrasound Med Biol 26(6):965–975
[PubMed]
Gao G, Guo Q, Zhi J (2019) Nanodiamond-based theranostic platform for drug delivery and
bioimaging. Small 15(48):1902238
García MC, Calderó n-Montañ o JM, Rueda M, Longhi M, Rabasco AM, Ló pez-Lázaro M et al (2022)
pH-temperature dual-sensitive nucleolipid-containing stealth liposomes anchored with PEGylated
AuNPs for triggering delivery of doxorubicin. Int J Pharm 619:121691
[PubMed]
Gellci K, Mehrmohammadi M (2014) Photothermal therapy. Encyclopedia of Cancer 1–5
Gharatape A, Salehi R (2017) Recent progress in theranostic applications of hybrid gold

nanoparticles. Eur J Med Chem 138:221–233
[PubMed]
Ghosh S, Chatterjee K (2020) Poly(ethylene glycol) functionalized graphene oxide in tissue

engineering: a review on recent advances. Int J Nanomedicine 15:5991
Gollavelli G, Ling YC (2014) Magnetic and fluorescent graphene for dual modal imaging and single
light induced photothermal and photodynamic therapy of cancer cells. Biomaterials 35(15):4499–
4507
[PubMed]
Gøtzsche PC (2011) Niels Finsen’s treatment for lupus vulgaris. J R Soc Med 104(1):41–42
Gregoriou Y, Gregoriou G, Yilmaz V, Kapnisis K, Prokopi M, Anayiotos A, Strati K, Dietis N,

Constantinou AI, Andreou C (2021) Resveratrol loaded polymeric micelles for theranostic
targeting of breast cancer cells. Nano 5(1):113
Groysbeck N, Stoessel A, Donzeau M, da Silva EC, Lehmann M, Strub JM et al (2019) Synthesis and
biological evaluation of 2.4 nm thiolate-protected gold nanoparticles conjugated to Cetuximab for
targeting glioblastoma cancer cells via the EGFR. Nanotechnology 30(18):184005
[PubMed]
Hejmady S, Singhvi G, Saha RN, Dubey SK (2020) Regulatory aspects in process development and
scale-up of nanopharmaceuticals. Ther Deliv 11:341–343
[PubMed]
Hö nigsmann H (2012) History of phototherapy in dermatology. Photochem Photobiol Sci

12(1):16–21
Hood L (2013) Systems biology and P4 medicine: past, present, and future. Rambam Maimonides
Med J 4(2):0012
Huang X, Lu Y, Guo M, Du S, Han N (2021) Recent strategies for nano-based PTT combined with
immunotherapy: from a biomaterial point of view. Theranostics 11(15):7546
Jain K, Zhong J (2022) Theranostic applications of nanomaterials. Curr Pharm Des 28(2):77–77
[PubMed]
Jain K, Mehra N, Jain N (2015a) Nanotechnology in drug delivery: safety and toxicity issues. Curr
Pharm Des 21(29):4252–4261
[PubMed]
Jain K, Verma AK, Mishra PR, Jain NK (2015b) Surface-engineered dendrimeric nanoconjugates for
macrophage-targeted delivery of amphotericin B: formulation development and in vitro and in
vivo evaluation. Antimicrob Agents Chemother 59(5):2479–2487
Jalalian SH, Taghdisi SM, Hamedani NS, Kalat SAM, Lavaee P, ZandKarimi M et al (2013) Epirubicin
loaded super paramagnetic iron oxide nanoparticle-aptamer bioconjugate for combined colon
cancer therapy and imaging in vivo. Eur J Pharm Sci 50(2):191–197
[PubMed]
Janib SM, Moses AS, MacKay JA (2010) Imaging and drug delivery using theranostic nanoparticles.
Adv Drug Deliv Rev 62(11):1052–1063
Kang C, Cho W, Park M, Kim J, Park S, Shin D et al (2016) H2O2-triggered bubble generating
antioxidant polymeric nanoparticles as ischemia/reperfusion targeted nanotheranostics.
Biomaterials (85):195–203
Kaur S, Mehra NK, Jain K, Jain NK (2016) Development and evaluation of targeting ligand-anchored
CNTs as prospective targeted drug delivery system. Artif Cells Nanomed Biotechnol 45(2):242–
250. https://doi.org/10.3109/2169140120161146728
[Crossref][PubMed]
Kenny GD, Kamaly N, Kalber TL, Brody LP, Sahuri M, Shamsaei E et al (2011) Novel multifunctional
nanoparticle mediates siRNA tumour delivery, visualisation and therapeutic tumour reduction in
vivo. J Control Release 149(2):111–116
[PubMed]
Kim GJ, Nie S (2005) Targeted cancer nanotherapy. Mater Today 8(8):28–33
Kim TH, Lee S, Chen X (2013) Nanotheranostics for personalized medicine. Expert Rev Mol Diagn
13(3):257–269
Kumar P, Huo P, Zhang R, Liu B (2019) Antibacterial properties of graphene-based nanomaterials.

Nanomaterials 9:737
Lammers T, Aime S, Hennink WE, Storm G, Kiessling F (2011) Theranostic nanomedicine. Account
Chem Res 44(10):1029–1038
Lammers T, Kiessling F, Hennink WE, Storm G (2012) Drug targeting to tumors: principles, pitfalls
and (pre-) clinical progress. J Control Release 161(2):175–187
[PubMed]
Lee W, Im HJ (2019) Theranostics based on liposome: looking back and forward. Nucl Med Mol
Imaging 53(4):242–246
Li B, Wang Q, Zou R, Liu X, Xu K, Li W et al (2014) Cu7.2S4 nanocrystals: a novel photothermal

agent with a 56.7% photothermal conversion efficiency for photothermal therapy of cancer cells.
Nanoscale 6(6):3274–3282
[PubMed]
Li H, Hu H, Zhao Y, Chen X, Li W, Qiang W et al (2015a) Multifunctional aptamer-silver conjugates

as theragnostic agents for specific cancer cell therapy and fluorescence-enhanced cell imaging.
Anal Chem 87(7):3736–3745
[PubMed]
Li T, Murphy S, Kiselev B, Bakshi KS, Zhang J, Eltahir A et al (2015b) A new interleukin-13 amino-
coated gadolinium metallofullerene nanoparticle for targeted MRI detection of glioblastoma tumor
cells. J Am Chem Soc 137(24):7881–7888
[PubMed]
Li Y, He D, Tu J, Wang R, Zu C, Chen Y et al (2018) The comparative effect of wrapping solid gold

nanoparticles and hollow gold nanoparticles with doxorubicin-loaded thermosensitive liposomes
for cancer thermo-chemotherapy. Nanoscale 10(18):8628–8641
[PubMed]
Lim W, Kim B, Jo G, Yang DH, Park MH, Hyun H (2020) Bioluminescence and near-infrared
fluorescence imaging for detection of metastatic bone tumors. Lasers Med Sci 35(1):115–120
[PubMed]
Liu X, Zhang M, Yan D, Deng G, Wang Q, Li C et al (2020) A smart theranostic agent based on Fe-
HPPy@Au/DOX for CT imaging and PTT/chemotherapy/CDT combined anticancer therapy.
Biomater Sci 8(15):4067–4072
[PubMed]
Ló pez-Lorente Á I (2021) Recent developments on gold nanostructures for surface enhanced

Raman spectroscopy: particle shape, substrates and analytical applications. A review. Anal Chim
Acta 1168:338474
[PubMed]
Lozano N, Al-Ahmady ZS, Beziere NS, Ntziachristos V, Kostarelos K (2015) Monoclonal antibody-
targeted PEGylated liposome-ICG encapsulating doxorubicin as a potential theranostic agent. Int J
Pharm 482(1–2):2–10
[PubMed]
Mallick N, Asfer M, Anwar M, Kumar A, Samim M, Talegaonkar S et al (2015) Rhodamine-loaded,

cross-linked, carboxymethyl cellulose sodium-coated super-paramagnetic iron oxide
nanoparticles: development and in vitro localization study for magnetic drug-targeting
applications. Colloids Surf A Physicochem Eng Asp 481:51–62
Mallick N, Anwar M, Asfer M, Mehdi SH, Rizvi MMA, Panda AK et al (2016) Chondroitin sulfate-
capped super-paramagnetic iron oxide nanoparticles as potential carriers of doxorubicin
hydrochloride. Carbohydr Polym 151:546–556
[PubMed]
Moghimi SM, Hunter AC, Murray JC (2005) Nanomedicine: current status and future prospects.
FASEB J 19(3):311–330
[PubMed]
Mohapatra A, Uthaman S, Park IK (2021 Jan) External and internal stimuli-responsive metallic
nanotherapeutics for enhanced anticancer therapy. Front Mol Biosci 11(7):437
Moscariello P, Raabe M, Liu W, Bernhardt S, Qi H, Kaiser U et al (2019) Unraveling in vivo brain

transport of protein-coated fluorescent nanodiamonds. Small 15(42):1902992
Muthiah M, Park IK, Cho CS (2013) Nanoparticle-mediated delivery of therapeutic genes: focus on
miRNA therapeutics. Expert Opin Drug Delivery 10(9):1259–1273
Nanotechnology Task Force Report 2007 | FDA [Internet]. [cited 2022 Sep 28]. Available from:
https://www.fda.gov/science-research/nanotechnology-programs-fda/nanotechnology-task-force-
report-2007
National Research Council (US) Committee on A Framework for Developing a New Taxonomy of
Disease (2011) Toward precision medicine: building a knowledge network for biomedical research
and a new taxonomy of disease, pp 1–128
Nicholls FJ, Rotz MW, Ghuman H, MacRenaris KW, Meade TJ, Modo M (2016) DNA–gadolinium–
gold nanoparticles for in vivo T1 MR imaging of transplanted human neural stem cells.
Biomaterials 77:291–306
[PubMed]
Ojha B, Jain VK, Mehra NK, Jain K (2021) Nanotechnology: Introduction and basic concepts. In:
Mehra NK, Jain K (eds) Dendrimers in nanomedicine: concept, theory and regulatory perspectives.
CRC Press, pp 1–17
Pan C, Liu Y, Zhou M, Wang W, Shi M, Xing M et al (2018) Theranostic pH-sensitive nanoparticles
for highly efficient targeted delivery of doxorubicin for breast tumor treatment. Int J
Nanomedicine 13:1119–1137
Papachristodoulou A, Signorell RD, Werner B, Brambilla D, Luciani P, Cavusoglu M et al (2019)
Chemotherapy sensitization of glioblastoma by focused ultrasound-mediated delivery of
therapeutic liposomes. J Control Release 295:130–139
[PubMed]
Paszko E, Ehrhardt C, Senge MO, Kelleher DP, Reynolds J, v. (2011) Nanodrug applications in
photodynamic therapy. Photodiagn Photodyn Ther 8(1):14–29
Qin JX, Yang XG, Lv CF, Li YZ, Liu KK, Zang JH et al (2021) Nanodiamonds: synthesis, properties, and
applications in nanomedicine. Mater Des 210:110091
Rajendrakumar SK, Cherukula K, Park HJ, Uthaman S, Jeong YY, Lee B et al (2018) Dual-stimuli-
responsive albumin-polyplex nanoassembly for spatially controlled gene release in metastatic
breast cancer. J Controlled Release 276:72–83
Reczyń ska K, Marszałek M, Zarzycki A, Reczyń ski W, Kornaus K, Pamuła E et al (2020)

Superparamagnetic iron oxide nanoparticles modified with silica layers as potential agents for lung
cancer treatment. Nanomaterials 10(6):1076
Richard C, de Chermont QLM, Scherman D (2008) Nanoparticles for imaging and tumor gene
delivery. Tumori 94(2):264–270
[PubMed]
Sainz V, Conniot J, Matos AI, Peres C, Zupančič E, Moura L et al (2015) Regulatory aspects on
nanomedicines. Biochem Biophys Res Commun 468:504–510
[PubMed]
Sarbadhikary P, George BP, Abrahamse H (2021) Recent advances in photosensitizers as

multifunctional theranostic agents for imaging-guided photodynamic therapy of cancer.
Theranostics 11(18):9054–9088
Sarwal A, Singh G, Singh K, Garg S (2019) Recent interventions for nanotechnology based drug
products: insights into the regulatory aspects. Curr Pharm Des 24(43):5219–5228
Shao L, Li Q, Zhao C, Lu J, Li X, Chen L et al (2019) Auto-fluorescent polymer nanotheranostics for

self-monitoring of cancer therapy via triple-collaborative strategy. Biomaterials 194:105–116
[PubMed]
Shi J, Wang L, Gao J, Liu Y, Zhang J, Ma R et al (2014) A fullerene-based multi-functional

nanoplatform for cancer theranostic applications. Biomaterials 35(22):5771–5784
[PubMed]
Siafaka PI, Okur NÜ , Karantas ID, Okur ME, Gü ndoğdu EA (2021) Current update on nanoplatforms
as therapeutic and diagnostic tools: a review for the materials used as nanotheranostics and
imaging modalities. Asian J Pharm Sci 16(1):24–46
[PubMed]
Skupin-Mrugalska P, Sobotta L, Warowicka A, Wereszczynska B, Zalewski T, Gierlich P et al (2018)

Theranostic liposomes as a bimodal carrier for magnetic resonance imaging contrast agent and
photosensitizer. J Inorg Biochem 180:1–14
[PubMed]
Song J, Hu Q, Huang J, Chen T, Ma Z, Shi H (2018) Mr targeted imaging for the expression of
tenascin-C in cervical cancer. Br J Radiol 91(1090):20170681
Sun JZ, Sun YC, Sun L (2019) Synthesis of surface modified Fe3O4 super paramagnetic nanoparticles
for ultra sound examination and magnetic resonance imaging for cancer treatment. J Photochem
Photobiol B 197:111547
[PubMed]
Syama S, Mohanan P (2019) Comprehensive application of graphene: emphasis on biomedical

concerns. Nano-Micro Lett 11(1):1–31
Taylor ML, Wilson RE, Amrhein KD, Huang X (2022) Gold nanorod-assisted photothermal therapy
and improvement strategies. Bioengineering 9(5):200
Vines JB, Yoon JH, Ryu NE, Lim DJ, Park H (2019) Gold nanoparticles for photothermal cancer
therapy. Front Chem 7:167
Wahsner J, Gale EM, Rodríguez-Rodríguez A, Caravan P (2019) Chemistry of MRI contrast agents:
current challenges and new frontiers. Chem Rev 119(2):957–1057
[PubMed]
Wan Q, Xie L, Gao L, Wang Z, Nan X, Lei H et al (2012) Self-assembled magnetic theranostic
nanoparticles for highly sensitive MRI of minicircle DNA delivery. Nanoscale 5(2):744–752
[PubMed]
Wang AZ, Bagalkot V, Vasilliou CC, Gu F, Alexis F, Zhang L et al (2008) Superparamagnetic iron oxide
nanoparticle–aptamer bioconjugates for combined prostate cancer imaging and therapy.
ChemMedChem 3(9):1311–1315
Weissleder R (2002) Scaling down imaging: molecular mapping of cancer in mice. Nat Rev Cancer
2(1):11–18
[PubMed]
Xiao YD, Paudel R, Liu J, Ma C, Zhang ZS, Zhou SK (2016) MRI contrast agents: classification and
application (review). Int J Mol Med 38(5):1319–1326
[PubMed]
Xiong C, Lu W, Zhou M, Wen X, Li C (2018) Cisplatin-loaded hollow gold nanoparticles for laser-
triggered release. Cancer Nanotechnol 9(1):1–13
Xu HL, Fan ZL, ZhuGe DL, Shen BX, Jin BH, Xiao J et al (2017) Therapeutic supermolecular micelles
of vitamin E succinate-grafted ε-polylysine as potential carriers for curcumin: enhancing tumour
penetration and improving therapeutic effect on glioma. Colloids Surf B Biointerfaces 158:295–307
[PubMed]
Yallapu MM, Foy SP, Jain TK, Labhasetwar V (2010) PEG-functionalized magnetic nanoparticles for
drug delivery and magnetic resonance imaging applications. Pharm Res 27(11):2283–2295
Yoon J, Cho SH, Seong H (2017) Multifunctional ultrasmall superparamagnetic iron oxide
nanoparticles as a theranostic agent. Colloids Surf A Physicochem Eng Asp 520:892–902
Zhang H, Li J, Hu Y, Shen M, Shi X, Zhang G (2016) Folic acid-targeted iron oxide nanoparticles as
contrast agents for magnetic resonance imaging of human ovarian cancer. J Ovarian Res 9(1):19
Zhao B, He YY (2014) Recent advances in the prevention and treatment of skin cancer using
photodynamic therapy. Expert Rev Anticancer Ther 10(11):1797–1809. https://doi.org/10.1586/
era10154
[Crossref]
Zhou LQ, Li P, Cui XW, Dietrich CF (2020) Ultrasound nanotheranostics in fighting cancer: advances
and prospects. Cancer Lett 470:204–219
[PubMed]
Zhou B, Yin C, Feng Q, Wu Y, Pan X, Liu C et al (2021) Polypyrrole-based nanotheranostic agent for
MRI guided photothermal-chemodynamic synergistic cancer therapy. Nanoscale 13(45):19085–
19097
[PubMed]
Another random document with
no related content on Scribd:
the best of herself, because she was a woman of spirit who, on entering a
room, made an impression. There was in Callendar a strange sort of vanity
which demanded satisfaction, a vanity which was, perhaps, another and a
masculine manifestation of his mother’s passionate sense of property. It
would have been impossible for him to have married a woman, no matter
how pretty she might have been, who was simply commonplace, sweet and
insipid. He demanded in his wife an element of the spectacular. He had
devoted himself to the tawny Lorna Vale, to the black and glittering Mrs.
Sigourney, and to that strange, uncivilized musician from the middle west.
About them all, there had been a spectacular quality, an undercurrent of
fierce vitality, of outward distinction from the mob which appeared to have
fascinated him.
She did not flatter herself that he had married her through desire; yet
from the moment of their marriage he had been passionate after a fashion
which shocked her. It was confusing to find that a man who was so polite
and indifferent, so free from the little tendernesses which, to be honest, she
had never expected, could at times display a passion so fierce and
unexpected. It was as if in some way, love, passion, desire—she could not
in his case define it precisely—were isolated, a thing apart.
There were reasons enough why she had married him. He was a great
match; women would have desired him even if he had not been rich. And,
she reflected with astonishing coldness, to have won him in the face of so
much competition was a triumph worth paying for with much unhappiness.
It was a victory over women who hated her and had sought with all the bag
of their nasty feminine tricks to outwit her. She had married him too
because she had come very nearly to the conclusion that she could never
fall passionately in love with any man and that, therefore, it was far better
to choose an interesting husband than a dull one. It was impossible, she felt,
for love to survive such a passion as hers for dissection and analysis; love
could not stand being pinned down and pulled apart. She did not then
expect great love, and for the rest of it, Callendar had fascinated her as no
other man had ever done, because he had always eluded her, just as he was
eluding her now that he was her husband. In a sense, he offered her material
vigorous enough to last a lifetime.
More than once in the midst of such reflections there returned to her the
memory of the night when the raw young creature, whom she now thought
of as “that musician,” had fainted. She remembered how, on this occasion,
she had regarded Callendar minutely as he stood, his hands clenching the
back of a chair, watching the naked Burmese dancer swaying to the
insidious rhythm of tom-tom and flageolet. She remembered how the
dancer and the barbaric music had shocked her a little as being wildly out of
place in the big stuffy drawing-room. It was music which to her meant very
little save that it was mildly exciting. Upon Callendar and his mother it had
produced the most astonishing effect. Could it be that in this lay the clue
alike to his fascination and to her failure to fathom that obscure thing which
people called his soul? Though he had been her husband, even her lover, for
a long time, she knew him no better than she had known him on the night of
his mother’s absurd soirée.
And lying in that preposterous boudoir that had once belonged to the
mistress of Wolff, she found herself admitting that slowly and certainly he
was gaining complete possession of her imagination. It troubled her because
she valued above all else in the world her own aloofness; so long as she did
not lose her sense of being a spectator, no one could hurt her, not even her
own husband. It troubled her too because she could not be certain whether
this new interest had any relation to love or whether it had its roots in a sort
of perverse attraction, fundamentally intellectual in quality ... an attraction
which carried an element of the sensual hitherto entirely foreign to her
nature. Day after day she found herself smiling over the thought that this
sensual attraction should have been a little shocking and was not. In one
sense he had overwhelmed her. He was a cruel, a passionate lover. If she
had been less intelligent, more innocent, more sentimental, he might have
wounded her very soul; but the curse which made romantic love impossible
also saved her. Never, for more than a passing moment, had he been able to
dissipate her awful awareness.
He had come to her, after all, from Lorna Vale, from Mrs. Sigourney,
perhaps even from that American girl (though of this she could not be
certain) and, doubtless, from many other women. So much experience, she
understood, made him dangerous to any woman possessed of curiosity.
During those first weeks in Paris, it amazed Sabine to find that her
husband knew so few of his own countrymen; he told her that most
Americans who chose to live in Paris were either silly or depraved and so
revealed for the first time the fact that he did not consider himself
American. He became sulky when she asked him to dine with a school
friend of hers whose husband chose to live in Paris.
“I know her husband,” he answered in contempt. “He is an ass who tries
to live like the French. He’s not a Frenchman. His money comes out of a
New England shoe factory.”
But he went all the same, perhaps because she managed to convey to
him without saying it, that he was neglecting her. During the day she spent
a great deal of time with friends and acquaintances, mostly women who had
married foreigners of one sort or another. In their company she went from
shop to shop buying an endless number of clothes. The same taste which
caused her to shudder at the monstrous house in the Avenue du Bois led her
to love clothes passionately. She knew too that beautiful clothes satisfied
the strain of vanity in her husband which demanded a wife who was dressed
with taste and distinction. She had begun already to plan how she might
attract and keep him.
One evening, while they were dressing for the Opera, he said to her as
she came out of the boudoir and faced him, “It is true what Jacques said at
the club to-day. It takes the Parisian to make the clothes and the American
to wear them. The Americans are the best dressed women in the world.”
And he looked at her in such a way that she grew warm suddenly in the
knowledge that her figure was superb, that her shoulders were marvelously
white and beautiful, and that her clothes were perfect. Until lately she had
dressed, like most American women, for the sake of other women; now she
understood that, without knowing it, she had been dressing of late to please
a man, because she had found one who understood the beauty and
importance of clothes. There was, despite all her other doubts, great
satisfaction in that.
She discovered too that his friends were not among the Americans and
the English but among the French and the Russians. She found herself,
night after night, at dinners watching him as he stood, straight, dark and
handsome, his queer gray eyes wrinkled a little with laughter, talking to
some friend who was a foreigner, and at such moments she was aware of his
great difference from her own people. He was, in some obscure fashion,
linked with that preposterous boudoir and its florid decorations. Perhaps,
secretly, he really liked the awful house as much as his mother liked it.
She saw too, with the green eyes which took in everything, that the
women about her were intensely conscious of him, and she knew then that
she had been at the same time lucky and tragically unlucky. It would be so
easy for him ... a man of so much intelligence and a beauty like that of a
fine animal.
Toward the end of the first winter, a day or two after she had made
certain that she was to have a baby, she interrupted her shopping long
enough to have lunch at the Ritz. She had a table, alone, in one corner of the
big room and, having no one to talk with her, she fell to observing the types
at the other tables and reflecting upon the vulgarity and self-conscious
glitter which marked the patrons of such hotels the world over. So she was
startled when she found that the personality of some one who entered the
room at that moment had the power of distracting her.
Two women came in together and stood for a time surveying the room.
The one (it was she who was disturbing) was tall, slender and handsome,
dressed smartly in a black suit with a black fur. The other, plainly a Jewess
(who understood perfectly the manipulation of head-waiters) was small,
with a ferrety, good-natured face and an energetic, chattering manner. They
took a table at a little distance so that Sabine was able to watch them.
In the beginning, as she realized that there was some reason for her
having noticed the pair, she became aware of a sense of familiarity in the
taller woman. Then, as she watched them, the reason became quite clear. It
was the American girl ... the musician, in Paris and in the Ritz of all places,
and no longer dowdy but handsomely dressed!
By long established precedent, Sabine made no move toward
approaching the newcomer. It was her habit to avoid involving herself with
too many people; such a course made life far too tiresome and complicated.
She had known the girl well enough, but there was no point now in
renewing the acquaintance; indeed, it seemed idiotic even to consider the
idea. Vaguely, she reflected, it was a good idea to leave what was well
enough alone.
But the old, insatiable curiosity had been aroused; she found herself
puzzled as to the presence of Ellen ... (Tolliver, that was her name) ... in
Paris. She had been poor. She had been, she told Sabine during those stark
conversations in the house on Murray Hill, hindered by a hundred obstacles.
Yet here she was, in Paris, dressed handsomely in clothes which the
appraising eye of Sabine told her had come from one of the best
establishments, probably Worth or Chanel. Sabine was curious too
regarding the whereabouts of the husband ... the husband whom she had
once mistaken very stupidly for the girl’s lover. And slowly, in the midst of
the noisy room filled with a fantastic assortment of people, there rose in her
memory a picture of that vulgar apartment the Babylon Arms, and a glimpse
as they opened the door of the tiny top floor flat, of a mild little man in shirt
sleeves. What had become of him?
She remembered too the confidences which she had exchanged with her
mother-in-law in the days when the young musician seemed so near to
upsetting their carefully laid plans. Mrs. Callendar had mentioned the mild
little man, saying, “I’m certain the girl doesn’t care a fig for him. She’s tied
to him by pity. That’s all. But we can be thankful for him. He stands
between her and Richard.”
Where was the little man to whom she was tied by pity?
Any one noticing Sabine as she made ready to leave the dining room
might easily have taken her for an adventuress. She drew her veil over her
face and holding her fur almost up to her eyes, she hastened out, taking care
on the way that her back was toward the tall girl and the busy little Jewess.
In the battle between an overwhelming curiosity and a vague instinct of
fear, it was fear which, unaccountably, won the victory.
As her motor, very small and very expensive, sped away along the Rue
de Rivoli and across the white spaces of the Place de la Concorde into the
Avenue des Champs Elysées, Sabine succumbed to an inexplicable sense of
depression. It occurred to her that she did not really know whether the girl
had ever been the mistress of her husband. She could not even be certain
that Callendar had ever asked Ellen Tolliver to be his wife. Thérèse
Callendar had the word of the girl that there had been nothing; yet with
Callendar, it was impossible to know. If he had asked her to marry him, it
must have been but a step toward seducing her from her husband, the mild
little man. It did not occur to Sabine that with two women a man might be
two quite different persons.
The motor sped smoothly along the asphalt past the Elysée Palace,
around the Arc de Triomphe and on toward the huge house in the Avenue
du Bois.
It might be, she thought, that Callendar himself knew the girl was in
Paris. It might even be that he had arranged it for her to be there.
And again Sabine reflected that in her good fortune there was a tragic
element of bad luck.
Callendar came in late for tea. She heard the footman speaking to him as
he came through the vast hall across the tesselated floor. She waited for
him, sitting behind the silver tea things in the small sitting room at the back
of the house, and as he entered she was seized again by the disturbing fear
of losing herself. He kissed her, casually, and said, “Well, have you had a
busy day?”
“Nothing.... I went shopping with Madeleine and lunched alone at the
Ritz.”
She might easily have added, “And whom do you think I saw there?”
But she did not. On the contrary, she said, “It’s a funny show ... the Ritz....
And you?... What have you done?”
She did not hear his answer, because her attention was swallowed up by
a sharp sense of his presence ... a vivid image of the dark face and the fine,
muscular hand as he raised his silk kerchief in a familiar gesture to stroke
his mustaches. In the back of her mind a small voice told her that it was
perilous and awful to have such emotions.
She poured his tea but he did not drink it.
“I’ll have a glass of port,” was his reply. And then, “I had luck to-day. I
won eleven thousand francs at baccarat ... playing with Henri and Posselt,
the Russian.”
“Good,” was her reply, and again it was not what she might have said.
This gambling worried her. It was not that he would bring them to poverty
by it; that was almost impossible. But there was in her mind a feeling of
disgust at the picture of men spending five hours of daylight in gambling.
She tried to reproach herself by the thought that the idea was American and
provincial. But she understood why his mother sometimes reproached him
for not thinking more of his business. (Always he retorted that she liked
business and he did not.)
There was silence and presently Sabine said, “I wonder, Dick, if we can’t
do something about this house ... either take one of our own or clear out
some of this rubbish.”
“It’s very comfortable.... There’s every luxury.”
She laughed. “Too much luxury.... I feel at times like a kept woman.
Wolff had it for his mistress.... I’m sure he did.”
Callendar smiled. “That’s true,” he replied. “Some of it is very bad, but
can’t we stick it out until spring? We’ll go to the country then or to England
for a time.”
She had spoken of the matter before and the answer had always been the
same. She now revived the discussion without hoping for any solution; she
wanted to know whether he really liked it, whether he was really linked in
some way to the extravagance of that awful boudoir. Watching him as she
spoke, she believed that he did.
For a time they smoked in silence and then Sabine, crushing out the ash
of her cigarette, observed with a magnificent air of indifference, “I wonder
what has become of that American girl ... the musician. You remember,
‘Miss Tolliver’ was her name.”
She saw that he looked at her sharply and then, disarmed by her
indifference, that his face assumed an expression which matched her own.
“I don’t know. I suppose she’s still in New York. She was very talented.”
“She planned to come to Paris some day. If she does, it would be a nice
thing to do to look her up.”
Her husband smiled before he answered her, a quiet amused smile such
as he used to display when he caught his mother in some intricate feminine
plot.
“I don’t see why we should. She probably wouldn’t like it. After all, it
wouldn’t be the same, would it?”
From this she could make nothing. All that he had said might mean
anything at all. It seemed to her that the more she talked, the more
confusing, the less clear everything became.
“I simply happened to think of her. She’s a remarkable girl. She’s had a
struggle from the beginning.”
“A damned fine lot,” was his comment. “You’ll hear from her some
day.”
She must have understood that all her slyness was of no use, that
methods such as this brought her nowhere, for she fell silent after this until
Dick rose and said, “Shall we go up? My nerves are on edge from playing
all afternoon. I think I’ll sleep a bit.”
Then while she watched him, as from a great distance, it occurred to her
that all this was scarcely the behavior of a bridegroom on his honeymoon; it
was, on the contrary, as if already they had been married for years.
As she rose to go with him, a sudden decision crossed her mind. Without
thinking why she was employing it, she used the one stake which she had at
hand.
“Dick,” she said abruptly, “I am going to have a baby.”
He turned, and into his face came an expression of pleasure the like of
which she had not seen there before. He smiled and, moving toward her,
took her gently into his arms.
“That’s fine,” he said softly. “That’s wonderful.” And she felt him kiss
her gently after a fashion that was new and disarming. It was neither a
casual kiss, nor a passionate one; those two moods she knew very well. This
was something new. She felt almost that she were an animal, a pet for
whom he had a great affection and a strong desire to protect.
“Your mother will be pleased,” she said, frightened again by the old
dread of losing herself. (She was ashamed too that he should feel her
tremble so.)
“She will be delighted. She wants an heir. She thinks I’m not much good
at taking care of all her money.” And he kissed her again in the same tender
fashion.
“But it might be a girl.”
He laughed a little. “No, I’m lucky.... Think of my eleven thousand
francs!”
But she saw that he wanted a boy, desperately, that he was not in the
least interested in a girl. It was very foreign of him ... that desire for some
one to carry on the name, to inherit all the fortune.
After they had gone up the stairs with the rail of red plush, he came into
the sitting room again to kiss her gently and to ask if she were feeling well,
and when he had gone Sabine, as she lay in the darkness among the gaudy
pillows of the chaise longue, understood clearly and bitterly for the first
time the change which their marriage had brought about. He was being
gentle and loving not because she was a woman or because he loved her,
but because she had become now by the course of nature an institution, a
wife, a prospective mother. He was being tender not toward her but toward
an idea. He placed her a little apart, so that the old sense of companionship
was no longer possible. She was a symbol now ... the wife and mother who
was the rock and foundation, the one who produced sons to carry on name
and property, but not by any chance the one who was loved because she was
a woman.
43
O F all the events, the emotions and the tragedy that occurred during the
turbulent years spent in the Babylon Arms, nothing had hurt Ellen so
much as the fashion in which Mrs. Callendar, after such a show of
friendship and interest, vanished quickly and completely from her life. Even
the affair with the son and the death of Clarence had had in them elements
which her feminine mind found not unpleasing; there was a certain romance
in the idea that it was herself whom Callendar really desired and not Sabine
at all; there was even more romance, though perhaps a trifle bitter, in the
idea that a man had taken his own life because he loved her too much to
spoil her existence. In her headlong fashion, she was conscious that these
elements contributed to her own personality; they made her an important
figure with enhancing shades of romance and tragedy. That the facts were
known to so few persons as to be almost secret, only increased their
fascination. Sometimes, as she walked along the boulevards or rode in the
Bois beside Schneidermann, paying little heed to the accompaniment of his
pretty speeches and comment upon people, pictures or music, she found
herself filled with a triumph at her secret knowledge. She thought, “People
who see me and talk with me little know all that has happened. They do not
know that they are talking with a powerful person. They do not know the
mystery and tragedy.”
She began even to think that she had consciously planned each step of
her progress, and she came after a time to forget that all that had happened
to her had been born either of headlong impulse or through some senseless
operation of circumstance.
Nevertheless there were times when she grew troubled by a sensation of
insecurity. Mrs. Callendar had deserted her without a word. Rebecca might
easily do the same. It was only Lily in whom she placed any real trust; with
Lily there were ties of family and of blood.
She was troubled too because she knew that there was still need of the
Jewess. For all the arrogance that came more and more to assert itself in her
nature, for all the confidence and the secret triumph with which she looked
out upon the strangers who passed by her on the boulevards and in the Bois,
she understood that she was not yet ready to stand alone. She needed the
guidance of persons like the gentle Schneidermann and the busy Rebecca.
They knew the world; they knew the tricks by which one advanced to fame;
they knew the people who were the right ones to know. She could not try
her own wings because they were not yet strong enough.
Yet she must have the aid of such as Schneidermann and Rebecca
without once acknowledging it. The old, twisted pride forbade her to lean
upon any of them. It was a hard business.
And she would pull in her horse so that the languid Schneidermann
might come abreast of her and talk without having to shout at her back. She
would smile indifferently at him and say, “It is a beautiful morning.... Look
at the dew shining beneath the hedge. And the spider webs like nets of
shining silver.”
Sometimes Schneidermann rode silently by her side, stealing glances at
the color in her cheeks and the blue black of her hair as she rode so straight
and so proud and yet so careless of her horse, reining him in at will or
galloping him madly through the long tunnels under the dripping linden
trees. He was a tall thin man with an arched nose and a blond drooping
mustache, rather pale and mild, who never disputed with her the choice of
bridle paths or the hour they were to return. She understood that he was
interested in her; he had helped her with her accent, though in this they had
made little progress, for she had a stubborn, careless way of sticking to her
own version of the tongue just as she had never lost completely her way of
saying “dawg” for dog and “watter” for water, and persisted in the burr
which came to her doubly through a Scottish heritage and a middle-western
childhood. She suspected sometimes that he might even be falling in love
with her and this made her knit up her brows and scowl at him furtively.
She did not want him, even with all his money. She had had one husband
who was mild and gentle and a bit stupid. Schneidermann was, to be sure,
more intelligent than Clarence, and he knew far more of the world; it
amused her to talk with him of music and art and politics, but a relationship
more intimate was to her inconceivable. Aside from this worldly knowledge
he was like Clarence; he possessed the same humbleness, the same physical
paleness. It annoyed her to believe that she attracted only men who must be
dominated.
Yet there was Callendar. Unconsciously she came to compare the
humbleness of Schneidermann and Clarence with the cat-like virility of
Callendar. It was as if she were putting aside all other men in the knowledge
that some day, at some time if she waited long enough, she would come to
possess him. Yet when she thought of him, as she frequently did after she
had gone up to the luxurious room looking out upon the white pavilion, she
grew angry at the memory of that last visit to the Babylon Arms. He had
watched her, cat-like, until, driven by some obscure desire, he could no
longer play the game of waiting.
She came slowly, as she grew to know and understand the world, to see
that he had looked upon her always as a naïve and helpless creature,
awkward and a little ridiculous. It gave her a sort of restless and unhappy
satisfaction that she had shown herself the more powerful.
It was not strange that she did not encounter the Callendars in Paris. The
world in which they moved was more remote from hers than the Babylon
Arms had been from the house on Murray Hill. True, the crêpe-hung
Madame de Cyon was an acquaintance of Thérèse, but Ellen took good care
that this fat, bedizened gossip should never learn of her acquaintance with
the Callendars, and so it did not occur to “Tiens! Tiens!” ever to mention
them. Of their life Ellen sometimes read a paragraph or two in the Daily
Mail or the Herald; they were off to New York or England or had just
returned to their house in the Avenue du Bois. She knew nothing of the
feverish, cosmopolitan society which surrounded them, nothing of the
seedy, impoverished Royalists who were the poor relations of Thérèse and
lived in fine, damp, decaying houses in the remote provinces, clinging to
the splendor of the past because so little else remained; she knew nothing of
the rich American women who had married titles.
At the lovely old house in the Rue Raynouard there were always the
friends of Lily and Madame Gigon, dowdy, bourgeois and dull, among
whom Lily moved with the calm of perfect security, as the one American
who had ever penetrated with any success the inmost circle about the
doddering Prince Bonaparte. The presence of so vigorous and arrogant a
creature as Ellen they resented bitterly and sometimes openly, so that Ellen
in the end was thrown for companionship, a thing of which she stood very
little in need, upon Rebecca Schönberg, Schneidermann and all their
hodgepodge of musicians, artists, writers and patrons of art.
Rebecca, as the months turned into years, had come to devote more and
more of her time to the house in the Rue Raynouard. When she returned
from Danzig, or Rome, or Vienna or wherever it happened to be, she came
day after day to Numéro Dix where it was her habit to sit quietly in the big
empty music room and listen with extraordinary attention while Ellen
played hour upon hour. She watched Ellen’s progress with an interest of
such intensity that Ellen at times grew ill-tempered and wished heartily that
the sandy haired creature would disappear forever. She would, doubtless,
have committed some act to sever their relationship forever save that
always in the back of her mind was the certainty that the Jewess was
valuable to her.
It was really the sense of Rebecca’s domination which at once annoyed
and confused her; otherwise she liked her well enough. It was Rebecca who
suggested the number of hours which she should practise; it was Rebecca
who bullied her into going out in the world; it was Rebecca who insisted on
helping her choose her clothes; it was Rebecca who even brought to the Rue
Raynouard people who sent Madame Gigon into the most distant part of the
house where she would be safe from the noise of their violent, modern
music. It was Rebecca who at times set the house by the ears and threatened
to bring about an open quarrel between Ellen and the Baron.
For a long time the enmity between these two had grown less and less
concealed. Lily must have sensed conflict and in her quiet, indolent way
have chosen to pretend that no strain existed. There was irony in the fact
that a woman who sought only quiet and leave to do as she pleased should
have found herself suddenly the battleground between two natures so
violent. In dealing either with insolence or domination Lily had no
difficulty; always she had gone quietly her own way achieving in the end by
some unviolent coup her own desire. When she chose, even the dark,
bumptious César obeyed her as a pet dog might have obeyed. She was even
able to cope with Ellen (though she seldom interfered) in the very midst of
the girl’s most stubborn moods. Yet when César and her cousin came into
conflict, she grew helpless; it was like living perpetually on the edge of a
volcano. She knew, perhaps by instinct, what it was that caused the trouble
... that each of them sought to rule the household.
So the peace had gone presently from the lovely old house. On one side
were ranged César and his aunt, the blind old Madame Gigon, reënforced
by the cohorts of crêpe-laden old women who came to her salons and
impressed upon her the sense of her injury. On the other were ranged Ellen
and her ally, the shrewd Rebecca. Between the opposing armies stood Lily
who wished only peace and luxury and indolence.
One night early in May, before Lily’s household had moved to

Germigny, Rebecca failed to appear for a concert they had planned to
attend. There had been good reason; an aunt of Rebecca’s, very rich, had
arrived without warning from Vienna. Yet Ellen was unreasonable and
believed that Rebecca had failed her deliberately. She had gone out for a
time to walk sullenly along the Seine and when she returned, she went
silently to her room and locked the door. The disappointment, the softness
of the evening, the look of the lights floating in the river ... all these things
created an overwhelming and terrible nostalgia.
Once inside the room she flung herself down on the canopied bed, her
blue black hair all tossed and disheveled, and, weeping, reproached herself
bitterly. She was, she believed, a horrible creature. She had treated her
mother cruelly; she had forgotten the existence of her brother—of Fergus,
with his humorous blue eyes and magical sympathy and his uncanny way of
understanding what it was that terrified her, what it was that made her
unhappy, what it was that drove her on and on without rest or peace. She
saw too her father, a mild man who loved her without making any claim,
without once speaking of love. On all these she had turned her back in a
heartless fashion.
And Clarence ... poor Clarence ... was always with her in these terrible
moments of solitude. She knew him then as she had never known him in
life; she saw him with a terrible clarity, moving about meekly with the
awful look of pleading in his near-sighted eyes. He had not been like that in
the beginning; he had changed while he lived with her, changed, as it were,
beneath her very eyes. And she saw him too as he lay for the last time on
the divan of the little flat in the Babylon Arms, peaceful at last and
untormented by a woman who always eluded him, a woman whom he loved
so much that he made way with himself that he might hinder her no longer.
And him she could never repay; it was impossible even to explain or to beg
for forgiveness, though he would have said, no doubt, that there was
nothing to forgive.
Then growing a little more quiet, she asked herself in one of her rare
moments of reflection what power had driven her to act as she had done. To
this there was no answer; it was quite beyond her. She knew, as indeed she
had always known, that she must go her way, solitary and ruthless, to fulfil
a rather shadowy ambition, a confused desire for vindication, a hunger for
the sight of the world at her feet.
It would do no good now to turn back, because such a course could only
create disaster. Sitting up among the pillows of the canopied bed she fell to
staring hopelessly into the darkness. For a long time she sat thus, pale and
disheveled, her long black hair streaming over the crimson peignoir. She
had discovered an awful thing. She, Ellen Tolliver, who had wanted only to
be free, was entangled and caught beyond all escape. She could not turn
back. She could only go forward along the path which she herself had
chosen, and it was a lonely path, a path so enveloped in solitude that she fell
to weeping again over the desolate waste of its loneliness.
There was a moon which painted all the garden outside with a pale green
light; the pastry-cake pavilion of Le Nôtre had turned to silver and the
leaves of the old plane trees, rustling together now in the soft spring air, cast
black shadows across the white terrace. Lured by the faint stream of silver
that spilled in through the darkness at the tall window, Ellen rose presently
and, sitting on the chaise longue, looked out over the garden. To-night the
familiar, distant sound of the boat whistles along the Seine seemed very
close. The hoofs of a horse passing along the cobblestones of the Rue de
Passy struck up a slow tattoo that leapt the garden wall and came up to the
very window. It was a foreign horse, passing along a foreign street and the
garden had become remote and melancholy with a new sort of beauty. It
was as if she suffered from an enchantment, as if all that had happened
since the day she had gone off to skate alone on Walke’s Pond had been an
hallucination, detached from all reality. She might wake and find herself
once more in the shabby comfortable sitting room of the house on
Sycamore Street. Still it could not be a dream; because if she returned to
that shabby room, she would find it occupied by strangers she had never
seen. Her mother would no longer be there, darning in the firelight, nor her
father sleeping on the great divan, nor Fergus, nor Robert. They were all
gone now ... gone, strange to say, in pursuit of herself. Perhaps one day they
would come as far as this lovely garden. Ma would like it only because her
children were there, but Fergus would know its meaning, how much of old
beauty that was beyond expression lay in the silver pavilion, in the mottled
trunks of the old trees and in the black filigree of shadows across the white
terrace. If only Fergus could be there she would not be lonely....
And for the first time in all her life, she became sharply aware of the
passing of time. She heard it rushing past her and knew that slowly, like a
tide rising upon a beach of shingle, the years were stealing upon her, the
years and a desperate haunting loneliness which it seemed impossible ever
to escape.
Sitting there in the moonlight, the whole of the past rose up in a queer,
muddled procession. There had been in the progression of events neither
rule nor reason. Fate, one might call it, but fate was a silly name. It meant
nothing; it could not explain how Clarence had turned toward her and so
changed all the course of her existence; it did not explain Mr. Wyck and his
muddled part in the suicide of Clarence; it did not solve that sudden,
passionate interval with Richard Callendar. It was all senseless and
muddled.
People might judge her as hard and cold and calculating but that, she
thought, would be unjust. She had been forced to make her own way, to
clear her path by the best means at hand. She had tried always to do it
without harm to others. She was not, like Sabine Cane, born with all that
one needed in this world. If she had been born, having those things, she
might have been more happy, less lonely, less aloof. Sabine, she reflected
bitterly, had everything ... wealth and friends and happiness. Even her
husband had been delivered into her hands, a man who, if chance had been
less cruel, might not have been hers. She envied Sabine.
So she fell to thinking of Callendar. What might have happened if she
had hurt Clarence deliberately and gone away with her lover? Callendar
would have married her. She would have been rich. She would have been
free. There would have been no more of this struggle.
But she could not be certain. For the first time, thinking of him now out
of the detachment of her loneliness, she doubted him. He might not have
married her, after all. Why should he have done it? And if he had married
her he might not have been stronger than this other thing which kept driving
her on, this terrible ambition that was like a disease with which one was
born.
What would love have been with a man like Callendar? She trembled a
little at the memory of him, grown softer now with the passing of time and
more sentimental. With Clarence love had been a poor timid growth,
choked and inarticulate, a thing that somehow he made shameful. Callendar
was not like that. Love with him must be a great glowing passion that
would overwhelm all else, even her own terrible awareness.
She sighed and bound up her hair. All that had passed long ago and was
done. She might die now without ever knowing anything more wonderful
than the stifled, timid embraces of Clarence.
Idly, out of nowhere, into her brain there strayed presently a memory of
old Julia Shane. It had happened when Ellen was a little girl and she could
not think why she had remembered it, yet unaccountably it was there in her
head, very clear, like an old photograph found by chance after many years.
She saw old Julia sitting in the big drawing-room of Shane’s Castle on a
Christmas day talking with Grandpa Barr. She was thin and hawklike and
leaned forward now and then on her ebony stick to give the coals in the
grate an angry poke. She had been quarreling with the vigorous old man
and presently she said sharply, poking the fire for emphasis, “Fate! Pooh!
Robert! Fate is no great tide that sweeps everything before it. It is a river
that goes this way and that, and the smart fellow is the one who jumps when
it turns in his direction!”
Aunt Julia has been right. Fate was like that and, Ellen reflected, she had
jumped when she saw it coming her way, but by ill luck she had jumped
sometimes full into the midst of the stream and been swept along by it.
Lost in this sudden memory she was interrupted sharply by a murmur of

voices arising from the garden. Without stirring she listened and, presently,
recognizing that one was Lily’s and the other that of the Baron, she made no
attempt to move out of hearing. Once, a long time ago when she had first
come to Paris, she would have moved away or have let them know by some
sign that she was nearby, watching and listening; but that time had long
gone by. She listened now either because she was shameless or because in
the mood of the moment it did not matter what things she learned. And in
some way the sight of the two dark figures, moving so close to each other
up and down the white terrace, dissipated the terrible loneliness.
The pair below her knew, no doubt, that Madame Gigon was long since
snoring among the gimcracks of her bedroom, and they believed that she
herself was out, at the theater with Rebecca. In the French manner, the
servants did not matter; it is probable that of all the people in the house they
knew most of Lily and her life.
The Baron’s voice, deep and rich, drifted up to the open window.
“Jean, you say, will be back from school in June?”
He wore his uniform, and the perfection of its lines emphasized all the
trim, masculine hardness of his slight figure. Beside him in her black gown,
with the stole of sable thrown round her for warmth, Lily was soft and
lovely. His voice it seemed, caressed her.
“He is growing big now ... fourteen. Think of it....” He laughed softly.
“You with a big boy of fourteen! It is impossible ... incroyable!”
Lily said something which was not audible and then, “Yes. We must be
more careful. He will begin to see things.”
“In England boys are not so sharp ... at least not about affairs between
men and women.”
In silence they walked for a time, once up and once down the terrace.
The leaves of the plane trees rustled and a boat far below in the Seine
whistled faintly. Once more they passed beneath the window.
“June is more than a month away,” said the Baron. “We could go to Nice
for three long weeks.”
Lily, it seemed, was unwilling, for he argued with her, saying in a voice
that would have melted steel, “Think of it.... We have not been alone for
months. Think of it ... the mornings ... waking together ... looking out over
the bay.... Alone ... alone.” He paused suddenly and seizing her in his arms
kissed her. For a long time they stood thus. Ellen could see them quite
plainly, standing in the shadow of one of the white urns, Lily with her head
against his shoulder while he kissed her again and again.
Then slowly, with the air of waking from a dream, Lily raised her head
and passing her hand against her eyes, murmured, “I should not like Ellen
to know.”
At this he laughed and a new note, one of hard anger, entered his voice.
“She knows already if she is not a fool.”
At the intonation Lily withdrew and leaned against one of the white urns.
“She doesn’t. I’m sure of it. She has said nothing.”
Again he laughed, scornfully. “She’s no fool. She knows it would be
more unpleasant for her than for you. She needs a home and money ... just
now. She’ll not open her eyes so long as it might harm her plans.”
Sitting there in the darkness, Ellen succumbed to a slow anger that rose
to her head like a fever. She had believed that he spoke against her; now she
was sure of it. She hated him vaguely, because he dared even to say such a
thing to her cousin. He was so sure of himself, the amorous beast.
She was hurt too, as if some one had struck her, because what César had
said was so near to the truth.
But Lily turned away from him. “I won’t have you say such things,” she
said. “It is ridiculous and unjust.”
He did not use words in defense of himself, perhaps because words were
to him such weak and awkward weapons. Instead, he simply took Lily once
more in his arms, and beneath his kisses, Ellen saw that all resistance, all
anger melted from her. It was like a bit of wax touched suddenly by a
flame.... An amazing sight which seemed to illumine sharply the whole of
Lily’s strange life.
After a moment, he placed his arm about her waist and they moved away
down the steps into the shadow of the plane trees. Once they halted for a
time while he kissed her again and then, resuming their way in the same
state of enchantment, they disappeared through the filigree of black
shadows into the white pavilion, silvered by the moon.
And in the room above the terrace, Ellen slipped from the chaise longue
to the floor where she lay flung out, weeping passionately. The loneliness
returned now more terribly than ever before.
44
I N the morning, after coffee and brandy, Ellen rose at dawn to ride in the
Bois. She went purposely without Schneidermann, leaving him to a vain
pursuit, in order that she might be alone; and when she returned she found
that Lily was already awake and had come down from her room to breakfast
on the terrace. The May sunlight poured into the garden and beat against the
stone of the façade, enveloping her with its reflected warmth, as she sat at
the iron table before a bowl of hot chocolate, a dish of rolls and two piles of
letters. One heap had been opened and the contents lay scattered over the
table and on the flagging beneath. As Ellen, tall and slim in her riding habit
and hard hat, stepped through the tall window Lily put down a letter and
said, “I brought your mail out here. It isn’t interesting this morning ...
mostly bills.”
Ellen throwing down her crop and hat, ran her fingers through her dark
hair and seated herself on the opposite side of the table, while Lily sent for
more chocolate and hot rolls.
“You look tired,” observed Lily. “Were you out late?”
“No. Rebecca couldn’t go with me, and I was tired so I didn’t go at all.
But I slept badly.”
Lily turned the page of the note she was reading. “You work too hard,”
she said. “Try taking a rest. Come down to the country with me in June.”
“No, I can’t do that.... I’m going to play in London. Rebecca and
Schneidermann have arranged it. It will be my début.”
She announced the news abruptly, without any show of emotion.
Lily put down the letter and leaned toward her. “You didn’t tell me it
would be so soon.”
“I only knew it for certain last night. I’m superstitious about speaking of
things until they’re certain. I’m to play in Wigmore Street on the third.”
Her cousin was all interest now. She drew her chair a little nearer and
carelessly pushed her letters off the edge of the table.
“Have you chosen a gown? We’ll send for the motor and choose one this
morning. That’s important, you know ... especially in England where they
recognize good clothes but never wear them.”

Full Download Multifunctional and Targeted Theranostic Nanomedicines Formulation Design and Applications Keerti Jain PDF

Uploaded by

Copyright:

Available Formats

Full Download Multifunctional and Targeted Theranostic Nanomedicines Formulation Design and Applications Keerti Jain PDF

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Full Download Multifunctional and Targeted Theranostic Nanomedicines Formulation Design and Applications Keerti Jain PDF

Uploaded by

Copyright:

Available Formats

Full download test bank at ebookmeta.

Multifunctional And Targeted Theranostic

Download More ebooks from https://ebookmeta.com

Advanced Multifunctional Lightweight Design Development

Herbal Product Development : Formulation and

Molecular Imaging and Targeted Therapy:

Building Offline Applications with Angular: Develop

Digitization in Dentistry: Clinical Applications

Cognitive Computing Systems: Applications and

Angular for Material Design: Leverage Angular Material

Fundamentals and Properties of Multifunctional

Multifunctional And Targeted

ISBN 978-981-99-0537-9 e-ISBN 978-981-99-0538-6

© The Editor(s) (if applicable) and The Author(s), under exclusive

The use of general descriptive names, registered names, trademarks,

This Springer imprint is published by the registered company Springer

1. Functionalized Targeted Theranostic

Mohammad Zaki Ahmad (Corresponding author)

Keerti Jain (Corresponding author)

Keywords Nanomedicines – Theranostic nanoparticles – Imaging agents –

1.2 Design of Nanotheranostic

Fig. 1.2 Schematic representation of the highly interdisciplinary field of nanotheranostics

1.3 Therapy in Nanotheranostic

1.3.2 Gene Delivery

1.3.3 Photodynamic Therapy

1.3.4 Photothermal Therapy

1.4 Nanotheranostic for Imaging

1.4.1 Optical Imaging

1.4.2 Magnetic Resonance Imaging

1.4.3 Computed Tomography

1.4.4 Ultrasound Imaging

1.5 Different Types of Nanotheranostics

Fig. 1.7 Types and applications of nanotheranostics

S. Types Functionalization Targeted disease Imaging References

1.5.1 Superparamagnetic Iron Oxide Nanoparticles

1.5.3 Carbon Nanomaterials

1.5.4 Graphene Oxide

1.5.5 Polymeric Nanoparticles

1.5.6 Polymeric Micelles

1.6 Regulatory Aspects

Akhter S, Ahmad I, Ahmad MZ, Ramazani F, Singh A, Rahman Z, et al (2013) Nanomedicines as

Alagarsamy KN, Mathan S, Yan W, Rafieerad A, Sekaran S, Manego H et al (2021) Carbon

Albertini B, Mathieu V, Iraci N, van Woensel M, Schoubben A, Donnadio A et al (2019) Tumor

Anani T, Rahmati S, Sultana N, David AE (2021) MRI-traceable theranostic nanoparticles for

Bai RG, Muthoosamy K, Manickam S (2015) Nanomedicine in theranostics. Nanotechnology

Choi J, Kim H, Choi Y (2015) Theranostic nanoparticles for enzyme-activatable fluorescence

Dao P, Ye F, Liu Y, Du ZY, Zhang K, Dong CZ et al (2017) Development of phenothiazine-based

Esmaeili Y, Zarrabi A, Mirahmadi-Zare SZ, Bidram E (2020) Hierarchical multifunctional graphene

Gellci K, Mehrmohammadi M (2014) Photothermal therapy. Encyclopedia of Cancer 1–5

Gharatape A, Salehi R (2017) Recent progress in theranostic applications of hybrid gold

Ghosh S, Chatterjee K (2020) Poly(ethylene glycol) functionalized graphene oxide in tissue

Gregoriou Y, Gregoriou G, Yilmaz V, Kapnisis K, Prokopi M, Anayiotos A, Strati K, Dietis N,

Hö nigsmann H (2012) History of phototherapy in dermatology. Photochem Photobiol Sci

Kumar P, Huo P, Zhang R, Liu B (2019) Antibacterial properties of graphene-based nanomaterials.

Li B, Wang Q, Zou R, Liu X, Xu K, Li W et al (2014) Cu7.2S4 nanocrystals: a novel photothermal

Li H, Hu H, Zhao Y, Chen X, Li W, Qiang W et al (2015a) Multifunctional aptamer-silver conjugates

Li Y, He D, Tu J, Wang R, Zu C, Chen Y et al (2018) The comparative effect of wrapping solid gold

Ló pez-Lorente Á I (2021) Recent developments on gold nanostructures for surface enhanced

Mallick N, Asfer M, Anwar M, Kumar A, Samim M, Talegaonkar S et al (2015) Rhodamine-loaded,