Ndds SK Project
Ndds SK Project
Ndds SK Project
Submitted to
RAJIV GANDHI PROUDYOGIKI VISHWAVIDHALAYA, BHOPAL
In Partial Fulfillment of the Requirement for the Degree of
BACHELOR OF PHARMACY
2021-2022
CERTIFICATE
He has collected the literature very sincerely and methodically and his work his authentic.
PROJECT INCHARGE
Mrs. ABHILASHA DELOURI
ASSO. PROFESSOR
VIVEKANAND COLLEGE OF PHARMACY
VIP CAMPUS, RATIBAD, SIKANDARABAD BHOPAL, 462044
FORWARDING LETTER
Mr. SHAHNAWAZ KHAN has completed his project work entitled “TUMOR SPECIFIC DRUG
DELIVERY: NOVEL APPROCHES” Under the Supervision and Guidence of Prof. Mrs .Sadhna
mangrole fulfillment for the degree of Bachelor of Pharmacy.
DECLARATION
This is to certify that the dissertation word entitled “TUMOR SPECIFIC DRUG DELIVERY :
NOVEL APPROCHES" for the award of carried by our laboratories and library under the
guidance and supervision of DR. VIVEKANAND KATARE.
It also declare that present work embody has not the basic award for any degree or fellowship
previously. The particular given in this project is true to be best knowledge.
STUDENT
SHAHNAWAZ KHAN
INDEX
ABSTRACT…………………………………………………………………………..…07
INTRODUCTION………………………………………………………………….…08
NOVEL DRUG DELIVERY SHYSTEM……………………………………..…10
TUMOR…………………………………………………………………………..……..12
TARGETED DRUG DELIVERY………………………………………………...16
TUMOR TARGETED THERAPY…………………………………………..….19
TUMOR TARGETING DRUG DELIVERY SYSTEM………………….....21
APPROCHES TO TARGETING TUMOR
PASSIVE TARGETING…………………………………………………………………..23
ACTIVE TARGETING……………………………………………………………………25
INVERSE TARGETING………………………………………………………………….26
PHYSICAL TARGETING,LIGAND MEDIATED TARGETING…………….27
DUAL TARGETING, Double Targeting…………………………………………28
TARGETED DRUG DELIVERY CARRIERS…………………………..29
Liposomes………………………………………………………………………………….31
Dendrimers………………………………………………………………………………..34
Hydrogels…………………………………………………………………………………..37
Lipid-polymer hybrid nanoparticles (LPNs)………………………………38
Polymer-drug conjugates…………………………………………………………..39
Magnetic nanoparticles (MNP)…………………………………………………..40
Quantum dots (QDs)…………………………………………………………………..41
Lipid-based ……………………………………………………………………………….42
Inorganic Nanoparticles…………………………………………………………….43
Nucleic Acid/ Peptide based………………………………………………………44
Transdermal approach in drug Transportation………………………...46
Folate Targeting………………………………………………………………………...47
INTRACELLULAR TARGETING
Targeting the cytomembrane…………………………………………………….48
Lysosomal targeting…………………………………………………………………..49
Targeting the endoplasmic reticulum………………………………………..50
Targeting the mitochondria……………………………………………………….51
Targeting the cell nucleus………………………………………………………….53
Targeting the tumor microenvironment……………………………………54
Keywords: Cancer; Cell Penetrating Peptides; Chemotherapeutics; Efflux Pumps; Gene therapy;
Immunotherapy; Stem cells; Targeted Drug Delivery; Tumor.
TUMOUR SPECIFIC DRUG DELIVERY SYSTEM
INTRODUCTION
9|Page
The cancer genome atlas (TCGA) was founded to explore opportunities that
may provide a holistic approach for classification. TCGA researchers hypothesized a
multiplatform analysis of 12 cancer types, unravelling similarity of tumors based on
genetics and molecular biology.
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Novel drug delivery systems is the new system Recent advances in the
understanding of pharmacokinetic & pharmacodynamic behaviour of drug have offer a more
rational approach to the development of optimal drug delivery system. the novel drug delivery
systems (NDDS) are carriers which maintain the drug concentration in therapeutic range for
longer period of time There are several advantages of novel drug delivery systems over
conventional drug delivery.
Various drug delivery systems have been developed and some of them under
development with an aim to minimize drug degradation or loss, to prevent harmful side effects
and to improve drug bioavailability and also to favour and facilitate the accumulation of the drug
in the required bio- zone (site). There are no. Of novel carries which have been established and
documented to be useful for controlled and targeted drug delivery. It is important to critically
evaluate different terms used under the different broad categories of novel drug delivery system.
Sustained- or controlled- drug delivery systems provide drug action at a pre determined rate
by providing a prolonged or constant (Zero-order) release respectively, at the therapeutically
effective levels in the circulation.
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Localized drug delivery devices provide drug action through spatial or temporal control of
drug release (usually rate- limiting) in the vicinity of the target.
Rate- pre-programmed drug delivery systems provide drug action by manipulating the
release of drug molecules by system design which control the molecular diffusion of drug
molecules.
Targeted drug delivery provides drug action by using carries either for passive or active
targeting or one base or self programmed approach, usually anchored with suitable sensory
devices, which recognize their receptor at the target.
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TUMOR
A tumor is an abnormal lump or growth of cells. When the cells in the tumor are
normal, it is benign. Something just went wrong, and they overgrew and produced a lump.
When the cells are abnormal and can grow uncontrollably, they are cancerous cells, and
the tumor is malignant.
If you have been diagnosed with a tumor, the first step your healthcare provider
will take is to find out whether it is malignant or benign, as this will affect your treatment
plan. In short, the meaning of malignant is cancerous and the meaning of benign is
noncancerous. Learn more about how either diagnosis affects your health.
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If the cells are not cancerous, the tumor is benign. It won't invade nearby tissues or spread
to other areas of the body (metastasize). A benign tumor is less worrisome unless it is
pressing on nearby tissues, nerves, or blood vessels and causing damage.
Benign tumors may need to be removed by surgery.1 They can grow very large, sometimes
weighing pounds. They can be dangerous, such as when they occur in the brain and crowd
the normal structures in the enclosed space of the skull. They can press on vital organs or
block channels.
Some types of benign tumors such as intestinal polyps are considered precancerous and
are removed to prevent them from becoming malignant. Benign tumors usually don't recur
once removed, but if they do, it is usually in the same place.
Malignant means that the tumor is made of cancer cells, and it can invade nearby tissues.
Some cancer cells can move into the bloodstream or lymph nodes, where they can spread
to other tissues within the body—this is called metastasis.2 Cancer can occur anywhere in
the body including the breast, intestines, lungs, reproductive organs, blood, and skin.
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For example, breast cancer begins in the breast tissue and may spread to lymph nodes in
the armpit if it's not caught early enough and treated. Once breast cancer has spread to the
lymph nodes, the cancer cells can travel to other areas of the body, like the liver or bones.
The breast cancer cells can then form tumors in those locations. A biopsy of these tumors
might show characteristics of the original breast cancer tumor.
PATHOGENESIS :
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TUMOR TARGETING
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Targeted drug delivery system is achieved with the advantage of morphology and
physiological differences between the normal cells and tumor cells.
An ideal anticancer drug delivery system should fulfill the following requirements
Effectively kill tumor cells
Altered expression of certain growth factors like epidermal growth factor receptor
(EGFr).
associated genes(TAA).
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Hormone therapies
o Hormone therapies slow or stop the growth of hormone-sensitive tumors, which require
certain hormones to grow Hormone therapies act by preventing the body from producing
the hormones or by interfering with the action of the hormones. Hormone therapies have
been approved for both breast cancer and prostate cancer.
Apoptosis inducer
o Apoptosis inducers cause cancer cells to undergo a process of controlled cell death called
apoptosis. Apoptosis is one method the body uses to get rid of unneeded or abnormal cells,
but cancer cells have strategies to avoid apoptosis. Apoptosis inducers can get around
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Angiogenesis inhibitor
o Angiogenesis inhibitors block the growth of new blood vessels to tumors (a process called
tumor angiogenesis). A blood supply is necessary for tumors to grow beyond a certain size
because blood provides the oxygen and nutrients that rumors need for continued growth
Treatments that interfere with angiogenesis may block tumor growth Some targeted
therapies that inhibit angiogenesis interfere with the action of vascular endothelial growth
factor (VEGF), a substance that stimulates new blood vessel formation. Other angiogenesis
inhibitors target other molecules that stimulate new blood vessel growth.
Immunotherapies
o Immunotherapies trigger the immune system to destroy cancer cells. Some
immunotherapies are monoclonal antibodies that recognize specific molecules on the
surface of cancer cells. Binding of the monoclonal antibody to the target molecule results
in the immune destruction of cells that express that target molecule. Other monoclonal
antibodies bind to certain immune cells to help these cells better kill cancer cells.
MONOCLONAL ANTIBODIES
o Monoclonal antibodies that deliver toxic molecules can cause the death of cancer cells
specifically. Once the antibody has bound to its target cell, the toxic molecule that is linked
to the antibody-such as a radioactive substance or a poisonous chemical is taken up by the
cell, ultimately killing that cell. The toxin will not affect cells that lack the target for the
antibody ie, the vast majority of cells in the body.
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Targeted drug delivery system is achieved with the advantage of morphology and
physiological differences between the normal cells and tumor cells.
An ideal anticancer drug delivery system should fulfill the following requirements
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first one should recognize and bind the target, while the second should provide a
therapeutic action in this target. Currently, the concept of ‘magic bullet’ includes a
coordinated behavior of three components – drug, targeting moiety and pharmaceutical
carrier.
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PASSIVE TARGETING
This is based on the accumulation of drug at areas around the site of interest,
such as tumor tissues, in higher quantities when compared to healthy body parts . Such an
accumulation at an area of interest is called Enhanced Permeability Retention (EPR) effect.
Solid tumors have inherent abnormalities of tumor vasculature. Conventional anticancer
drugs rely on passive targeting due to the fact that comparatively higher concentration of
the drug is accumulated in cancerous cells due to faster and higher blood supply to them.
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ACTIVE TARGETING
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These receptors have high affinity to folate and hence they mediate
cellular uptake of folate. Folate receptors such as FRα are present in very low levels in
ordinary tissues but they are expressed at high levels in many cancers in order to meet the
folate demand of rapidly dividing cells under low folate conditions. This is exploited in the
administration of anti-FRα antibodies, high-affinity antifolates, folatebased imaging agents
and folate-conjugated drugs and toxins.
As such, folate can be coencapsulated with the active drug or combination
of drugs in porous nanoparticles for active targeting of the formulation to cancer cells.
Active targeting can be sub-divided into three different targeting levels; First Order, Second
Order and Third Order Targeting. In the first order targeting, the drug is distributed to
capillary beds of general target sites such as organ or tissue. In lymphatic tissues,
peritoneal cavity, pleural cavity, cerebral ventricles, eyes and joints are such targeting sites.
In the second order targeting, the targeting of drugs is aimed at specific sites such as the
tumor cells. One such example is the targeting of drugs to Kupffer cells in liver . Third order
targeting is the next type of drug targeting wherein the drug is intracellularly localized at
the target site via endocytosis or through receptor-based ligand mediated interactions.
INVERSE TARGETING
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PHYSICAL TARGETING
Ligands are carrier surface group(s) which can selectively direct the carrier to the pre-
specified site(s) housing the appropriate receptor units to serve as "homing device to the
carrier/drug.
Most of the carrier systems are colloidal in nature & can be specifically functionalized using
various biologically-relevant molecular ligands including antibodies, polypeptides,
oligosaccharides, viral proteins & fusogenic residues.
The ligands confer recognition & specificity upon drug carrier & endow them with an
ability to approach the respective target selectivity & deliver the drug.
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DUAL TARGETING
The specialty in this targeting approach is that the carrier molecule itself has
its own therapeutic activity and hence increases the therapeutic effect and the activity of
the drug. For instance, a carrier molecule with its own antibacterial or antifungal activity
can be loaded with antibacterial drug or antifungal drug and the net synergistic effect of
drug conjugate or the composite can be observed. For example, ZnO nanoparticles have
antibacterial activities and when antibacterial drugs are loaded in porous ZnO
nanoparticles both the carrier and the drug are effective against the bacteria and hence the
corresponding TDD is dual targeting.
Double Targeting
When temporal and spatial methodologies are joined to target a carrier system
then it is termed dual targeting. Here, the spatial placement targets drugs to specifically
identified organs, tissues, cells or even subcellular compartments and temporal delivery
enables controlling the rate of drug delivery to target site of interest
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Liposomes
Liposomes are the first to be discovered as drug delivery vehicles. These are
vesicles consisting of an aqueous core bounded by a hydrophobic lipid bilayer as
diagrammatically shown in Fig.
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that they have a fat metabolic action and lower toxicity apart from in vitro and in vivo anti-
cancerous activity. Once drugs are encapsulated in the core of liposomes, the drugs are not
in contact with biological fluids containing enzymes, acidity etc. Therefore, the drugs are
protected from untimely degradation. Additionally, liposomes can be coated with polymers
such as poly(ethylene glycol) (PEG) to enable the entrapped drugs to have increased half-
life. In order to intensify target-specificity, liposomes can be associated with ligands or
antibodies. Such liposomal drugs are already in the clinical use. For example, DOXIL
(Doxorubicin.HCl liposome injection) is doxorubicin hydrochloride (Fig. ), which is an
anthracycline topoisomerase II inhibitor, encapsulated in STEALTH® liposomes
(Illustrated in Fig. ) for intravenous use which was given the approval in 1995 as a remedy
for AIDS-related Kaposi’s sarcoma in patients after failing prior systemic chemotherapy or
intolerance to such therapy . The STEALTH liposome carriers are composed of cholesterol
(3.19 mg/mL), fully hydrogenated soy phosphatidylcholine (HSPC) (9.58 mg/mL) and N-
(carbonylmethoxypolyethylene glycol 2000)-1,2- distearoyl-sn-glycero-3-
phosphoethanolamine sodium salt (MPEG-DSPE) (3.19 mg/mL). Each milliliter also
contains ammonium sulphate (~ 0.6 mg), histidine as a buffer; hydrochloric acid and/or
sodium hydroxide for pH control and sucrose to maintain isotonicity. It is important to note
that greater than 90% of the drug is encapsulated in the STEALTH liposomes.
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Dendrimers
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Dendrimers can be used as TDD vehicles to carry different drugs. The drugs
may either be encapsulated in the core via hydrogen bonding, hydrophobic interactions,
and chemical bonding or else via covalent bonding on the terminal groups. Bioactive
molecules such as DNA can be carried using electrostatic interactions. The use of
dendrimers for delivering photosensitizers in photodynamic therapy of cancer treatment
was reported by Zhang et al.
Recently, Generation 3 (G3) PAMAM-implanted porous hollow silica
nanoparticles (PHSNPs) have been developed for carrying photosensitizers for
photodynamic therapy .Poly(amidoamine) (PAMAM) dendrimes are particularly used for
delivering low molecular weight anti-cancer drugs, such as, methotrexate, cisplatin,
doxorubicin, 5-FU, and anti-inflammatory drugs including ibuprofen, piroxicam,
indomethacin (The structural formulae of these drugs are given in Figs.
The potential of these dendrimers can be intensified by attaching targeting
ligands to their multivalent surface. As an example, PANAM dendrimer conjugated with
folic acid and methotrexate drug was shown to selectively bind and kill KB tumor cells that
overexpress folate receptor (FR) in vitro and in vivo. Surface charge of the dendrimers also
have profound effect on drug interactions. For example, positively charged surface of (G4-
PAMAM-NH2) and neutral surface (G4 PAMAM-OH), were found to be able to inhibit
enzymatic activity of pepsin which has negatively charged surface while negatively
charged dendrimer (G3.5 PAMAMCOOH) was not able to inhibit the enzymatic activity of
pepsin. This indicates important role played by electrostatic interactions between
dendrimers and the proteins.
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Hydrogels
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Polymer-drug conjugates
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Figure 9: ZnCdSeS alloyed Quantum dots with vivid colours stretching from violet to deep
red.
Lipid-based
Liposomes are commonly used for targeting water insoluble drugs, enabling
them to be used as targeted delivery systems particularly for such drugs. For example, the
biocompatibility and possible diversity with structures and compositions make them
suitable for a number of TDD applications. There are several types of liposomes that are
used in the biomedical field. These include conventional liposomes, stimuli-responsive
liposomes, stealth liposomes, targeted liposomes, and polymer composite liposomes.
Liposome-based drug delivery systems enable passive/active targeting and easy and rapid
internalization. They also have low immunogenicity. Another important advantages are
high bioavailability and high biocompatibility. But there are some drawbacks as well. Rapid
degradation of liposomes in the cell system (uptake by RES (reticuloendothelial system),
poor scale-up ability, need for extensive modifications of liposomes for different tasks, are
some of those drawbacks.
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Targeted liposomes and environment- sensitive liposomes are the ones with
maximum potential for targeting to cancers and treating neurodegenerative disorders.
Several of such prevailing chemotherapeutics have been entrapped in stimuli-responsive
liposomes for successful drug targeting.
Inorganic Nanoparticles
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Carbon nanotubes and nanoparticles and different types of nanoconjugates have been
studied as drug delivery carriers. As their size confines to the nanometer range, they can
move effortlessly inside the body. Drugs can be either introduced into the nanotube or
attached externally or internally on to the particle surface. These nanomaterials include
silica, metal nanoparticles, metal hydroxides, carbon and so on. A number of
multifunctional, inorganic nanoparticles are being developed for TDD and imaging
applications. Carbon-based nanoparticles and gold-based (AuNPs) nanoparticles are very
much common in TDD. They have inherent optical properties enabling them in imaging
applications. Silica/Alumina/ZnO nanoparticles, quantum dots, metal/oxide/sulfide-based
nanoparticles are some such examples. Drawbacks are mainly the issues with regard to
toxicity and non-biodegradability leading to accumulation of chemicals in the body.
Inorganic nanoparticles with multiple functionalities can be developed which will prompt
further research for development of effective cellular delivery systems. Gold-based colloids
and nanoshells are currently used in clinical trials for cancer applications.
Peptides are short chains of amino acid monomers (lesser than 50 amino acids) connected
by peptide (amide) bonds. The covalent chemical bonds are formed from the reaction of
carboxyl group of one amino acid with the amino group of another. Dipeptides are the
shortest, consisting of 2 amino acids joined by a single peptide bond. Tripeptides,
tetrapeptides can be synthesized by the linkage of respective amounts of amino acids
reacting with each other. A polypeptide is a long, continuous, and unbranched peptide
chain. With the development and the popularization of recombinant proteins and effective
protein purification methods, exquisite potency of the peptide based drug delivery systems
has been realized. A new protein-based drug classification was introduced.
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Transdermal drug delivery systems, such as the use of patches, ointments and
creams, have been around for several years. These systems enhance the skin permeation
of low molecular weight usually < 500 Da, lipophilic drugs that are effective at low doses.
However, improvements to this approach is required for hydrophilic molecules and
macromolecules. In order to make the transdermal drug delivery methodology suitable for
large, hydrophilic molecules and macromolecules, nano-carriers made of lipids, metals, or
polymers have been successfully used. Nanocarriers increase penetration of drugs or
vaccines. In this way, it is possible to achieve controlled drug release and also to target
drugs to specific areas of skin in vivo. A transdermal drug delivery carrier can be of a
passive design or an active design.
It provides an alternative pathway for administering drug to specific site
where the drug is delivered across the skin barrier. The passive approach relies on the
optimization of formulation or drug carrying vehicle to increase skin permeability.
However, passive methods are not very suitable for large drug molecules of over 500 Da
molecular weights. Active methods rely on physical or mechanical methods of enhancing
drug delivery and hence active methods have been shown to be much superior to passive
methods. Active methods have been used for the delivery of drugs of differing lipophilicity
and molecular weight.
These include proteins, peptides, and oligonucleotides. Electrical methods such
as iontophoresis, electroporation, mechanical methods such as abrasion, ablation,
perforation, and other energy-related techniques such as ultrasound and needless
injection have been successfully used in active transdermal drug delivery. Transdermal
delivery id associated with significant advantages compared with the oral pathway.
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Folate Targeting
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INTRACELLULAR TARGETING
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Lysosomal targeting
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The cell nucleus is the control centre of a cell and plays an important role
in cell metabolism, growth and differentiation. It is also the main storage site of genetic
materials. More importantly, the action sites of most therapeutic anticancer drugs, such as
DNA intercalators and topoisomerase inhibitors, are in the nucleus.
Thus, directly targeting drug delivery to the nucleus can effectively increase
the therapeutic effect due to the bypassing of drug efflux pumps, which makes nuclei-
targeting an important delivery strategy for tumor therapy. From a structural perspective,
the nuclear membrane is constituted by two layers of membrane and decorated by nuclear
pore complex (NPC) on the membrane surface.48 Nanoparticles witha diameter
oflessthan9 nm could gain entry nuclear area via NPC.49 However, such small
nanoparticles would be easily removed from blood circulation before they could even
reach the tumor site. Large nanoparticles can be delivered to the nucleus through NPC
facilitated by the nuclear localization signal (NLS). The NLS is a signal sequence located in
the C-terminal of nucleo plasmins. It usually contains 4–8 amino acids and is positively
charged. NLS complexes with NPC and forms a hydrophilic channel on the nuclear
membrane.
Subsequently, the cargo that previously bound to NLS can enter the nuclear
area in an energy-dependent manner.51 In addition, there are adequate amounts of
glucocorticoid receptors on the nucleus;52 therefore, small molecular glucocorticoids such
as dexamethasone,53 triamcinolone acetonide,54 betamethasone,55 etc. could be used as
nucleus-targeting molecules. More interestingly, when the nanoparticles are transported
to the nucleus mediated by glucocorticoid, the NPC channel could be expanded up to 60
nm, so that the nanoparticles may enter the nucleus more easily.
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DOXORUBICIN :
Doxorubicin is a cytotoxic anthracycline antibiotic isolated from
cultures of Streptomyces peucetius var. caesius. Doxorubicin binds to nucleic acids,
presumably by specific intercalation of the planar anthracycline nucleus with the DNA
double helix.
Mechanisms of action:
Doxorubicin forms complexes with DNA by intercalation between base pairs.
It inhibits topoisomerase II activity by stabilizing the DNA-topoisomerase II complex.
It preventing the religation portion of the ligation-religation reaction that
topoisomerase II catalyzes.
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Cellular uptake :
Briefly, BEL-7402 cells were seeded into 96-well plates at the density of
104 cells per well and allowed to grow overnight and subsequently incubated with
different concentrations of MWCNTs/DOX/TC or free DOX for 4h and 12h, the cells were
then washed three times with PBS and fixed with immune staining fix solution for 20min
at room temperature, followed by the labeling of the intracellular microfilament with actin-
tracker green and subsequent staining of the nucleus with DAPI (Beyotime Institute of
Biotechnology, Shanghai, China). The cellular uptake of MWCNTs/TC/DOX or DOX was
analyzed with the GE IN Cell Analyzer 2000 High-Content Cellular Analysis System
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33% and 50% for mass ratio of 1/2, 1/1 and 3/1, respectively), whereas the loading
efficiency demonstrated the opposite trend (about 63%, 50% and 35% for mass ratio of
1/2, 1/1 and 3/1, respectively). As shown in Figure 2, that the DOX release rate was
increased with increasing DOX/MWCNTs ratio in PBS at pH of both 7.4 and 5.5. It was also
found that DOX
was released at a significantly lower rate at pH 7.4 from MWCNTs/DOX/TC than that at pH
5.5, which is beneficial for intracellular drug delivery and release. Coating of MWCNT/DOX
with TC significantly slowed the release efficiency of DOX from MWCNTs/DOX/TC by
comparing with MWCNTs/DOX at each condition.
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Balb/c nude mice (6 weeks, male) were purchased from Peking Union
Medical College. All animal procedures were conducted following the protocol approved
by the Institutional Laboratory Animal Ethics Committee, and all animal experiments were
performed in compliance with the Guiding Principles for the Care and Use of Laboratory
Animals, Peking Union Medical College. Luciferaseexpressing Bel-7402 cells (1106) in
0.1mL normal saline (NS) were injected into the armpit region of Balb/ c nude mice. When
the volume of tumors reached to 100mm3, the mice were divided into different treatment
groups (6 mice/group) and free DOX or MWCNTs/DOX/ TC at the dose of 10mg/kg,
20mg/kg or 30mg/kg DOX were injected into the center of tumor with NS-treated mice as
the negative control. Fluorescence imaging was conducted to monitor the drug release
process using an live animal imaging system (IVIS Lumina system, Xenogen, Alameda, CA)
until the fluorescence signal disappeared, with excitation wavelength being set at 532nm.
To investigate the antitumor effect, luminescence imaging was conducted 5min after
intraperitoneal injection of 200mL luciferin (15mg/mL) using the IVIS Lumina imaging
system for a period of 25 days.
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Similarly, at the concentration of 20 lg/mL, 50% fluorescent signal remained in the tumors
in MWCNTs/DOX/ TC group versus a 35% remanence in the free DOX group on the first
day. The fluorescence signals in the free DOX group disappeared completely 4 days after
injection, while around 20% of the fluorescence intensity still remains at day 4 in the
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ADVANTAGES DISADVANTAGES
Reduced toxicity. o Rapid clearance of targeted system.
Cancer cells can become resistant to them. Resistance can occur in two ways
The target itself changes through mutation so that the targeted therapy no longer
interacts well with it.
The tumor finds a new pathway toachieve tumor growth that does notdepend on
the target.
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CONCLUSION
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REFERENCES
[1] Lees, P.; Cunningham, F.; Elliott, J. Principles of pharmacodynamics and their
applications in veterinary pharmacology. J. Vet. Pharmacol. Ther., 2004, 27, 397-414.
[2] Moolenaar, F.; Bakker, S.; Visser, J.; Huizinga, T. Biopharmaceutics of rectal
administration of drugs in man IX. Comparative biopharmaceutics of Diazepam after single
rectal, oral, intramuscular and intravenous administration in man. Int. J. Pharm., 1980, 5,
127-137.
[3] Cheng, Y.; Xu, Z.; Ma, M.; Xu, T. Dendrimers as drug carriers: Applications in different
routes of drug administration. J. Pharm. Sci., 2008, 97, 123-143.
[4] Berlin, C.M.; May-McCarver, D.G.; Notterman, D.A.; Ward, R.M.; Weismann, D.N.; Wilson,
G.S.; Cote, C.J. Alternative routes of drug administration - Advantages and disadvantages
(subject review). Pediatrics, 1997, 100, 143-152.
[5] Redding, J.S.; Asunlcion, J.S.; Pearson, J.W. Effective routes of drug administration during
cardiac arrest. Anesth. Analg., 1967, 46, 253-258.
[6] Prausnitz, M.; Langer, R. Transdermal drug delivery. Nat. Biotechnol., 2018, 26, 1261-
1268.
[7] Gibaldi, M.; Boyes, R.; Feldman, S. Influence of first-pass effect on availability of drugs
on oral administration. J. Pharm. Sci., 1971, 60, 1338-1340.
[8] Hoffken, G.; Lode, H.; Prinzing, C.; Borner, K.; Koeppe, P. Pharmacokinetics of
ciprofloxacin after oral and parenteral administration. Antimicrob. Agents Chemother.,
2018, 27, 375-379.
[9] Orlowski, J. Comparison study of intraosseous, central intravenous, and peripheral
intravenous infusions of emergency drugs. Am. J. Dis. Child, 1990, 144(1), 112-117.
[10] Hughes, M.; Glass, P.; Jacobs, J. Context-sensitive half-time in multicompartment
pharmacokinetic models for intravenous anesthetic drugs. Anesthesiology, 1992, 76, 334-
341.
67 | P a g e
[11] Bruera, E.; Brenneis, C.; Michaud, M.; Bacovsky, R.; Chadwick, S.; Emeno, A.; Macdonald,
N. Use of the subcutaneous route for the administration of narcotics in patients with cancer
pain. Cancer, 1988, 62(02), 407-411.
[12] de Boer, A.; Moolenaar, F.; de Leede, L.; Breimer, D. Rectal drug administration: clinical
pharmacokinetic considerations. Clin. Pharmacokinet., 1982, 7(4), 285-311.
[13] Thrimawithana, T.; Young, S.; Bunt, C.; Green, C.; Alany, R. Drug delivery to the
posterior segment of the eye. Drug Discov. Today, 2011, 16(5-6), 270-277.
[14] Türker, S.; Onur, E.; Ózer, Y. Nasal route and drug delivery systems. Pharm. World Sci.,
2014, 26, 137.
[15] Illum, L. Nasal drug delivery—possibilities, problems and solutions. J. Control.
Release, 2003, 87(1-3), 187-198.
[16] Illum, L. Nasal drug delivery: new developments and strategies. Drug Discov. Today,
2002, 7(23), 1184-1189.
[17] Tanner, T.; Marks, R. Delivering drugs by the transdermal route: Review and
comment. Skin Res. Technol., 2008, 14, 249-260.
[18] Rowland, M. Influence of route of administration on drug availability. J. Pharm. Sci.,
1972, 61, 70-74.
[19] Sinha, R. Nanotechnology in cancer therapeutics: Bioconjugated nanoparticles for
drug delivery. Mol. Cancer Ther., 2006, 5(8), 1909-1917.
[20] Fang, J.; Nakamura, H.; Maeda, H. The EPR effect: Unique features of tumor blood
vessels for drug delivery, factors involved, and limitations and augmentation of the effect.
Adv. Drug Deliv. Rev., 2011, 63, 136-151.
[21] Chidambaram, M.; Manavalan, R.; Kathiresan, K. Nanotherapeutics to overcome
conventional cancer chemotherapy limitations. J. Pharm. Pharm. Sci., 2011, 14, 67-77.
[22] Cho, K.; Wang, X.; Nie, S.; Chen, Z.; Shin, D. Therapeutic nanoparticles for drug delivery
in cancer. Clin. Cancer Res., 2008, 14, 1310-1316.
68 | P a g e
[23] Jong, W.H.D.; Borm, P.J.A. Drug delivery and nanoparticles: Applications and hazards.
Int. J. Nanomedicine, 2008, 3, 133-149.
[24] Bertrand, N.; Leroux, J. The journey of a drug-carrier in the body: An
anatomophysiological perspective. J. Control. Release, 2012, 161, 152-163.
[25] Bae, Y.; Park, K. Targeted drug delivery to tumors: Myths, reality and possibility. J.
Control. Release, 2011, 153, 198-205.
[26] Sagnella, S.; Drummond, C. Drug delivery: A nanomedicine approach. Australian
Biochemist 2012, 43, 5-8, 20. The Australian Society for Biochemistry and Molecular
Biology.
[27] Greish, K. Enhanced Permeability and Retention (EPR) effect for anticancer
nanomedicine drug targeting. Methods Mol. Biol. 2010, 624, 25-37.
[28] Mishra, N.; Pant, P.; Porwal, A.; Jaiswal, J.; Samad, A.M.; Tiwari, S. Targeted drug
delivery: A review. Am. J. PharmTech Res, 2016, 6(1), 1-24.
[29] Chen, C.; Ke, J.; Zhou, X.E.; Yi, W.; Brunzelle, J.S.; Li, J.; Yong, E.L.; Xu, H.E.; Melcher, K.
Structural basis for molecular recognition of folic acid by folate receptors. Nature, 2013,
500, 486-489.
[30] Kelemen, L.E. The role of folate receptor α in cancer development, progression and
treatment: cause, consequence or innocent bystander? Int. J. Cancer, 2016, 119, 243-250.
[31] Leamon, C.P.; Reddy, J.A.; Vlahov, I.R.; Westrick, E.; Dawson, A.; Dorton, R.; Vetzel, M.;
Santhapuram, H.K.; Wang, Y. Preclinical antitumor activity of a novel folate-targeted dual
drug conjugate. Mol. Pharm., 2007, 4, 659-667.
[32] Matsue, H.; Rothberg, K.G.; Takashima, A.; Kamen, B.A.; Anderson, R.G.; Lacey, S.W.
Folate receptor allows cells to grow in low concentrations of 5-methyltetrahydrofolate.
Proc. Natl. Acad. Sci. USA., 1992, 89(13), 6006-6009.
[33] McGuire, J.J. Anticancer antifolates: current status and future directions. Curr. Pharm.
Des., 2003, 9, 2593-2613.
69 | P a g e
[34] Reddy, J.A.; Dorton, R.; Westrick, E.; Dawson, A.; Smith, T.; Xu, L.C.; Vetzel, M.; Kleindl,
P.; Vlahov, I.R.; Leamon, C.P. Preclinical evaluation of EC145, a folate-vinca alkaloid
conjugate. Cancer Res., 2007, 67, 4434-4442 .
[35] Leamon, C.P.; Reddy, J.A. Folate-targeted chemotherapy. Adv. Drug Deliv. Rev., 2004,
56, 1127-1141.
[36] Kane, M.A.; Elwood, P.C.; Portillo, R.M.; Antony, A.C.; Najfeld, V.; Finley, A.; Waxman,
S.; Kolhouse, J.F. Influence on immunoreactive folate-binding proteins of extracellular
folate concentration in cultured human-cells. J. Clin. Invest., 1988, 81, 1398-1406.
[37] Deng, Y.; Zhou, X.; Desmoulin, S.K.; Wu, J.; Cherian, C.; Hou, Z.; Gangjee, A. Synthesis
and biological activity of a novel series of 6-substituted thieno[2,3-d]pyrimidine antifolate
inhibitors of purine biosynthesis with selectivity for high affinity folate receptors over the
reduced folate carrier and proton-coupled folate transporter for cellular entry. J. Med.
Chem., 2009, 52(9), 2940-2951.
[38] Melgert, B.N.; Olinga P.; Van Der Laan J.M.S.; Weert B.; Cho J.; Schuppan D.; Groothuis
G.M.M.; Meijer K.F.; Poelstra K. Targeting dexamethasone to Kupffer cells: Effects on liver
inflammation and fibrosis in rats. Hepatology, 2011, 34(04), 719-728.
[39] Balthasar, J.P.; Fung, H.L. Inverse targeting of peritoneal tumors: Selective alteration
of the disposition of methotrexate through the use of anti-methotrexate antibodies and
antibody fragments. J. Pharm. Sci., 1996, 85, 1035-1043.
[40] Morachis, J.M.; Mahmoud, E.A.; Almutairi, A. Physical and chemical strategies for
therapeutic delivery by using polymeric nanoparticles. Pharmacol. Rev., 2012, 64(3), 505-
519
. [41] Noimark, S.; Weiner, J.; Noor, N.; Allan, E.; Williams, C.K.; Shaffer, M.S.P.; Parkin, I.P.
Dual-mechanism antimicrobial polymer–ZnO Nanoparticle and crystal violet-encapsulated
silicone. Adv. Funct. Mater., 2015, 25, 1367-1373.
70 | P a g e
[42] Sun, Z.; Yan, X.; Liu, Y.; Huang, L.; Kong, C.; Qu, X.; Qin, H. Application of dual targeting
drug delivery system for the improvement of anti-glioma efficacy of doxorubicin.
Oncotarget, 2017, 8(35), 58823-58834.
[43] Cho, K.; Wang, X.; Nie S.; Chen, Z.G.; Shin, Dong M. Therapeutic nanoparticles for drug
delivery in cancer. Clin. Cancer Res., 2008, 14(5), 1310-1316.
[44] Singh, R.; Lillard, J.W. Nanoparticle-based targeted drug delivery. Exp. Mol. Pathol.,
2009 86(3), 215-223.
[45] Ali-Boucetta H, Al-Jamal KT, Mccarthy D, et al. (2008). Multiwalled carbon nanotube-
doxorubicin supramolecular complexes for cancer therapeutics. Chem Commun (Camb)
459–61.
[46] Appel AA, Anastasio MA, Larson JC, Brey EM. (2013). Imaging challenges in
biomaterials and tissue engineering. Biomaterials 34: 6615–30.
[47] Das BK, Tlili C, Badhulika S, et al. (2011). Single-walled carbon nanotubes
chemiresistor aptasensors for small molecules: picomolar level detection of adenosine
triphosphate. Chem Commun (Camb) 47: 3793–5.
[48] Depan D, P.K A, Singh R, Misra R. (2014). Stability of chitosan/ montmorillonite
nanohybrid towards enzymatic degradation on grafting with poly(lactic acid). Mater Sci
Tech 30:587–92.
71 | P a g e
72 | P a g e