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Chapter
Role of Drug Repurposing in
Cancer Treatment and Liposomal
Approach of Drug Targeting
Sunil T. Galatage, Arehalli S. Manjappa,
Raghwendra R. Waghmode, Swapnil S. Harale,
Rushikesh B. Katkar, Sujit A. Desai, Swapnil S. Chopade,
Kranti S. Bille, Rubina U. Watangi, Shweta N. Kalebere,
Aditya S. Hebalkar, Shradhey V. Dhobale,
Harshada N. Gunjate, Poonam R. Dhenge, Purva S. Ikke,
Saheblal A. Shaikh, Rutuja J. Patil, Sakshi B. Shinde,
Rutuja V. Khatavakar, Anuja B. Patil, Prajakta N. Khatavakar,
Sourabh S. Hegaje and Suresh G. Killedar
Abstract
Cancer is the leading cause of death, and incidences are increasing significantly
and patients suffering from it desperately need a complete cure from it. The science
of using an already-invented drug that has been approved by the FDA for a new
application is known as “drug repurposing.” Currently, scientists are drawn to drug
repositioning science in order to investigate existing drugs for newer therapeutic uses
and cancer treatment. Because of their unique ability to target cancer cells, recently
repurposed drugs and the liposomal approach are effective in the treatment of cancer.
Liposomes are nanovesicles that are drastically flexible, rapidly penetrate deeper
layers of cells, and enhance intracellular uptake. More importantly, liposomes are
biocompatible, biodegradable; entrap both hydrophobic and hydrophilic drugs. This
chapter summarizes various approaches to drug repurposing, as well as drug repurposing methods, advantages and limitations of drug repurposing, and a liposomal
approach to using repurposed drugs in cancer targeting. This chapter also summarizes
liposomal structure, drug loading, and the mechanism of liposomes in targeted
cancer treatment. The lipid-based liposomal approach is emerging as a powerful
technique for improving drug solubility, bioavailability, reducing side effects, and
improving the therapeutic efficacy of repurposed drugs for cancer treatment.
Keywords: cancer, drug repurposing, liposomes, drug targeting, enhanced
permeability effect, Etc.
1
Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery
1. Introduction
During the treatment of cancer in a patient, it is necessary to follow certain
principles, such as diagnosing the disease at an early stage, making efforts for its
prevention, and completing the eradication of malignant cells. Whereas three modes
of treatment are available to treat cancer, including surgery, chemotherapy (also
called pharmacotherapy), and radiation therapy [1], Radiation therapy is nothing
but the eradication of malignant cells by means of radiation. This technique helps
to destroy localized cancer cells (Figure 1). In pharmacotherapy, various chemical
entities are used to kill and disorganize an uncontrolled cell growth programme in a
body [2]. Cancer does not only affect humans; it can also harm wildlife and other life
forms. Tumour cells might break out from the initial bulk and begin the unregulated
growth cycle all over again. The phenomenon of tumour cells leaving one location
and developing cells that travel and proliferate over other body parts is known as
metastasis. It was estimated by the WHO that cancer is the foremost cause of death
in the world, and in the year 2018, it is expected that 9.6 million people died as a
result of it. It is categorized by the development of osteocytes, bone lesions, anaemia,
skeletal destruction, renal failure, and hypocalcaemia. It is a bone marrow cancer
that affects both the marrow and the bones. It also affects different body locations;
hence it is called multiple myeloma. Bone marrow-originating myeloid cells such as
myeloid resultant suppressor cells, macrophages, myeloid dendritic cells, monocytes,
osteoclasts, and lymphocytes are drafted to tumours, which can either increase antitumour immune function or encourage tumour growth [3]. Recent research indicates
that anti-resorptive targeted therapies can have an impact on tumour-associated
myeloid cells through direct or indirect pathways, indicating that anti-resorptives
have an osteoclastin-dependent mechanism of action. As the cancer progresses, the
signs and symptoms change dramatically. Symptoms can be entirely dissimilar from
Figure 1.
Schematic representation of cancer treatments.
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Role of Drug Repurposing in Cancer Treatment and Liposomal Approach of Drug Targeting
DOI: http://dx.doi.org/10.5772/intechopen.110105
patient to patient. A few symptoms are most common, like fatigue, bone problems,
kidney problems, and low blood counts. Some symptoms become severe; these are:
osteoporosis, osteocytes, bone lesions, and skeletal destruction [4].
Targeted cancer treatment, in which the selected cancer cells are eliminated
and healthy cells are left alone, is becoming extremely prevalent [5]. The arrival of
nanostructures has resulted in the development of advanced materials and channels
for cancer treatment targeting [6, 7]. Nanotechnology has opened up new possibilities for biological and biomedical applications, such as improving the targeted
administration of anticancer drugs. Nanotechnology has a lot of benefits for treating
cancer. In reality, tumour blood vessels are severely disordered, with an ineffective
lymph capillary network and loose endothelial cells in comparison with normal tissue.
Because of their improved permeability and high body retention, nanoparticles such
as liposomes can be transported preferentially to the tumour location [8].
2. Drug repurposing in cancer treatment
This technique helps to destroy localized cancer cells. In pharmacotherapy,
various chemical entities are used to kill and disorganize an uncontrolled cell growth
programme in a body [8]. Chemotherapeutic agents pose the greatest risk to cancer
patients because of the drugs’ lethal effects and the possibility of cell damage to their
bone marrow, which makes them more susceptible to other diseases. If we have not
targeted the malignant cell only, then these chemotherapeutic agents also kill the
normal cells in the same host, which creates more damage to the patient’s body and
its biological structure [9]. Different strategies of drug repurposing are denoted in
Figure 2.
Extensive research is carried out to investigate and develop new therapeutic
entities in the oncology field and drug research to achieve the maximum therapeutic
effect with greater patient comfort and a lower toxicity profile. On the other hand
it raises the cost of treatment for a patient, making it necessary to exert maximum
effort to achieve desired treatment goals at the lowest possible cost of treatment. Drug
repurposing is the most effective way to reduce the effort required to develop new
drug molecules while also lowering treatment costs. The science of using an alreadyinvented drug that has been approved by the FDA for a newer application is known as
drug purposing. Now a day drug repositioning science attracts the more researchers to
investigate existing drugs for its newer therapeutic use. The drug being repositioned
is already being used to treat diseases in humans, giving the manufacturer access to
knowledge regarding its safety, effectiveness, therapeutic, and toxicity profiles. To
reposition medications that are already approved for human use efficiently, rigorous selection is required, followed by a detailed demonstration of the treatment’s
usefulness in new biological contexts. The following methods are used to select drug
candidates for drug repositioning [10].
2.1 Repositioning based on therapeutic activity
This method involves testing the therapeutic effectiveness of a drug by performing an in vitro or in vivo study. For the finding of therapeutic entities, comprehensive
public library data is used. The therapeutic agent is examined for its protein targets
and cellular targets while searching for a suitable drug candidate through activitybased repurposing of the drug (Figure 3) [11, 12].
3
Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery
Figure 2.
Strategies to repurpose the drug candidates.
2.2 Drug repositioning through literature evidence
This drug repurposing method involves the selection of a drug based on its
published therapeutic evidence. The literature study of such drug databases available
on PubMed, ClinicalTrail.gov, Drug Quest, MEDLINE, and other available databases
is screened, and the required potential molecules are identified by applying such data
in a dynamic way (Figure 4) [13].
2.3 In silico method: In this method
Various bioinformatics tools and a public database are used to understand
drug protein interactions. For this method, extensive genomic studies and structural evaluations of various proteins are carried out. Most pharmaceutical drug
manufacturers adopt the in silico method for drug repurposing. To identify the
protein interaction and possible drug candidate, researchers use the science of
4
Role of Drug Repurposing in Cancer Treatment and Liposomal Approach of Drug Targeting
DOI: http://dx.doi.org/10.5772/intechopen.110105
Figure 3.
Diagrammatic representation of Drug Repositioning (Case A).
artificial intelligence, neural network techniques, and other bioinformation tools
(Figure 5) [11, 14].
2.4 Advantages of drug repositioning
1. Drug repositioning helps to curtail the drug development cost, which leads to an
improvement in the economy of the treatment [15].
2. It helps to cut down the risk associated with the task of drug development.
3. Minimize the time requirement in drug investigation as compared to the
traditional method of drug development.
4. The availability of extensive data related to drug kinetic and dynamic properties
reduces the efforts required to select a suitable dosage form, and assess the safety
and toxicity of a drug.
5. Researchers can skip performing preclinical experiments by relocating drugs,
which helps reduce the drug development cost.
5
Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery
Figure 4.
Diagrammatic representation of Drug Repositioning (Case B).
Figure 5.
Diagrammatic representation of drug repurposing approaches.
2.5 Limitations of drug repositioning
1. More money is spent on licensing requirements for drug repositioning to investigate new therapeutic applications of already approved drugs [16].
6
Role of Drug Repurposing in Cancer Treatment and Liposomal Approach of Drug Targeting
DOI: http://dx.doi.org/10.5772/intechopen.110105
2. The drug repositioning process includes intellectual property protection for
repurposed medications, which is especially important for off-patent drugs.
3. Pharmaceutical industries have shown little interest in repurposing medications
because such rights are difficult to grant.
4. Anticancer activity of repurposed medications is more commonly reported when
used in conjunction with established cytotoxic drugs rather than as single agents.
3. Repurposed drug targeting
Nanoparticulate drugs (including liposomal drugs) are generally developed for
therapeutics developed against cancer to avoid non-specific distribution to healthy
cells and tissues that generally causes lethal side effects. Due of the permeable tumour
vasculature and decreased lymphatic outflow, the nanomedicines (including liposomes) with prolonged circulation durations preferentially penetrate tumour tissue.
This phenomenon is referred to as the “increased permeability and retention (EPR)
effect Drug repurposing is a technique for finding new applications for medicines that
go beyond their original medicinal indications. On the other hand, drug repurposing
is the most effective way to reduce the coast, time and effort required to develop new
drug molecules while also lowering treatment costs. The development of nanomedicines (including liposomes) for these repurposed drugs could provide many benefits;
increased kinetic, dynamic and biopharmaceutical characteristics, and avoids their
primary indications via targeting them to tumour through EPR effect. Furthermore,
these nanomedicines could be easily surface modified to passively and actively target
tumour cells and cellular components. Therefore, nanomedicines composed of repurposed drug could be preferred over plain drugs or their conventional generic dosage
forms currently available in the market.
4. Liposomes (LPs)
An LPs is a spherical vesicle made up of one or more lipid vesicles that is increasingly being used to deliver therapeutic entities. Liposomes are one of several promising drug delivery systems that represent an efficient approach for delivering active
compounds to the target site, and various formulations are currently in clinical
use. LPs technology has been developed from typical vesicles to second generation
liposomes, which are created by changing the lipid composition, length, and charge
of vesicle liposomes and can be employed on a regular basis as what the body does
to drugs and what drugs do to the body can be controlled. The LPs provide selective
passive targeting to tumour tissues, and the encapsulation method contributes to
increased effectiveness, therapeutic index, and stability. Reduced polymer toxicity, site evading effect, helping to enhance the pharmacokinetics of the therapeutic
moiety, and suppleness to bind ligands at specific sites to achieve active targeting, to
name a few advantages [6]. Liposomes were studied for the first time at the Babraham
Institute in Cambridge by two scientists who used an electron microscope to examine phospholipids in dry form with negative staining. These two scientists are Dr.
Alec Bengham and R. W. Horne, who identified the liposome assembly in 1961 and
7
Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery
published their study in 1964. Liposome is the name given to a compound made up of
lipids (lipo) and body (soma). So that liposome is nothing but a lipid body in which
medicine is to be delivered [17]. Many anticancer medications have been designed
to terminate tumour cells that are developing uncontrollably because they divide
more quickly than normal cells. However, in this instance, ordinary cells grow fast,
and a chemotherapeutic agent might harm such cells, resulting in chemotherapy
side effects. Blood cells that create bone marrow, cells in the digestive tract (cells in
the mouth, stomach, gut, and oesophagus), and sexual organs and hair follicles are
among the fast-growing normal cells that are impacted. Some anticancer medications
have the capacity to harm cells in key organs, including the heart, kidney, bladder,
lungs, and neurological system. Medication diffusion in solid tumours is hampered
by a variety of vascular supply and cellular gravity within tumour cells, particularly
in tumour regions. Drug delivery design develops in such a way to ensure that macromolecular medicines are released slowly via the tumour. Advanced technologies are
designed to improve tumour tissue permeability. These are triggered by the maladaptive nature of tumorigenesis, which is characterized by structural and physiological
abnormalities that lead to hyperpermiability. The medicinal compounds have a larger
molecular structure, which leads to the build-up of high-molecular-weight molecules
with limited distribution volumes and the ability to circulate for lengthy periods of
time through aberrant arteries and concentrate in tumours [18–20].
4.1 Structural features of liposome
LPs are small cell membrane sacs. Because these LPs can be packed with
medications, they are a viable option for treating illnesses and cancer. Liposome
membranes are composed of phospholipids with a head and a tail group. Because of
the length of the hydrocarbon chain, the head part is hydrophilic and the tail part
is hydrophobic. Phospholipids are naturally occurring two-layer stable membranes.
Because head groups are hydrophilic, they are fascinated by water and arrange in
such a way to form a surface-like assembly away from it when there is water present. In a cell with outside water, while the other is fascinated by water within the
cell. They resemble tiny spheres that are smaller than a normal cell’s size, whether
as bilayers or monolayers. Liposomes are created as bilayers, while micelles are
formed as monolayers. Phospholipids form the mainstream of the lipids in the
plasma membrane; these phospholipids are phosphatidyl ethanolamine and phosphatidylcholine [19–21]. Liposomes have the capability to penetrate cancer in its
natural state. Endothelium cells are contained by tight junctions in the endothelial
walls of all healthy human blood vessels. These tight connections prevent large
blood particles from spilling out of the vessel. In the event of a tumour vessel, this
type of arrangement does not exist, making it symptomatically porous. This capacity is known as the enhanced permeability and retention effect (EPR) (Figure 6).
Liposomes with a diameter of less than 400 nm can enter tumours quickly from the
bloodstream, but they are maintained in the bloodstream by the endothelium wall
in healthy tissue [23–25].
4.2 Drug loading mechanism into liposome
The drug features and the lipids determine how pharmaceuticals are loaded into
liposomes. Hydrophilic medications are confined in the inner watery compartment,
8
Role of Drug Repurposing in Cancer Treatment and Liposomal Approach of Drug Targeting
DOI: http://dx.doi.org/10.5772/intechopen.110105
Figure 6.
Diagrammatic representation of EPR effect [22].
Figure 7.
Active loading of drug into liposome [26].
while hydrophobic pharmaceuticals can screen within the lipid hydrocarbon area. In
practice, few medicines may segregate into hydrocarbon or aqueous compartments;
for example, Amphotericin-B (Amph-B) binds to hydrophobic lipid membranes. The
resulting lipid configuration influences Amph-B parcelling and its rate of exchange
outside of the liposome envelope (Figure 7). Incorporating a negatively charged lipid
improves the stability of the membrane’s connection [27, 28].
According to the trans-membrane pH gradient, weak bases can concentrate in
liposomes. Liposome formation is dependent on two critical steps: the formation of a
pH gradient with a lower intra-liposomal pH and the subsequent loading of the drug.
Gradient generation of a trans-membrane proton can be done in a variety of ways.
Liposomes are made in citrate buffer, and then transferred to a pH 7.5 buffer by an exogenous buffer exchange. Ionophores, on the other hand, can be employed with action
gradients. Ultimately, liposomes developed in the presence of significant amounts of
ammonium sulphate (Figure 8). The withdrawal of salt solution causes the creation of a
pH gradient, which is also accountable for the drug entrapment mechanism [22, 30, 31].
9
Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery
Figure 8.
Passive loading of drug into liposome [29].
5. Drug targeting
Much of the effort in liposome research has been focused on tumour targeting.
Liposomes in circulation extravagate through the ‘leaky’ tumour vasculature; alternatively, attachment of specific antibodies or other proteins to the liposome surface
may cause specific targeting. However, the increased clinical efficacy of such targeting
in human patients has not been easy to prove. Most of a liposomal drug given intravenously is taken up by phagocytosis into the reticulo-endothelial system, which is
extremely efficient at trapping particulate matter circulating intravenously (Figure 9).
The reticulo-endothelial system may be circumvented by several different methods,
such as saturation with large doses of liposome particles or selective macrophage
inactivation by pharmacological means However, such a strategy could theoretically
further compromise the immune system of cancer patients [33, 34].
Liposomes as a Drug Depot Many drugs are most effective when they are delivered over extended periods of time. For example, agents specific for the division
phase of the cell cycle kill cancer cells only when they are dividing. However, even
for the most rapidly growing tumours, only a small fraction of the cells are dividing
during the drug’s residence time. Therefore, depot formulations are needed to maintain therapeutic concentrations for prolonged periods. In contrast to biodegradable
polymers or chemical modifications of the standard drug, liposomes and other
lipid-based formulations have the advantage of not creating a new chemical entity,
and the need for extensive toxicological studies is largely avoided. This is especially
the case for the more efficient lipid-based drug delivery systems, where the amount
of lipid used is small relative to the amount of drug delivered (Figure 9). Even if
10
Role of Drug Repurposing in Cancer Treatment and Liposomal Approach of Drug Targeting
DOI: http://dx.doi.org/10.5772/intechopen.110105
Figure 9.
Liposomal drug delivery to treat cancer [32].
efficacy and toxicity remain unchanged, the convenience and improved patient
compliance of fewer painful injections may be sufficient for those drugs that require
frequent multiple injections or continuous infusions [35–37].
6. Conclusions
Nowadays drug repurposing and drug targeting through nanoparticulate drug
delivery gain significant attention for delivering various APIs in treatment of cancer
through oral and topical route successfully. Loading the repurposing drug in to liposomes escalate therapeutic efficacy and residences toxic effects along with patients
compliance. Nanomedicines could be easily surface modified to passively and actively
target tumour cells and cellular components. Therefore, nanomedicines composed
of repurposed drug could be preferred over plain drugs or their conventional generic
dosage forms currently available in the market. The advantages of various methodologies and strategies for drug targeting are outlined in the current chapter, along
with information on liposomal drug targeting, liposomal structure, mechanism of
liposomal drug loading, and liposomal drug targeting. Drug repurposing and liposomal drug targeting are potent methods for enhancing solubility and bioavailability,
minimizing side effects, and developing innovative drug delivery systems to increase
the therapeutic effectiveness of drug repurposing to treat cancer.
Acknowledgements
The authors are thankful to Department of Pharmaceutics Sant Gajanan Maharaj
College of Pharmacy Mahagaon and Trustees of Sant Gajanan Maharaj College of
Pharmacy Mahagaon for providing required guidance and support for completion of
this work.
11
Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery
Conflict of interest
The authors declare no conflict of interest.
Notes/thanks/other declarations
Special thanks to Supriya S. Galatage and Shivtej S. Galatage for their continuous support throughout the work.
Abbreviations
API
HA
LP
PCB
PEG
NDDS
WHO
EPR
12
active pharmaceutical ingredient
hyaluronic acid
liposomes
poly carboxybetaine
poly ethylene glycol
nanoparticulate drug delivery
World Health Organization
enhanced permeability and retention effect
Role of Drug Repurposing in Cancer Treatment and Liposomal Approach of Drug Targeting
DOI: http://dx.doi.org/10.5772/intechopen.110105
Author details
Sunil T. Galatage1*, Arehalli S. Manjappa2,3, Raghwendra R. Waghmode4,
Swapnil S. Harale1, Rushikesh B. Katkar5, Sujit A. Desai6, Swapnil S. Chopade2,
Kranti S. Bille1, Rubina U. Watangi1, Shweta N. Kalebere7, Aditya S. Hebalkar8,
Shradhey V. Dhobale9, Harshada N. Gunjate1, Poonam R. Dhenge1, Purva S. Ikke1,
Saheblal A. Shaikh1, Rutuja J. Patil1, Sakshi B. Shinde1, Rutuja V. Khatavakar1,
Anuja B. Patil1, Prajakta N. Khatavakar1, Sourabh S. Hegaje2 and Suresh G. Killedar1
1 Sant Gajanan Maharaj College of Pharmacy Mahagaon, Maharashtra, India
2 Tatyasaheb Kore College of Pharmacy, Kolhapur, Maharashtra, India
3 Vasantidevi Patil Institute of Pharmacy, Kolhapur, Maharashtra, India
4 Krishna Institute of Pharmacy, Krishna Vishwa Vidyapeeth, Karad, Maharashtra,
India
5 Vijayrao Naik College of Pharmacy, Shirval Kankavali, Maharashtra, India
6 Annasaheb Dange College of D Pharmacy, Ashta, Walawa, Maharashtra, India
7 Genesis Institute of Pharmacy, Radhanagari, Maharashtra, India
8 IQVIA Biotech, Thane, Maharashtra, India
9 National Institute of Pharmaceutical Education and Research (NIPER),
Ahmadabad, India
*Address all correspondence to:
[email protected]
© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of
the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.
13
Drug Repurposing - Advances, Scopes and Opportunities in Drug Discovery
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