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Editors
Keerti Jain and N. K. Jain
Multifunctional And Targeted

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
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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,

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absence of a specific statement, that such names are exempt from the
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Nature Singapore Pte Ltd.
The registered company address is: 152 Beach Road, #21-01/04
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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.
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© 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_2
2. Designing of Smartly Functionalized

Dheeraj Pandey1, Parth Patel2, Keerti Jain2 and Abha Sharma1
(1) Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research, Raebareli, India
(2) Department of Pharmaceutics, National Institute of
Pharmaceutical Education and Research (NIPER) – Raebareli,
Lucknow, India
Abha Sharma
Email: abha.sharma@niperaebareli.edu.in
Abstract
The consistent advances in the synthesis of nanoparticles (NPs) enable
their potential use in the field of treatment and diagnosis. The NPs that
are utilized for simultaneous diagnosis and treatment of disease are
known as theranostic nanomedicines. The controlled size, shape,
surface area, and permeation of NPs enable their superiority over
conventional medicines. Functionalized NPs are advantages to achieve
the desired effect, local or direct delivery, prolonged drug effects, and
carrying off the theranostic property. Functionalization is achieved by
altering the properties of NPs through chemical or physical
modifications. Numerous functional technologies have been engaged
for the modification and functionalization of NPs for theranostic
applications. The functionalizations are mainly classified as small
molecule functionalization or bio-functionalization. Small molecule
functionalization entails the conjugation of drugs, chemical ligands,
imaging agents, etc. to the NPs using chemical crosslinking reagents.
For chemical functionalization copious chemical approaches such as
click reactions, maleimide coupling, amide coupling, etc. have been
utilized. Latterly, bio-functionalizations of NPs have drawn extensive
debate because of their high biocompatibility, low cost,
biodegradability, and eco-friendliness in contrast with their chemical
counterparts. Bio-functionalization of NPs involves the use of natural
phytochemicals, bio-inspired ligands, and the use of natural bio-
resources such DNA, RNA, protein enzymes, etc. A brief information
about various methods and approaches for the functionalization of NPs
has been provided in this chapter.
Keywords Theranostic – Functionalized nanoparticles –

Nanomedicines – Gold nanoparticles – Bio-functionalization – Chemical
functionalization – Diagnosis
2.1 Introduction
Nanotechnology is the study committed to design and synthesis of
nanosize molecules for various applications such as therapeutic,
imaging, target site drug delivery, tissue repair, etc. Nanotechnology is
one of the most rapidly extending areas in diverse scientific research
domains. The term nanotechnology was first ever coined in 1959 by
Nobel physicist Richard Feynman (Drexler 2004). In the past decades,
multiple forms of NPs have attracted a lot of attention tremendous in
various applications because of their unusual physicochemical and
mechanical properties. Unlike small molecules, NPs are capable of
carrying wide range of therapeutic, diagnosis, and selectivity agents to
the target site (Caruthers et al. 2007; Xie et al. 2010; Sun 2010;
Lammers et al. 2010). Even though development of nanoparticle-based
therapeutic and imaging NPs into clinical trials is grappling due to
toxicity concerns, advancements have been recorded in the last decade.
More than 35 imaging or therapeutic NPs are approved by the Food and
Drug Administration till date, for clinical trials e.g., CRLX101, Rexin-G,
etc. (Thakor and Gambhir 2013).
The combination of therapeutic and diagnosis application within a
single nanomedicine dosage form is known as theranostic
nanomedicine (Jokerst and Gambhir 2011). Theranostic NPs are
utilized for monitoring drug delivery, for imaging drug release and to
monitor the efficacy of drugs. Theranostic NPs are employed as
contrast agents that can be chased in vivo utilizing minimum of one of
the available options of optical imaging technique, e.g., positron
emission tomography (PET), magnetic resonance imaging (MRI),
computed tomography (CT), fluorescence, or surface-enhanced Raman
scattering (SERS). Theranostic NPs comprise of a therapeutic part such
as immunotherapeutic agent, chemotherapeutics, or photosensitive
molecules along with the contrast agents (Nicolson et al. 2020).
Theranostic NPs can be formulated by employing various techniques,
e.g., already existing imaging agents such iron oxide nanoparticle
(IONPs) quantum dots (QDs) are conjugated with therapeutic agents
(e.g., anticancer drugs and photosensitizers). Additionally,
encapsulation of both imaging and therapeutic agent in a nanoplatform
is also effective (Chen et al. 2014). Theranostic agents make it possible
for the fine tune drug dose delivery and simultaneous imaging of the
dose reaching target site. Ideal theranostic NPs must reach selectively
and rapid to their target. In recent years theranostic applications of NPs
have been flourished and explored widely due to their superiority in
simultaneous diagnosis and treatment of disease. Theranostic
nanomedicines enable the real-time monitoring of treatment progress
and efficacy of the treatment regimen (Kelkar and Reineke 2011).
Theranostic nanomedicines are composed of therapeutic drug on one
hand along imaging agents on other either conjugated with each other
or co-loaded in classical drug delivery systems, such as NPs. This
conjugation of the nanoimaging agent along with the therapeutic agent
is known as functionalization (Lammers et al. 2005).
2.2 Approaches for Functionalization of

Theranostic Nanoparticles
Functionalization of NPs allows inculcation of specific properties of
interest to the NPs. Additionally, functionalized NPs have good physical
properties, noninvasive characteristics, anti-corrosion, and anti-
agglomeration properties (Subbiah et al. 2010). To overcome the
toxicity-related issues and enhance the imaging properties, there is a
need for modification of surface characters of NPs. Similarly, to enhance
the theranostic properties and selectivity of NPs for the biological
application, the surface of the NPs is modified, i.e., functionalization of
NPs, which includes conjugation of chemicals (small molecules) or
biomolecules on to their surface (Herranz et al. 2012; Aravind et al.
2012). It not only improves the image quality, but also enables the
treatment of disease. Various budding theranostic nanoplatforms such
as carbon nanodots (CDs), superparamagnetic iron oxide nanoparticles
(SPIONs), gold nanoparticles (AuNPs), and graphene oxide (GO) are
capable of diagnosis and treatment combinedly. Nowadays, surface
functionalization has a very beneficial obligation for productively
modulating the structures, physicochemical properties, and interface
features of these nanoplatforms. This method is comparatively
dependable and compliant for the adjustment to achieve both
regulatory and physicochemical requirements as a justification for their
applications in specific field (Mauro et al. 2021). Surface modification of
NPs is a demanding task; as a result the role of chemists comes into
picture as they are fully furnished to provide functionality using various
synthetic strategies (Boisselier and Astruc 2009). Theranostic NPs can
be developed using both organic and inorganic NPs (Xie et al. 2010).
NPs can be functionalized using various ligands such as small
molecules, fluorescent dyes, polymers, and biomolecules like enzymes,
antibodies, DNA, RNA, proteins, carbohydrates, etc. (Fig. 2.1). Many
biomolecules or therapeutic drugs can be incorporated on polymeric
ligands and even on the surface of NPs by utilizing covalent or non-
covalent binding strategies (Moyano and Rotello 2011). As a result,
biocompatibility and specific recognition qualities can be achieved in
case of biomolecule-conjugated NPs (Rana et al. 2012). Different
chemical approaches have been utilized for the functionalization of NPs
that can be classified as covalent and non-covalent strategies. Covalent
strategies involve amide coupling, click chemistry reaction, thiol
coupling, etc., while the non-covalent approaches include ionic coupling
and hydrophobic coupling (Conde et al. 2014a). Further in this chapter
the different types of functionalizations will be elaborated in brief.
Fig. 2.1 Functionalization of NPs using various biomolecules and small molecule
ligands
2.2.1 Functionalization of Nanoparticles Using

Small Molecule Ligands
A wide range of small molecule ligands can be conjugated on the
surface of NPs that allows the use of NPs in wide-ranging applications
such as diagnosis, targeting, intracellular delivery, treatment of disease
like cancer, etc. (El-Boubbou et al. 2010). It is also used for the
identification of some specific cells; the NPs are conjugated with the
ligands that have affinity towards the specific cells (Saha et al. 2011).
The surface charge of the NPs is due to the groups present on them that
allows the conjugation of molecules on the NPs. The cellular interaction
and uptake of small molecules depends on their surface charge, so in
general high cellular uptake is expected in case of positively charged
molecules as compared to neutral and negatively charged molecules
(Nel et al. 2009; Cho et al. 2009). For the incorporation of diagnostic
properties on the therapeutic NPs, various fluorescent dyes are
incorporated on the surface of NPs. Zhou et al. developed fluorescent
molecule conjugated NPs for targeting cancer cells. In this report
cyanine structure molecule was conjugated with IONPs, and the ability
of the formulated NPs to target cancer cells was observed (Zhou et al.
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hours you have been spending alone.” “Alone!” he exclaimed, in a
joyful tone, “I am never alone, and never weary. How should I be
either, when my days are passed in the company of innocent
animals, and time is given me to think of God!” The priest smiled
even more approvingly than before; and I remarked to him, “We are
here in Arcadia.” “But not without human sin,” said he, and pointing
to a woman at a distance, who was in the employ of the farmer’s
wife, he asked the latter how she could still have anything to do with
a well-known thief. “Eh, father,” was the comment of a woman whom
John Howard would have kissed, “starving her in idleness would not
cure her of pilfering; and between working and being well-watched,
she will soon leave her evil habits.” “You are a good Christian,” I said
to her, “be you of what community you may.” “She is a good
Catholic,” added the priest. “I am what the good God has made me,”
was the simple reply of the Walloon wife; “and my religion is this to
go on my knees when all the house is asleep, and then pray for the
whole world.” “Ay, ay,” was the chorus of those around her, “that is
true religion.” “It is a part of true religion,” interposed the priest; but I
could not help thinking that he would have done as well had he left
Marie Justine’s text without his comment. We walked together down
to the bank of the river opposite the Chateau of the young Count de
Levignon the proprietor and burgomaster of Houx. I looked up from
the modern chateau to the ruins of the vast castle where the sons of
Aymon once held barbaric state, maintained continual war, and
affected a reverence for the mother of Him who was the Prince of
Peace. The good priest seemed to guess my thoughts, for he
remarked, “We live now in better times; the church is less splendid,
and chivalry less ‘glorious,’ if not extinct; but there is a closer
brotherhood of all men—at least,” he added hesitatingly—“at least I
hope so.” “I can not remember,” said I, “a single virtue possessed by
either Aymon or his sons, except brute courage, and a rude sort of
generosity, not based on principle, but born of impulse. It is a pity
that Belgium can not boast of more perfect chevaliers than the old
proprietors of Poilvache, and that you have not a hero to match with
Bayard.” “Belgium,” was his answer, “can make such boast, and had
a hero who had finished his heroic career long before Bayard was
born. Have you never heard of ‘the Good Knight without fear and
without doubt’?” “I have heard of one without fear and without
reproach.” “That title,” he remarked, “was but a plagiarism from that
conferred on Jacques de Lelaing, by his contemporaries.” And then
he sketched the outline of the good knight’s career, and directed me
to sources where I might gather more detailed intelligence. I was
interested in what I learned, and it is because I hope also to interest
readers at home, that I venture to place before them, however
imperfectly rendered, a sketch of the career of a brave man before
the time of Bayard; one who illustrates the old saying that—
“Vixere fortes ante Agamemnona.”
Jacques de Lelaing, the good knight, without fear and without doubt,
was born in the château of Lelaing, in the first quarter of the fifteenth
century. The precise year is not known, but it was full half a century
before the birth of Bayard. He came of a noble race; that is, of a
race, the male portion of which saw more honor in slaughter than in
science. His mother was celebrated for her beauty as well as nobility.
She was wise, courteous, and débonnaire; well-mannered, and full
of all good virtues. So, at least, in nearly similar terms, wrote George
Chastellan of her, just two centuries ago.
Jacques de Lelaing was as precocious a boy as the Duke of
Wharton in his youth. At the age of seven, a priestly tutor had
perfected him in French and Latin, and the good man had so imbued
him with literary tastes that, in after life, the good knight found time to
cultivate the acquaintance of Captain Pen, as well as of Captain
Sword; and specimens of his handiwork are yet said to exist in the
libraries of Flanders and Brabant.
Jacques, however, was never a mere student, “sicklied o’er with the
pale cast of thought.” He loved manly sports; and he was yet but a
blooming youth when the “demoiseau of Clèves,” nephew of that
great Duke whom men, for no earthly reason, called Philip the Good,
carried off his young friend from the castle of Lelaing, and made of
him a squire, not of dames, but of knights, in the turbulent court of
the ducal Philip, with the benevolent qualification to his name.
The youth entered upon his career with a paternal provision which
bespoke at once the liberality and the wisdom of his father, stout
William de Lelaing. The sire bestowed upon his son four splendid
horses, a well-skilled groom, and a “gentleman of service” which, in
common phrase, means a valet, or “gentleman’s gentleman.” But the
young soldier had more than this in his brain; namely, a well-lettered
cleric, commissioned to be for ever expounding and instructing, with
a special object, to boot, that Jacques should not forget his Latin!
Excellent sire thus to care for his son! If modern fathers only might
send into barracks with their sons, when the latter first join their
regiments, reverend clerks, whose office it should be to keep their
pupils well up in their catechism, the Eton grammar, and English
orthography, what a blessing it would be to the young gentlemen and
to all acquainted with them! As it is, we have officers worse
instructed and less intelligent than the sons of the artists who make
their uniforms.
When Jacques went forth into the world, his sire gave him as good
advice as Polonius threw away on his son Laertes. The sum of it was
according to the old French maxim, “Noblesse oblige”—“Inasmuch,”
said the old man, “as you are more noble than others by birth, so,”
said he, “should you be more noble than they by virtues.” The hearty
old father added an assurance, that “few great men gained renown
for prowess and virtue who did not entertain love for some dame or
damoiselle.” This last, however, was but an equivocal assurance, for
by counselling Jacques to fall in love with “some dame or
damoiselle,” he simply advised him to do so with any man’s wife or
daughter. But it was advice commonly given to young gentlemen in
arms, and is, to this day, commonly followed by them. Jacques
bettered the paternal instruction, by falling in love with two ladies at
the same time. As ambitious youths are wont to do, he passed by
the white and pink young ladies whom he met, and paid his
addresses, with remarkable success, to two married duchesses.
Neither of these suspected that the smooth-chinned young “squire”
was swearing eternal fidelity to the other, or that this light-mailed
Macheath wooed his madiæval Polly with his pockets full of “favors,”
just bestowed on him by an unsuspecting Lucy. Thus has love ever
been made by officers and highwaymen.
But if Jacques loved two, there was not a lady at the Court of
Burgundy who did not love him. The most virtuous of them sighingly
expressed a wish that their husbands, or their lovers, were only like
him. The men hated him, while they affected to admire his grace, his
bearing, and his irresistible bravery. Jacques very complacently
accepted the love of the women and the envy of the men; and
feeling that he had something to be thankful for, he repaired to the
shrine of the Virgin at Hal, and thanked “Our Lady,” accordingly.
Now Philip the Good was good only just as Nicholas the Czar was
“good.” He had a fair face and a black heart. Philip, like Nicholas,
joined an outward display of conjugal decency with some private but
very crapulous indecency; and the Duke, like the Czar, was the
appalling liar of his day. Philip had increased the ducal territory of
Burgundy by such means as secured Finland to Muscovy, by
treachery of the most fiendish quality; and in 1442, affecting to think
that Luxembourg was in the sick condition which Nicholas described
as the condition of Turkey—when the imperial felon thought he was
making a confederate of Sir Hamilton Seymour, the Duke resolved to
seize on the territory in question, and young Jacques de Lelaing was
in an ecstacy of delight at being permitted to join in this most rascally
of expeditions.
Within a year, desolation was spread throughout a wide district. Fire
and sword did their devastating work, and the earth was swept of the
crops, dwellings, and human beings, which lay between the invaders
and Luxembourg. The city was ultimately taken by surprise, and the
good Philip delivered it up to pillage; then ensued a scene which hell
itself could not equal; and the Duke and his followers having enacted
horrors from which devils would have recoiled, they returned to
Brussels, where they were received with ten times more delight than
if they had come back from an expedition which had been
undertaken for the benefit of humanity.
What was called peace now followed, and Jacques de Lelaing,
having fleshed his maiden sword, and gained the praise of brave
men, and the love of fair women, resolved to commence a series of
provincial excursions for his own especial benefit. As, in modern
times, professors without scholars, and actors without engagements,
wander from town to town, and give lectures at “the King’s Arms,” so
Jacques de Lelaing went forth upon his way, offering to fight all
comers, in presence of kings themselves.
His first appearance on this provincial tour was at Nancy, in 1445,
where a brilliant French Court was holding joyous festival while
awaiting the coming of Suffolk, who was commissioned to escort to
England a royal bride, in the person of Margaret of Anjou. The
French knights made light of the soldier of Burgundy; but Jacques,
when announcing that he was the holder of the tournament, added
that no French knight should unhorse him, unless God and his good
lady decreed otherwise.
The latter was not likely, and he felt himself secure, doubly so, for he
rode into the lists decorated with favors, gold embroidery, and rich
jewels, the gifts of the Duchesses of Orleans and Calabria, each of
whom fondly believed that she was the sole fair one by whose bright
eyes Jacques de Lelaing swore his prettiest oath. Accordingly, there
was not a cavalier who rode against him in that passage of arms,
who left the field otherwise than with broken or bruised bones. “What
manner of man will this be?” cried they, “if, even as a lad, he lays on
so lustily?”
The lad, at the subsequent banquet, to which he was borne in
triumph, again proved that he had the capacity of a man. He was
fresh as a rose just blown; gay as a lark in early spring. The queens
of France and Sicily conversed with him by the half hour, while ladies
of lower degree gazed at him till they sighed; and sighed, knowing
full well why, and caring very much, wherefore. Charles VII. too,
treated him with especial distinction, and conferred on him the rich
prizes he had won as victor in the rough tourney of the day. But there
were other guerdons awarded him that night, which he more highly
prized. Jacques visited the Duchess of Orleans in her bower, and
carried away with him, on leaving, the richest diamond she had to
bestow. He then passed to the pavilion of the Duchess of Calabria, a
lady who, among other gifts willingly made by her, placed upon his
finger a brilliant ruby set in a gorgeous gold ring. He went to his own
bed that night as impudently happy as a modern Lifeguardsman who
is successfully fooling two ladies’ maids. His cleric had left him, and
Jacques had ceased to care for the keeping-up of his Latin, except,
perhaps, the conjugation of the imperative mood of amo. “Amemus,”
let us love, was the favorite part of the mood, and the most
frequently repeated by him and his brace of duchesses.
Sometime after this very successful first appearance, and toward the
end of 1445, our doughty squire was traversing the cathedral of
Notre Dame of Antwerp, and was on the point of cursing the singers
for their bad voices, just as one might be almost justified in doing
now, so execrable are they; he was there and thus engaged, when a
Sicilian knight, named Bonifazio, came jingling his spurs along the
transept, and looking jauntingly and impertinently as he passed by.
Jacques looked boldly at this “pretty fellow” of the time, and
remarked that he wore a golden fetter ring on his left leg, held up by
a chain of the same metal fastened to a circlet above his knee. His
shield bore the device, “Who has fair lady, let him look to her well!”
“It’s an impertinent device,” said Jacques, touching the shield, by
way of token that he would fight the bearer for carrying it. “Thou art
but a poor squire, albeit a bold man,” said the Sicilian, with the air of
one who was half inclined to chastise the Hainaulter for his
insolence. Toison d’Or, the herald, whispered in the ear of the
Hainaulter; thereupon, Jacques exclaimed, “If my master, Duke
Philip, will give me permission to fight, thou darest not deny me, on
his Grace’s territory.” Bonifazio bowed by way of assent. The
permission was gained, and the encounter came off at Ghent. The
first day’s combat was a species of preliminary struggle on
horseback, in which Jacques showed himself so worthy of the spurs
he did not yet wear, that Philip fastened them to his heels the next
day, and dubbed him Knight in solemn form. As the combatants
strode into the lists, on the second day, the Duke of Orleans
remarked to his Duchess, that Jacques was not so “gent as the
Sicilian.” The Duchess smiled, as Guinever smiled when she looked
on Sir Launcelot, while her husband, King Arthur, commented upon
him; and she said, in phrase known to all who read Spenser, “he
loves a lady gent;” and she added, with more of the smile and less of
the blush, “he is a better man than the Sicilian, and, to my thinking,
he will this day prove it.”
“We shall see,” remarked the Duke carelessly.
“We shall see,” re-echoed the Duchess, with the sunniest of smiles.
Jacques, like the chivalric “gent” that he was, did honor to the
testimony of the Duchess. The combatants went at it, like stout men.
Jacques belabored his antagonist with a staff, the Sicilian answered
by thrusting a javelin at his adversary’s uncovered face. They then
flung away their arms and their shields, and hewed at each other
with their battle-axes. Having spoiled the edges of these, and
loosened them from their handles, by battering at each other’s skulls,
they finally drew their lusty and well-tempered swords, and fought so
fiercely that the gleaming of their swiftly manœuvred blades made
them seem as if they were smiting each other with lightning. Jacques
had well-nigh dealt a mortal thrust at the Sicilian, when, at the
intervention of the Duke of Orleans, Philip the Good flung his
truncheon into the lists, and so saved the foreign knight, by ending
the fray. The Duchess reproved her consort for being over-intrusive,
but she smiled more gleesomely than before. “Whither away, Sir
Jacques?” asked she, as the latter modestly bowed on passing her
—the multitude the while rending the welkin with their approving
shout. “To the chapel in the wood,” replied Jacques, “to render
thanks for the aid vouchsafed to me by our Lady.” “Marry,” murmured
the Duchess, “we will be there too.” She thought it not less edifying
to see knight at his devotions than at beholding him in the duello. “I
am grateful to the Lady of Good Succor,” said Jacques. “And thou
doest right loyally,” was the comment of the Duchess.
The victory of the Belgian cavalier over the Sicilian gained for him
the distinctive name which he never lost, that of “the Good Knight.”
To maintain it, he proceeded to travel from court to court, as pugilists
itinerate it from fair to fair, to exhibit prowess and to gather praise.
The minor pugilist looks to pence as well as praise, and the ancient
knight had an eye to profit also—he invariably carried off the horse,
armor, and jewels of the vanquished. As Sir Jacques deemed
himself invincible, he looked to the realization of a lucrative tour. “Go
on thy way, with God’s blessing,” exclaimed his sire. “Go on thy way,
Jacques,” murmured his mother through her tears; “thou wilt find
ointment in thy valise, to cure all bruises. Heaven send thee a
surgeon, and thou break thy bones.”
Across the French frontier merrily rode Sir Jacques, followed by his
squire, and attended by his page. From his left arm hung a
splendidly-wrought helmet, by a chain of gold—the prize offered by
him to any one who could overcome him in single combat. Jacques
announced that, in addition, he would give a diamond to any lady or
demoiselle indicated to him by his conqueror. He stipulated that
whichever combatant first dropped his axe, he should bestow a
bracelet upon his adversary; and Jacques would only fight upon the
condition that neither knight should be fastened in his saddle—a
regulation which I should never think of seeing insisted upon
anywhere, except by equestrian aldermen when they amble on Mr.
Batty’s horses, to meet the Sovereign at Temple Bar. For the rest
Jacques put his trust in God, and relied upon the strength given him
in the love of “the fair lady who had more power over him than aught
besides throughout the entire world.” A hundred ladies fair, matrons
and maids, who heard of this well-advertised confidence, did not
hesitate to exclaim, “Delicious fellow! He means me!”
It was the proud boast of Jacques, that he traversed the capital, and
the provincial cities of France, without meeting with a knight who
would accept his defiance. It would be more correct to say—a knight
who could take up his challenge. Charles VII. forbade his chivalry
from encountering the fierce Hainaulter anywhere but at the festive
board. In the South of France, then held by the English, he met with
the same civility; and he rode fairly into Spain, his lance in rest,
before his onward career was checked by the presence of an
adversary. That adversary was Don Diego de Guzman, Grand-
master of Calatrava, and, although he knew it not, ancestor to a
future Empress of the French. The Don met the Belgian on the
borders of Castile, and accepted his published challenge out of mere
love, as the one silly fellow said of the other, out of mere love for his
“très aimée dame.” The “dames” of those days enjoyed nothing so
much as seeing the gentlemen thwack each other; and considering
what a worthless set these latter, for the most part, were, the ladies
had logically comic reasons to support their argument.
It was necessary, however, for Don Diego to obtain the consent of
his sovereign to encounter in mortal combat a knight of the
household of Burgundy, then in alliance with Spain. The Sovereign
was absent from the country, and while an answer was being
expected from him to the application duly made, Jacques, at the
head of a most splendid retinue, trotted leisurely into Portugal, to
tempt the Lusitanian knights to set their lances against him. He rode
forward to the capital, and was greeted by the way, as if he had been
as illustrious a monarch as his ducal master. It was one ovation, from
the frontier to Lisbon, where he was welcomed by the most crowded
of royal balls, at which the King (Alphonso XV.) invited him to foot it
with the Queen. The King, however, was but an indifferent master of
the ceremonies. The late Mr. Simpson of Vauxhall, or the illustrious
Baron Nathan of Rosherville, would never have dreamed of taking
the lady to introduce her to the gentleman. This uncourteous process
was, however, the one followed by Alphonso, who taking his consort
by the hand, led her to Sire Jacques, and bad him tread a measure
with her. Messire Jacques consented, and there was more than
enough of dancing, and feasting, and pleasure-seeking, but no
fighting. Lisbon was as dull to the Belgian as Donnybrook Fair
without a skrimmage used to be to all its lively habitués. “I have had
a turn with the Queen,” said Jacques, “let me now have a tourney
with your captains.” “Burgundy is my good friend,” answered the
King—and he was right in a double sense, for Burgundy was as dear
to him as Champagne is to the Czar’s valet, Frederick William, who
resides at Berlin. “Burgundy is our good friend,” answered Alphonso,
“and Heaven forbid that a knight from such a court should be roughly
treated by any knights at mine.” “By St. George! I defy them!”
exclaimed Jacques. “And even so let it rest,” said the monarch; “ride
back to Castile, and do thy worst upon the hard ribs of the Guzman.”
Jacques adopted the suggestion; and on the 3d of February, 1447,
there was not a bed in Valladolid to be had “for love or money;” so
crowded was that strong-smelling city with stronger-smelling
Spaniards, whose curiosity was even stronger than the odors they
distilled, to witness the “set-to” between the Belgian Chicken and the
Castile Shaver!
I will not detail the preliminary ceremonies, the processions to the
field, the entry of the sovereigns, the fluttering of the ladies, the
excitement of the knights, and the eagerness of the countless
multitude. Jacques was on the ground by ten o’clock, where Guzman
kept him waiting till three; and then the latter came with an axe so
much longer than that wielded by the Belgian, that even the Spanish
umpires forbade its being employed. Don Diego’s own “godfather”
for the occasion was almost minded to thump him with the handle;
and there was all the trouble in the world to induce him to select
another. This being effected, each knight was conducted to his tent,
with the understanding that he was not to issue therefrom until the
clarions had thrice sounded by way of signal. At the very first blast,
however, out rushed the Guzman, looking as ferocious as a stage
Richard who has killed five false Richmonds, and is anxiously
inquiring for the real one wherewith to finish the half-dozen. The too
volatile Don was beckoned back by the chief herald as haughtily as
when the sempiternal Widdicombe points out with his whip some
obvious duty to be performed by Mr. Merryman. Diego retired
muttering, but he again appeared in front of his tent at the second
note of summons from the trumpet, and only withdrew after the king
had assailed him “with an ugly word.” At the third “flourish,” the two
champions flew at each other, battle-axe in hand. With this weapon
they hammered at each other’s head, until there was little sense left
in either of them. At length, Diego was disarmed; then ensued a
contest made up partly of wrestling and partly of boxing; finally, they
had recourse to their swords, when the king, perceiving that murder
was likely to ensue, to one or both, threw his bâton into the lists, put
an end to the combat, and refused permission to the adversaries to
continue the struggle on horseback. The antagonists shook hands,
and the people shouted. The Spanish knight is deemed, by Belgian
chroniclers, as having come off “second best” in the struggle; but it is
also clear that Diego de Guzman was by far the “toughest customer”
that ever confronted Jacques de Lelaing. There was some jealousy
on the part of the Iberian, but his behavior was, altogether, marked
by generosity. He praised the prowess of Jacques, and presented
him with an Andalusian horse covered with the richest trappings; and
de Lelaing, as unwilling to be outdone in liberality as in fight, sent to
Guzman, by a herald, a magnificent charger, with coverings of blue
velvet embroidered in gold, and a saddle of violet velvet, to be
seated in which, was of itself a luxury. Much dancing at court
followed; and finally, the “good knight” left Valladolid loaded with gifts
from the king, praises from men, and love from the ladies, who made
surrender of more hearts than he had time to accept.
In Navarre and in Aragon he challenged all comers, but in vain.
Swords slept in scabbards, and battle-axes hung quietly from
saddle-bows, and there was more feasting than fighting. At length
Jacques, after passing through Perpignan and Narbonne, arrived at
Montpelier, where he became the guest of the famous Jacques
Cœur, the silversmith and banker of Charles VII. Old Cœur was a
hearty old host, for he offered the knight any amount of money he
would honor him by accepting; and he intimated that if De Lelaing, in
the course of his travels had found it necessary to pawn any of his
plate or jewelry, he (Jacques Cœur) would redeem it free of
expense. “My good master, the Duke of Burgundy,” replied the errant
chevalier, “provides all that is necessary for me, and allows me to
want for nothing;” and thereupon he went on his way to the court of
Burgundy, where he was received with more honor than if he had
been executing a mission for the especial benefit of humanity.
But these honors were little, compared with the rejoicings which took
place when the “good knight” revisited his native château, and the
parents who therein resided. His sire hugged him till his armor was
warm again; and his lady mother walked about the halls in a state of
ecstacy and thanksgiving. Finally, the rafters shook at the efforts of
the joyous dancers, and many a judicious matron instructed her
daughter how Jacques, who subdued the stoutest knights, might be
himself subdued by the very gentlest of ladies. The instruction was
given in vain. The good chevalier made love alike to young widows,
wives, and daughters, and having broken more hearts than he ever
broke lances, he suddenly left home in search of new adventures.
Great was the astonishment, and that altogether of a pleasurable
sort, when the herald Charolais appeared at the Scottish court in
July, 1449, and delivered a challenge from Jacques to the whole of
the Douglases. It was accepted in their name by James Douglas, the
brother of the lieutenant-general of the kingdom; and in December of
the year last named, Jacques, with a retinue of fighting uncles,
cousins, and friends, embarked at Ecluse and set sail for Caledonia.
The party were more battered about by the sea than ever they had
been by enemy on land; and when they arrived at Leith, they looked
so “shaky,” were so pale and haggard, and had so little of a
“slashing” look, wrapped up as they were in surcoats and comforters,
that the Scottish cavaliers, observing the draggled condition of the
strangers and of the plumes which seemed to be moulting from their
helmets, fairly asked them what motive induced them to come so far
in so sorry a plight, for the mere sake of getting bruised by knights
ashore after having been tossed about, sick and sorry, during whole
nights at sea. When the northern cavaliers heard that honor and not
profit had moved the Belgian company, they marvelled much thereat,
but prepared themselves, nevertheless, to meet the new-comers in
dread encounter at Stirling.
James II. presided at the bloody fray, in which three fought against
three. What the Scottish chroniclers say of the struggle, I can not
learn, but the Belgian historians describe their champions as having
been eminently victorious with every arm; and, according to them,
the Douglases were not only soundly drubbed, but took their beating
with considerable sulkiness. But there is much poetry in Belgian
history, and probably the doughty Douglas party may not have been
so thoroughly worsted as the pleasant chroniclers in question
describe them to have been. No doubt the conquerors behaved well,
as we know “les braves Belges” have never failed to do, if history
may be credited. However this may be, Jacques and his friends
hurried from Scotland, appeared at London before the meek
Lancastrian king, Henry VI.; and as the latter would not license his
knights to meet the Burgundians in the lists, the foreign fighting
gentlemen had their passports visé, and taking passage in the fast
sailer “Flower of Hainault,” duly arrived at home, where they were
hailed with enthusiasm.
Jacques had short space wherein to breathe. An English knight,
named Thomas Karr, speedily appeared at the court of Philip the
Duke, and challenged De Lelaing, for the honor of old England. This
affair caused a great sensation, and the lists were dressed in a field
near Bruges. The English knight was the heavier man in flesh and
armor, but Jacques, of course, was the favorite. Dire was the conflict.
The adversaries strove to fell each other with their axes, as butchers
do oxen. Karr paralyzed, if he did not break, the arm of Jacques; but
the Belgian, dropping his axe, closed with his foe, and after a
struggle, fell with and upon him. Karr was required, as a defeated
man, to carry the gauntlet of the victor to the lady pointed out by him.
But obstinate Tom Karr protested against this, as he had only fallen
on his elbow. The umpires declared that he had had a full fall, “head,
belly, arms, and legs;” Jacques, however, was generous and would
not insist. On the contrary, adverting to the fact that he had himself
been the first to drop his own axe, he presented Karr with a rich
diamond, as the forfeit due by him who first lost a weapon in the
combat.
Karr had terribly wounded Jacques, and the wound of the latter took
long to cure. The Duke Philip hastened his convalescence by
naming him counsellor and chamberlain; and as soon as the man so
honored by his master, had recovered from his wounds, he repaired
to Chalons on Saone, where he opened a “tourney,” which was
talked of in the country for many a long year afterward. Jacques had
vowed that he would appear in the closed lists thirty times before he
had attained his thirtieth year; and this tourney at Chalons was held
by him against all comers, in order the better to enable him to fulfil
his vow. The detail would be tedious; suffice it to say that the affair
was of barbarian magnificence, and that knights smashed one
another’s limbs, for personal honor, ladies’ love, and the glory of Our
Lady in Tears! Rich prizes were awarded to the victors, as rich
forfeits were exacted from the vanquished, and there was not only a
sea of good blood spilt in this splendidly atrocious fray, but as much
bad blood made as there was good blood shed. But then there was
empty honor acquired, a frail sort of affection gained, and an
impalpable glory added to the non-existent crown of an imaginary
Venus Victrix, decorated with the name of Our Lady of Tears! What
more could true knights desire? Chivalry was satisfied; and
commonplace men, with only common sense to direct them, had to
look on in admiring silence, at risk of being cudgelled if they dared to
speak out.
Jacques was now at the height of his renown. He was “the good
knight without fear and without doubt;” and Duke Philip placed the
last rose in his chaplet of honor, by creating him a knight of the
illustrious order of the Golden Fleece. Thus distinguished, he rode
about Europe, inviting adversaries to measure swords with him, and
meeting with none willing to accept the invitation. In 1451 he was the
embassador of Burgundy at Rome, charged to negotiate a project of
crusade against the Turks. M. Alexander Henne, the author of the
best compendium, gathered from the chronicles, of the deeds of
Jacques de Lelaing—says that after the knight’s mission to Rome,
he appeared at a passage of arms held in the park at Brussels, in
honor of the Duke of Burgundy’s son, the Count of Charolais, then
eighteen years of age, and about to mate his first appearance in the
lists. The Duchess, tender of her son as the Dowager Czarina who
kept her boys at home, and had not a tear for other mothers, whose
children have been bloodily sacrificed to the savage ambition of
Nicholas—the Duchess careful of the young Count, was desirous
that he should make essay before he appeared in the lists. Jacques
de Lelaing was accordingly selected to run a lance with him. “Three
days before the fete, the Duke, the Duchess, and the Court repaired
to the park of Brussels, where the trial was to be made. In the first
onset, the Count de Charolais shattered his lance against the shield
of Jacques, who raised his own weapon, and passed without
touching his adversary. The Duke perceived that the good knight had
spared his young adversary; he was displeased thereat, and sent
Jacques word that if he intended to continue the same course, he
would do well to meddle no further in the matter. Other lances were
then brought, and Jacques, running straight against the Count, both
lances flew into splinters. At this incident, the Duchess, in her turn,
gave expression to her discontent; but the Duke only laughed; and
thus mother and father were of different opinions; the one desiring a
fair trial, the other security for her son.” On the day of the great
tourney, there were assembled, with the multitude, on the great
square at Brussels, not less than two hundred and twenty-five
princes, barons, knights, and squires. Some of the noblest of these
broke a lance with, and perhaps the limbs of, their adversaries. The
Count de Charolais broke eighteen lances on that day, and he
carried off the the prize, which was conferred upon him by the ladies.
This was the last of the show-fights in which Jacques de Lelaing
exhibited himself. The bloodier conflicts in which he was
subsequently engaged, were far less to his credit. They formed a
part of the savage war which the despotic Duke and the nobles
carried on against the free and opulent cities, whose spirit of liberty
was an object of hatred, and whose wealth was an object of
covetous desire, to the Duke and his body of gentleman-like
assassins. Many a fair town was devastated by the Duke and his
followers, who affected to be inspired by religious feelings, a desire
for peace, and a disinclination to make conquests. Whereby it may
be seen that the late Czar was only a Burgundian duke enlarged,
impelled by much the same principle, and addicted to a similar sort
of veracity. It was a time of unmitigated horrors, when crimes enough
were committed by the nobles to render the name of aristocracy for
ever execrable throughout Belgium; and atrocities were practised by
the enraged commons, sufficient to insure, for the plebeians, the
undying hatred of their patrician oppressors. There was no respect
on either side for age, sex, or condition. The people, of every
degree, were transformed into the worst of fiends—slaying, burning,
violating, and plundering; and turning from their accursed work to
kneel at the shrine of that Mary whose blessed Son was the Prince
of Peace. Each side slaughtered, hung, or drowned its prisoners; but
the nobles gave the provocation by first setting the example, and the
commons were not cruel till the nobility showed itself alike destitute
of honor and of mercy. The arms of the popular party were nerved by
the infamy of their adversaries, but many an innocent man on either
side was condemned to suffer, undeservedly, for the sins of others.
The greatest efforts were made against the people of the district and
city of Ghent, but all Flanders sympathized with them in a war which
was considered national. In the struggle, the Duke won no victory
over the people for which the latter did not compel him to pay a
frightful price; he was heartily sick of the war before it was half
concluded—even when his banner was being most successfully
upheld by the strong arm and slender scruples of Jacques de
Lelaing.
The good knight was however, it must be confessed, among the few
—if he were not the only one—of the betterminded nobles. He had
been commissioned by the Duke to set fire to the Abbey of
Eenaeme, and he obeyed without hesitation, and yet with reluctance.
He destroyed the religious edifice with all which it contained, and
which could be made to burn; but having thus performed his duty as
a soldier, he forthwith accomplished his equally bounden duty, as a
Christian—and, after paying for three masses, at which he devoutly
assisted, he confessed himself to a predicant friar, “making a case of
conscience,” says one of his biographers, “of having, out of respect
for discipline, committed an act which the uprightness of his heart
compelled him to condemn as criminal.” Never was there a better
illustration of that so-called diverse condition of things which is said
to represent a distinction without a difference.
The repentance of Jacques de Lelaing came, it is hoped, in time. He
did well, at all events, not to defer it any longer, for he was soon on
the threshold of that world where faith ceases and belief begins. He
was engaged, although badly wounded, in inspecting the siege-
works in the front of the Chateau de Pouckes, that Flemish cradle of
the Pooks settled in England. It was on a June afternoon of the year
1453, that Jacques, with a crowd of nobles half-encircling him, rode
out, in spite of the protest of his doctors (because, as he said, if he
were to remain doing nothing he should certainly die), in order that
he might have something to do. There was a famous piece of
artillery on the Burgundian side, which was sorely troublesome to the
stout little band that was defending Pouckes. It was called the
“Shepherdess,” but never did shepherdess speak with so
thundering-unlovely a voice, or fling her favors about her with such
dire destruction to those upon whom they were showered. Jacques
drew up behind the manteau of this cannon, to watch (like our gallant
seamen at Sebastopol) the effects of the shot discharged from it. At
the same moment a stone projectile, discharged from a culverin by
the hand of a young artilleryman of Ghent, who was known as the
son of Henry the Blindman, struck Jacques on the forehead, carrying
away the upper part of his head, and stretched him dead upon the
field. A Carmelite brother rushed up to him to offer the succor and
consolation of religion, but it was too late. Jacques had sighed out
his last breath, and the friar decently folded the dead warrior’s arms
over his breast. A mournful troop carried the body back to the camp.
The hero of his day died in harness. He had virtues that fitted him for
a more refined, a more honest, in short, a more Christian, period.
These he exercised whenever he could find opportunity, but such
opportunity was rare. He lived at a period when, as M. de Sismondi
has remarked, “Knights thought of nothing but equalling the Rolands
and Olivers of the days of Charlemagne, by the destruction of the
vile canaille”—a sort of pastime which has been recently
recommended in our senate, although the days of chivalry be gone.
The noble comrades of Jacques, as M. Henne observes,
acknowledged but one species of supreme pleasure and glory, which
consisted in making flow abundantly the blood of villains—or, as they
are now called, the lower orders. But in truth the modern “villain” or
the low-class man is not exclusively to be found in the ranks which
have had such names applied to them. As Bosquier-Gavaudan used
so joyously to sing, some thirty years ago, in the Ermite de St.
Avelle:—
“Les gens de bien

Sont souvent des gens de rien;
Et les gens de rien
Sont souvent des gens de bien!”
For a knight, Jacques was really a respectable man, and so

disgusted with his butcher-like occupation, that, just before his death,
he had resolved to surrender his estate to a younger brother, and,
since fate had made of him a licensed murderer, to henceforth
murder none but eastern infidels—to slay whom was held to be more
of a virtue than a sin. Let us add of him, that he was too honest to
earn a reputation by being compassionate to half-a-dozen helpless
foes, after directing his men to slaughter a score of the mutilated and
defenceless enemy. Jacques de Lelaing would sooner have sent his
dagger up to the hilt in his own heart, than have violated the
safeguard of a flag of truce. Such days and such doings of chivalry
are not those most agreeable to Russian chivalry. Witness Odessa,
where the pious governor directed the fire on a flag of truce which he
swore he could not see; and witness the massacre of Hango, the
assassins concerned in which exploit were defended by their worthy
superior De Berg.
Jacques de Lelaing, however, it must not be forgotten, fell in a most
unworthy cause—that of a despot armed against free people. His
excellent master swore to avenge him; and he kept his word. When
the Château de Pouckes was compelled to surrender, Philip the
Good ordered every one found alive in it to be hung from the walls.
He made exception only of a priest or two, one soldier afflicted with
what was called leprosy, but which has now another name in the
catalogue of avenging maladies, and a couple of boys. It was
precisely one of these lads who had, by his well-laid shot, slain “the
good knight without fear and without doubt;” but Philip was not aware
of this till the lad was far beyond his reach, and in safety at Ghent.
Those who may be curious to know the course taken by the war until
it was terminated by the treaty of Lille, are recommended to study
the Chronicles of De Lettenhooe, of Olivier de la Marche, of
Chastellain, and Du Clery. I had no intention, at setting out, to paint a
battle-piece, but simply to sketch a single figure. My task is done,
however imperfectly, and, as old chroniclers were wont to say, May
Heaven bless the gentle reader, and send pistoles and abounding
grace to the unworthy author.
Such is the history of an individual; let us now trace the fortunes of a
knightly house. The story of the Guises belongs entirely to chivalry
and statesmanship.
THE FORTUNES OF A KNIGHTLY FAMILY.
“This deals with nobler knights and monarchs,
Full of great fears, great hopes, great enterprises.”
Antony Brewer, “Lingua.”
In the pleasant spring-time of the year 1506, a little boy, mounted on

a mule, and accompanied by a serving man on foot, crossed over
the frontier from Lorraine into France. The boy was a pretty child,
some ten years old. He was soberly clad, but a merry heart beat
under his gray jerkin; and his spirits were as light as the feather in
his bonnet. The servant who walked at his side was a simple yet
faithful follower of his house; but there was no more speculation in
his face than there was in that of the mule. Nothing could have
looked more harmless and innocent than the trio in question; and yet
the whole—joyous child, plodding servitor, and the mule whose bells
rang music as he trod—formed one of the most remarkable
invasions of which the kingdom of France has ever been the victim.
The boy was the fifth child of René and Philippa de Gueldres, the
ducal sovereigns of Lorraine. This duchy, a portion of the old
kingdom of Lotharingia—in disputes for the possession of which the
children of Charlemagne had shed rivers of blood—had maintained
its independence, despite the repeated attempts of Germany and
France to reduce it to subjection. At the opening of the sixteenth
century, it had seen a legal succession of sovereign and
independent masters during seven centuries. The reigning duke was
René, the second of that name. He had acquired estates in France,
and he had inherited the hatred of Lorraine to the Capetian race
which had dethroned the heirs of Charlemagne. It was for this double
reason that he unostentatiously sent into the kingdom of France one
of his sons, a boy of fair promise. The mission of the yet
unconscious child was to increase the territorial possessions of his
family within the French dominions, and ultimately to rule both
Church and State—if not from the throne, why then from behind it.
The merry boy proved himself in course of time to be no unfitting
instrument for this especial purpose. He was brought up at the
French court, studied chivalry, and practised passages of arms with
French knights; was the first up at réveillée, the last at a feast, the
most devout at mass, and the most winning in ladies’ bower. The
princes of the blood loved him, and so did the princesses. The army
hailed him with delight; and the church beheld in him and his brother,
Cardinal John, two of those champions whom it records with
gladness, and canonizes with alacrity.
Such was Claude of Lorraine, who won the heart and lands of
Antoinette de Bourbon, and who received from Francis I. not only
letters of naturalization, but the title of Duke of Guise. The locality so
named is in Picardy. It had fallen to the house of Lorraine by
marriage, and the dignity of Count which accompanied it was now
changed for that of Duke. It was not long before Claude made the
title famous. The sword of Guise was never from his grasp, and its
point was unceasingly directed against the enemies of his new
country. He shed his own blood, and spilled that of others, with a
ferocious joy. Francis saw in him the warmest of his friends and the
bravest of his soldiers. His bravery helped to the glory that was
reaped at Marignan, at Fontarabia, and in Picardy. Against internal
revolt or foreign invasion he was equally irresistible. His sword drove
back the Imperialists of Germany within their own frontier; and when
on the night of Pavia the warriors of France sat weeping like girls
amid the wide ruin around them, his heart alone throbbed with
hopeful impulses, and his mind only was filled with bright visions of
victories to come.
These came indeed, but they were sometimes triumphs that earned
for him an immortality of infamy. The crest of his house was a double
cross, and this device, though it was no emblem of the intensity of
religion felt by these who bore it, was significant of the double
sanguinary zeal of the family—a zeal employed solely for selfish
ends. The apostolic reformers of France were, at this period, in a
position of some power. Their preachers were in the pulpit, and their
people in the field. They heard the gospel leaning on their swords;

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Multifunctional And Targeted

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

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