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Current Cancer Drug Targets, хххх, хх, 1-26 1
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REVIEW ARTICLE
Advancement and Strategies for the Development of Peptide-Drug Conju-
gates: Pharmacokinetic Modulation, Role and Clinical Evidence Against
Cancer Management
Rishabha Malviya1,*, Swati Verma1 and Sonali Sundram1
1Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, India
ARTICLE HISTORY
Received: May 11, 2021
Revised: July 29, 2021
Accepted: September 09, 2021
DOI:
10.2174/1568009621666211118111506
Abstract: Currently, many new treatment strategies are being used for the management of cancer.
Among them, chemotherapy based on peptides has been of great interest due to the unique features
of peptides. This review discusses the role of peptide and peptides analogues in the treatment of
cancer, with special emphasis on their pharmacokinetic modulation and research progress. Low
molecular weight, targeted drug delivery, enhanced permeability, etc., of the peptide-linked drug
conjugates, lead to an increase in the effectiveness of cancer therapy. Various peptides have recent-
ly been developed as drugs and vaccines with an altered pharmacokinetic parameter which has sub-
sequently been assessed in different phases of the clinical study. Peptides have made a great impact
in the area of cancer therapy and diagnosis. Targeted chemotherapy and drug delivery techniques
using peptides are emerging as excellent tools in minimizing problems with conventional che-
motherapy. It can be concluded that new advances in using peptides to treat different types of can-
cer have been shown by different clinical studies indicating that peptides could be used as an ideal
therapeutic method in treating cancer due to the novel advantages of peptides. The development of
identifying and synthesizing novel peptides could provide a promising choice to patients with can-
cer.
Keywords: Pharmacokinetics, peptide, cancer therapy, clinical studies, targeted delivery, cellular targeting.
1. INTRODUCTION
According to WHO, cancer is the third biggest reason be-
hind mortality globally. Despite the intrinsic interest of re-
searchers in cancer therapy, cancer is growing significantly,
as seen by recent statistics. Breast cancer in women and lung
cancer in men are the leading cancer subtypes worldwide.
According to the American Cancer Society, the number of
deaths may rise to 13 million out of 21.7 million by 2030
globally [1]. It was also observed that cases of cancer are
much more in developed countries as compared to develop-
ing countries [2]. In developed countries, lung cancer is the
major cause of death in males, while it is breast cancer for fe-
males. The genetic mutation leading to alteration in protein
function is the basic reason for cancer. Cancer is a cluster of
diseases mainly characterized by the uncontrolled division
of cells that invade tissues, leading to the formation of a tu-
mor. This deregulated growth is a series of mutations that
trigger the aberrant expression of gene products necessary
for regulating the proliferation, survival, and growth activi-
ties of cells. [3] The formation of new blood vessels from
pre-existing vessels, i.e., angiogenesis, is an important funda-
mental step in the transition of cancerous cells to malignant
ones.
* Address correspondence to this author at the Department of Pharmacy,
School of Medical and Allied Sciences, Galgotias University, Greater Noi-
da, India; Tel: +91-9450352185; E-mail: rishabhamalviya19@gmail.com
Associated collateral toxicity of approved anticancerous
formulations is a basic limitation of the current treatment
strategies. Peripheral toxicity and toxicity in healthy tissues
lead to significant damage to the patient’s health. In the last
decades, biomedical manufacturers have invested a lot of
funds in the development of protein-derived biologics for
cancer therapy [4].
Nanomedicine holds the potential to improve anticancer
therapy. Traditionally, nanomedicines have been used to mo-
dulate the biodistribution and the target site accumulation of
systemically administered chemotherapeutic drugs, thereby
improving the balance between their efficacy and toxicity.
When compared to non-formulated pharmaceuticals,
nanomedicines often limit tumor growth and prolong survi-
val, but in practice, patients often only benefit from
nanomedicines because of reduced or altered side effects
[5].
The two approaches are followed for the development of
nanomedicines of cancer, i.e., surface nanoengineering of
nanoparticles by conjugating active recognition moieties to
their surfaces to improve chemotherapeutic targeting selec-
tivity and therapeutic payload accumulation and efficacy by
overcoming biological barriers and boosting tumor penetra-
tion of nanomedicines [6].
Furthermore, the pathogenic properties of tumors, as
well as their aberrant blood artery design and function, de-
2 Current Cancer Drug Targets, хххх, Vol. хх, No. хх Malviya et al.
crease the effectiveness of traditional cancer treatments. As
a result, it is necessary to explore strategies that can improve
the therapy’s efficacy, such as nanoparticles. In the develop-
ment of cancer nanomedicines, various types of nanoparti-
cles are prepared for the treatment of different types of can-
cer. Nanoparticles have a number of characteristics, includ-
ing their wide surface area, small size, capacity to load a va-
riety of medicines, and ability to improve conjugated absorp-
tion. As a result, nanoparticles are thought to be good tu-
mor-targeting vehicles [7].
Actively targeted nanoparticles can be tailored to target
tumor cells depending on tumor microenvironment and li-
gand targeting. As a result of nanoparticles’ unique ability to
target solid tumors, the nanoparticle is regarded as an effec-
tive tumor-targeting vehicle. As a result, nanoparticles are
accumulated at the tumor site [8].
The main advantage of nanoparticles in cancer treatment
is related to their features which includes improvement in
the existing anticancer compounds’ pharmacokinetic and
pharmacodynamic profiles, minimized harmful toxicity and
adverse effects of anticancer drugs on healthy cells, pro-
viding more sensitive cancer detection, improving therapeu-
tic efficacy and specificity, demonstrating the feasibility of
combining cancer therapies, providing cost-effectiveness, im-
proving the quality of life, and also applicability in different
routes of administration [6].
Peptide-derived molecules are available in the market,
and the continuously increased number for clinical investiga-
tion shows their future trend and market potential. The signi-
ficant therapeutic potential of peptides is overshadowed by
their ability to degrade before reaching target tissues. Syn-
thetic and natural peptides utilized for cancer therapy and
metabolic disorders generally interact with G-protein cou-
pled receptors. Traditionally attenuated vaccines are used,
but modern approaches shifted towards the use of peptide
units [9]. Therapeutic peptides are biodegradable, biocompat-
ible, less or non-immunogenic, small in size, specific, and
have high affinity.
Signaling pathways are completed by the inherent proper-
ties of peptides. Intervention in natural signaling by using
peptides open an opportunity for biochemist in the treatment
of various biological disorders. Peptide units have a better
safety profile, specificity, and assay. Although recently, a lot
of peptide molecules have been synthesized and have a po-
tential therapeutic effect, utilization of these molecules in
clinics is limited by the physiochemical properties of
molecules. Fortunately, the characteristics of these
molecules can be modified for their preferred use by clinical
practitioners [10]. The focus of next-generation therapy for
cancer is recently shifted towards the use of peptide-based
angiogenesis inhibitors. In recent years, considerable
progress has been made to enhance the ongoing cancer treat-
ment strategies. To discover new cancer drugs, the develop-
ment of peptides as new drugs has motivated research activi-
ties [11]. Peptides have a unique advantage as therapeutic
agents as they are short polymers with molecular weight less
than 10kDa and less than 50 amino acids in length [12, 13].
When compared with proteins and small molecules, pep-
tides offer better tissue penetration, lower manufacturing
cost, greater potency, activity, selectivity, and specificity,
less drug-drug interaction, and lower off-target toxicity [11].
Due to the mentioned reasons, peptides have wide applica-
tions in diagnostic and cancer treatment [3]. The major limi-
tations with peptides as drug candidates are: highly suscepti-
ble to proteolytic degradation in vivo, shorter plasma half-
life, and low oral bioavailability due to large molecular
weight with low metabolic stability. They often display half
lifetimes in the range of a few minutes to a few hours. In
most cases, the half-life of a few minutes is inefficient in de-
livering enough drug to the target tissue. Despite the draw-
backs, peptides are biologics that occur naturally; they are
safer than synthetic medications and have higher efficacy, se-
lectivity, and specificity. They offer more advantages to-
wards protein and antibodies. Peptides show high biological
activities, high specificity, and low toxicity, while nanoparti-
cles are used as drug carriers which shows high stability,
high carrier capacity, the feasibility of administration route,
and the feasibility of incorporation of both hydrophilic and
hydrophobic drugs.
Some protein molecules are also commercially available
in the market, such as Avastin (bevacizumab), Nexawar (so-
rafinib), and Sutent (sunitinib).
Schematic representation to show the peptide-drug conju-
gate formulation is depicted in Fig. (1).
The conjugation of drug-loaded nanocarrier system to
peptide or protein requires surface conjugation of ligands,
whereas drugs can be easily conjugated with proteins by a
suitable linker. This will overcome the problem of drug load-
ing. The protein-drug conjugate retains the therapeutic poten-
tial by passive targeting and improved circulation in the
blood because of the high molecular weight of drugs. Fur-
thermore, specific linker molecules can be used to design
such conjugates as they provide target-organ specific cleav-
age of the conjugate, improved flexibility which enhances
its binding to the receptor, and improved drug hydrophilicity
[14].
The use of small peptide molecules in place of long-
chain protein may lead to a reduction in the risk associated
with protein molecules and biopharmaceutical limitations
and improved target specificity [15]. Cyclic disulfides are in-
termediate-sized peptide molecules, which have a potential
therapeutic effect against various diseases and disorders
such as cancer. They are also available naturally, e.g., kalata
B1 (kB1), Momordica cochinchinensis trypsin inhibitor-II
(MCoTI-II), and sunflower trypsin inhibitor-1 (SFTI-1)
[16]. These molecules are stable due to their cyclic back-
bone and stronger hydrogen bonding. Better stability of
cyclic disulfides makes them interesting molecules, gaining
significant interest by researchers worldwide. The grafting
of small active amino acid sequences into cyclic disulfide
backbone leads to high output potential therapeutic
molecules. Grafting with epitope leads to more stability with
suppressed undesirable activities [16]. Grafting also leads to
cyclization of the structure of linear amino acid chains and
Advancement and Strategies for the Development of Peptide-Drug Conjugates Current Cancer Drug Targets, хххх, Vol. хх, No. хх 3
Fig. (1). Schematic representation to show the peptide-drug conjugate formulation. (A higher resolution / colour version of this figure is avai-
lable in the electronic copy of the article).
Fig. (2). Schematic representation to show conjugation of anti-
body, peptide, and protein with polymer, biological cells, and drug.
(A higher resolution / colour version of this figure is available in
the electronic copy of the article).
stabilization of the therapeutics. In a study, the kB1 back-
bone was grafted with anti-angiogenic epitope poly R, and it
showed inhibition of endothelial growth factor A [10].
Multi-organ targeting of peptide molecules is a challeng-
ing approach and needs next-generation anticancer therapy.
In a study, Chan et al. developed dual targeting endothelial
growth factor A inhibitors by grafting β-turn-derived pep-
tides from somatostatin (SST-0122 and SST-0223) and an
anti-VEGF-derived peptide from phage display (poly R) to
cyclic disulfide backbone [16]. SST-0122 and SST-0223 tar-
gets the neuroendocrine tumors, a pigment epitheli-
um-derived factor, while poly R inhibits endothelial growth
factor-A. As observed by researchers in a study, grafted pep-
tides showed better inhibition of proliferation, migration,
and cellular growth [16]. Conjugation of antibody, peptide,
and protein to polymer-drug and various cells are depicted
in Fig. (2).
2. MECHANISM OF CANCER DEVELOPMENT AND
GENERAL THERAPEUTIC TARGETING
Tumors are formed by the overgrowth of normal somatic
cells. However, not all forms of tumors are malignant. Can-
cer is a diverse collection of diseases marked by uncon-
trolled development, tumor formation, and invasion of the
body surrounding tissues. Cancer is a complex and adapt-
able disease that can affect almost any part of the body.
Breast cancer, prostate cancer, colon cancer, lymphoma,
lung cancer, leukemia, and other cancers are typically classi-
fied by their anatomic origin. Self-sufficiency in growth sig-
nals, insensitivity to growth-inhibitory signals, evasion of
programmed cell death, infinite replicative potential, pro-
longed angiogenesis, and tissue invasion and metastasis are
six traits that have been considered as hallmarks of cancer
[17].
Tumor development is divided into several stages. (1)
Hyperplasia is a stage in which genetically altered or abnor-
mal cells proliferate rapidly and uncontrollably. (2) Dyspla-
sia is a stage of tumor growth in which overgrowing cells re-
vert to their original shape. It has a higher proportion of im-
mature cells than mature cells. (3) In situ cancer is a neoplas-
tic lesion in which cells do not go through the maturation
process, lose their tissue identity, and develop uncontrollab-
ly. (4) In a malignant tumor, overgrowing cells rupture the
basal membrane, allowing them to invade other areas. (5)
Metastases arise when cancer cells spread through the lym-
4 Current Cancer Drug Targets, хххх, Vol. хх, No. хх Malviya et al.
phatic system and blood circulation to distant parts of the
body [18].
For targeted tumor therapy, cellular receptors that are ac-
tivated by peptide molecules as ligands are of great interest.
These receptors must meet two fundamental criteria: first,
they must be overexpressed on cancer cells in a way that is
distinct from nonmalignant cells. A 3:1 or higher tumor- to-
normal-cell expression ratio is frequently preferred. Second,
the total expression levels of the target receptor on cancer
cells should be high enough to ensure that the medicine is de-
livered to the cancer cells in sufficient amounts to provide
the intended therapeutic effect [19].
Many peptide-binding receptors have these characteris-
tics, and their activating peptide ligands (agonists) are there-
fore promising tumor-selective carriers for drug conjugates.
Additionally, chemically engineered small molecule binders
or antibodies can be used to target peptide-binding recep-
tors. Engineering a modular conjugate system, which con-
sists of the drug compound covalently bonded to the recep-
tor-binding molecule, allows for targeted drug administra-
tion [20].
Ideally, the latter should also facilitate cancer cell pene-
tration in order to administer the drug selectively intracellu-
larly. In many cases, a smart linker is used between the drug
and the targeting unit to ensure that the drug is released in a
regulated manner inside the tumor cells [21, 22].
3. MOLECULAR DOCKING IN PROTEIN INTERAC-
TION
The molecular docking approach may be used to repre-
sent the atomic level interaction between a small molecule
and a protein, allowing us to define small molecule behavior
in target protein binding sites as well as to elucidate key bio-
chemical processes. The docking procedure consists of two
main steps: predicting the ligand structure as well as its posi-
tion and orientation within these sites (known as pose) and
determining the binding affinity [23].
Knowing where the binding site is before starting the
docking process improves docking efficiency dramatically.
In many cases, the binding site is identified before ligands
are docked into it. Also, by comparing the target protein to a
family of proteins with comparable functions or proteins co-
crystallized with other ligands, one can learn more about the
sites. Cavity detection tools or web servers, such as GRID,
POCKET, SurfNet, PASS, and MMC, can be used to locate
probable active sites within proteins when the binding sites
are unknown. Blind docking is the process of docking with-
out making any assumptions about the binding sites [24].
The lock and key theory presented by Fischer, in which
the ligand fits into the receptor-like lock and key, was the
first explication of the ligand-receptor binding mechanism.
The initial docking approaches were based on this principle,
and the ligand and receptor were both considered as rigid en-
tities. The “induced-fit” theory proposed by Koshland ex-
tends the lock-and-key theory by claiming that as ligands en-
gage with the protein, the active site of the protein is cons-
tantly altered by interactions with the ligands. This hypothe-
sis implies that during docking, the ligand and receptor
should be viewed as malleable [25].
Molecular docking has been the most widely employed
technique. Though the main application lies in struc-
ture-based virtual screening for identification of new active
compounds towards a particular target protein, in which it
has produced a number of success stories, it is actually not a
stand-alone technique but is normally embedded in a work-
flow of different in silico as well as experimental tech-
niques. Docking could be used in conjunction with other
computational tools and experimental data to analyze drug
metabolism and extract important information from the cy-
tochrome P450 system [26].
Docking against heme-containing complexes appears to
be difficult because some ligands coordinate directly to the
heme iron atom, and the precise energetics of this contact
for different chelating groups must be properly balanced
with other energetic terms, and the environment above the
heme group in the case of the P450s is very hydrophobic
compared to other enzymes. 45 complexes, including heme-
containing proteins and ligands, were chosen from the PDB
library for this study. The native ligands were removed, and
the GOLD software, which uses genetic algorithms to build
ligand conformations, was used to dock them into the pre-
scribed active cavities. Goldscore and Chemscore were the
scoring functions used to rate the docking pose [27].
The success rates for Chemscore and Goldscore are 64%
and 57%, respectively, which is much lower than the 79%
seen with both scoring systems for the entire GOLD valida-
tion set. Furthermore, the data indicates that the search
method was very unlikely to be the cause of the docking fail-
ure. Further research found that re-parameterizing metal-ac-
ceptor interactions and the lipophilicity of planar nitrogen
atoms in the scoring functions resulted in a significant in-
crease in the percentage of successful docking poses against
heme-binding proteins (Chemscore 73%, Goldscore 65%),
which could be useful in docking applications on P450 en-
zymes and other heme-binding proteins (Chemscore 73%,
Goldscore 65%) [27].
4. MODULATION IN PHARMACOKINETICS OF
PEPTIDE-DRUG CONJUGATES FOR THERAPEU-
TIC BENEFITS
The smaller size of peptide molecules results in the short
half-life of molecules. It also leads to wider distribution of
active molecules hence poor tissue targeting. Narrow thera-
peutic index due to non-specific binding is another draw-
back associated with the small size of peptides. Approaches
can be used to improve the pharmacokinetics and pharmaco-
dynamics of molecules that lead to better therapeutic bene-
fits [28]. Conjugation of small molecules with pharmacologi-
cally active peptides is a newer approach to overcome the
size-associated problems of peptides. Conjugation of peptide
molecules leads to the addition of prerequisite PK-PD param-
eters. Limitations in the physicochemical properties of pep-
tides restrict their role in pharmaceutical research [29]. Pep-
Advancement and Strategies for the Development of Peptide-Drug Conjugates Current Cancer Drug Targets, хххх, Vol. хх, No. хх 5
tide drugs are quite difficult to develop due to multiple is-
sues in the ADME profile. For instance, lower penetrability,
metabolic instability, shortened lifetime, and inadequate resi-
dence time are also related [29]. The minimal oral availabili-
ty in the biological system is mainly due to elevated first-
pass metabolism, pH-mediated breakdown, and lower ab-
sorption. The low cellular permeability of peptides is due to
the lower lipophilicity. Peptides can be directed either as in-
jectables or by employing other delivery routes, for instance,
Buccal, Transdermal, and Intranasal. Rapid renal clearance
and extensive proteolysis resulted in brief half-lives of pep-
tides. Strategies involving structural modification are primed
to boost peptide developability [30]. GI obstructs the distri-
bution of peptide drugs. Along the cellular peptidases from
mucosal cells, the brush-border membranes of epithelial
cells form a chief enzymatic blockade. Exopeptidases,
aminopeptidases, and carboxypeptidases in the GI break
down sequences from the N- and C-terminal, whereas en-
dopeptidases recognize cleavage sites with amino acid se-
quences [29]. The combination of aminopeptidases, exopep-
tidases, and exopeptidases aids rapid and competent degrada-
tion and acts as a considerable barrier to the processing of
peptide therapeutics and acid-labile peptide bonds, leading
to poor oral bioavailability. Chemical alterations at positions
that are quite vulnerable to enzymatic cleavage were stated
to increase in vivo stability [31].
4.1. Absorption
Upon ingestion, peptides go into an intimidating environ-
ment where they might undergo chemical or enzymatic
degradation. Dietetic protein gets hydrolyzed into a blend of
amino acids and small peptides by the suit of exopeptidases
[32]. The assimilation of peptides is restricted to dipeptides
and tripeptides. This involves facilitated diffusion that is dist-
inct from the amino acid carrier systems [33]. Either by
methylation of nitrogen present in the peptide bond or in the
terminal amino group or by conversion of carboxy-terminal
to amide group, absorption can be decreased [34]. General-
ly, active transport of intact tetra and higher oligopeptides
across the intestine does not occur [30, 34].
Passive diffusion via lipid membrane, transporter-mediat-
ed processes, and paracellular pathway are some of the path-
ways through which peptide absorption can occur. In vitro
permeability of minor molecules and transport-based assay
stages are mostly related to survey peptide permeability and
transporter characteristics; for instance, diffusion coeffi-
cient, Caco-2, Madin-Darrby canine kidney (MDCK), and
SMVT [35]. The major encounters of these assays assessing
peptide permeability are: degradation of the peptide by en-
zymes in the cellular system, pH mediated hydrolysis of pep-
tides, and non-specific binding of peptides to assay plates,
transwell filter membranes, and pipette tips.
A sink condition was created to diminish the impact of
non-specific binding, which resulted in the minimization of
nonspecific binding by the frequent addition of serum pro-
teins on the walls of the receiver [30]. Protease inhibitors or
cocktails are usually put into the system to lessen peptide
proteolysis. In order to enhance the permeability of the mem-
brane, pairs of one or the other hydrogen bond acceptor or
donors are usually added.
Hydrophobic or lipophilic coefficient, polar surface area,
size, and HB coefficient are the key descriptors involved in
peptide permeability. There is a need to stabilize the blood
samples for peptides having issues related to stability
[36-38]. In order to prevent nonspecific binding, hydrolysis
during sample preparation and sample analysis, protease in-
hibitors are added frequently to the cooled collection tubes,
usually nonabsorptive in nature [39]. Displacement proteins
(e.g., serum albumin) or proteins (structural analogues) are
now and then supplemented to compete for the binding sites
[30]. The solubility of peptides can be increased upon the ad-
dition of organic solvents, acids, salts, or surfactants
[39-41].
Oral drug delivery is the most attractive and supportive
approach for drug administration to the patient [42]. The ba-
sic obstacle in peptide formulation development is less oral
bioavailability due to enzymatic degradation and fast renal
clearance. The polarity and molecular weight of therapeutic
peptides also hinder absorption through the gastrointestinal
tract.
4.2. Peptidases and Proteases Affecting Plasma Lifetime
Blood, liver, and kidney are the important compartments
concerned about the degradation of peptides and proteins by
enzymes. The peptides/proteins that are orally administered,
either absorbed from the stomach or the intestine, enter into
the systemic circulation via vena portae.
Parenterally administered drugs have to pass to the liver
and kidney well supplied with blood (approx. 1-litre blood
per minute or more than that) [43]. The kidney, as well as
the liver, holds several proteolytic enzymes. Molecules ei-
ther bound to plasma proteins or having molar mass below
5kDa can pass through the filter completely. In the glomeru-
lar filtrate, there is only 1% of albumin with a molar mass of
69 kDa.
Peptides or proteins having hydrophilicity undergo degra-
dation by enzymes present in the blood or by enzymes
bound to the membrane rather than enzymes present exclu-
sively in the cytoplasm. Exopeptidases can be amino and car-
boxypeptidases [32]. Cleavage of the peptide at the N-termi-
nal is by aminopeptidases, while at C-terminal, it is by car-
boxypeptidases. Plasma, liver, and blood also contain numer-
ous exopeptidases. Protection of N or C terminal by the clea-
vage of exopeptidases is quite less challenging than modify-
ing peptide drugs to provide stability against endopeptidases
[32, 44].
4.3. Approaches to Improve Peptide Permeability
Approaches like N-methylation, cyclization, intramolecu-
lar hydrogen bonding, and flexibility lessen hydrogen bond-
ing potential, upsurge inflexibility, and enhance peptide
permeability [38, 45-48]. Cyclic backbone, seven N-methyl
groups, four intramolecular hydrogen bonds are various
6 Current Cancer Drug Targets, хххх, Vol. хх, No. хх Malviya et al.
strategies comprised by an 11-residue peptide, i.e., cyclos-
porin A [49, 50]. Other approaches may include the use of
pepducins, stapled peptides, and prenylated peptides, pro-
duced by many processes like pepducins by the lipidation of
the nitrogen terminal of the peptide by palmitoyl or other fat-
ty acids, stapled peptides formed by the connection of two
amino acids to upsurge stability, permeability, potency, and
flexibility of peptides [51, 52]. GI stability and oral bioavail-
ability can be increased by alterable lipidization to boost the
half-life of peptides [53, 54].
It overwhelms the limitations of a conventional lipidiza-
tion approach. Processes mediated by transport play a signifi-
cant role in oral absorption. Absorption enhancers can be
used to enhance the oral absorption of peptides. Permeabili-
ty can be enhanced by the use of surfactants, glycerides, fat-
ty acids, bile salts, etc., as these increase intestinal absorp-
tion [45]. Enhancers lead to an increase in permeability by
undergoing any of the following mechanisms: enhancing
transcellular permeability by altering membrane fluidity,
forming a noncovalent complex with a payload to be ab-
sorbed, and opening tight epithelial junctions [55].
Better penetration of peptides through the blood-brain
barrier is also achieved. It will be a very effective and inter-
esting approach in the treatment of various neurological dis-
orders. The study suggested that conjugation of endomor-
phin-1 with cell-penetrating peptide synB3 improves the
analgesic activity within the brain [56]. In an investigation,
it was observed that conjugation of Paclitaxel with LRP-1tar-
geting peptide enhances 15 folds improvement in the concen-
tration into the brain, resulting in better therapeutic effect
[57]. During a clinical study, it was observed that an anti-
cancerous drug conjugated with peptide improved the elimi-
nation half-life up to 21 h [58].
4.4. Approaches to Stabilize Peptides from Proteolysis
The numerous approaches leading to the improvement of
the ADME profile include cyclization, upsurges in the stabil-
ity and permeability, and macromolecular conjugation,
which enhances stability and diminishes renal clearance
[59-64]. Maintenance of potency and avoidance of toxicity
are important parameters affecting ADME and stability pro-
file [65, 66]. For instance, significantly prolonged plasma
stability of the immunogenic peptide MART-I27-35 by amida-
tion of the C-terminal or acetylation of the N-terminal. Also,
N-pyroglutamylation improved the enzymatic stability of
GLP-17-36 [67, 68]. Fatty acids have chain lengths extend-
ing from 4 to 18, coupled to RC-160 (somatostatin ana-
logue), having anti-proliferative activity. In comparison to
RC-160, numerous compounds displayed greater resistance
for trypsin and serum degradation [37, 38, 45, 69-73]. At-
tachment of polyethylene glycol covalently either or to both
of the terminals of the peptide or protein drugs can be
another approach. Modification in the N-terminal of glu-
cose-dependent insulinotropic polypeptide revoked function-
al activity, though PEGylation of GIPI-30 sustained full ag-
onism, which was stable to DPIV cleavage [74, 75]. Degra-
dation caused by exopeptidase can be prevented by the pro-
cess of cyclization, i.e., by the creation of an amide bond be-
tween the N and C terminals of peptides. Sometimes, the pro-
cess of cyclization may produce certain conformational
changes resulting in shape alteration that may lead to inactiv-
ity [76].
4.4.1. Replacement of L-Amino Acids by D-Amino Acids
Substitution of D amino acids in place of L amino acids
resulted in the decrease of substrate recognition and binding
affinity of proteolytic enzymes that, in turn, improved stabili-
ty [77].
4.4.2. Renewal of Labile Amino Acids
Another strategy to increase plasma half-life is the re-
placement of amino acids susceptible to enzymatic cleavage,
which results in delayed degradation. Stabilization can be im-
proved by the renewal of amino acids at both terminals [78].
4.4.3. Amendment and Cyclization of Amino Acids
Amendment and cyclization of amino acids can be used
as an approach to increase the stability of peptides either by
persuading steric hindrance or by a break-up enzyme recog-
nition [44]. Cyclization of protein or peptide is one of the
methods to reduce proteolytic degradation and to extend half
lifetime [44]. Cyclization introduces conformational cons-
traints in the peptide, reduces flexibility, and enhances stabil-
ity and penetrability. Depending upon functional groups, cy-
clization of peptides can be tail or head-to-side chain, head
to tail, or side-chain to side-chain. Lactamization, lactoniza-
tion, and sulfate-based bridge formation can be used to
achieve cyclization [28]. Serum stability can be enhanced by
the use of stapled peptides as they reinforce α-helix to form
a shield against the lysis of proteins. Stability, potency, and
selectivity can be improved by employing foldings created
by disulphide bridges [79-81].
4.5. Enzyme Inhibition
An interesting approach to enhance the half-life is the
co-administration of enzyme inhibitors with the peptides.
The administration of enzyme inhibitors produces an inhibi-
tory response, leading to the prevention of enzymatic degra-
dation of peptides. The inhibitory effect has already been ex-
hibited by various in vivo and in vitro experiments [82-85].
4.6. Renal Clearance
Renal clearance can be determined utilizing glomerular
filtration and reabsorption in the proximal tubule. Various
physicochemical properties and plasma protein binding can
be used to prognosticate renal clearance of a variety of com-
pounds [44]. Numerous peptides displayed positivein vitro
pharmacological activity but failed to reveal in vivo efficien-
cy. Rapid clearance and short half-life of peptides can ob-
struct their development into successful drugs [44].
Enzymatic proteolysis and rapid renal clearance are the
reasons for the rapid clearance of peptides from systemic cir-
culation. Reabsorption, a phenomenon occurring in the renal
Advancement and Strategies for the Development of Peptide-Drug Conjugates Current Cancer Drug Targets, хххх, Vol. хх, No. хх 7
tubule, is the whole sole responsible for short half-life and
rapid renal clearance [83].
Generally, conjugates are eliminated by the kidney and
metabolized by the liver. Pharmacokinetics also depend up-
on the type of peptide analogue and labelled radioisotopes.
Peptide conjugates have proven to be effective as diagnostic
agents as well as therapeutic agents. Conjugation of peptides
also enhances the retention of molecules in the body by re-
ducing renal clearance. Conjugation enhances the wider dis-
tribution of peptides as compared to a non-conjugated pep-
tide [86]. For example, in a study, it was found that PEGyla-
tion of Bac7 (an antibacterial peptide generated against Sal-
monella typhimurium infection) decreases renal elimination,
better cellular internalization, and wider distribution. The
conjugated peptide was also found in the liver and peritoneal
cavity, which was not observed in the case of the non-conju-
gated peptide.
Peripheral clearance is a limiting process for the dragga-
bility of therapeutic peptides after administration. Renal
clearance and receptor interaction are the key pillars affect-
ing the pharmacokinetics of molecules. Intravenous delivery
has been carried out for a few decades, but it is less conve-
nient, less acceptable for the patients, and costly [87]. Other
routes of parenteral delivery such as transdermal, subcuta-
neous, depot, and intramuscular are gaining the interest of
scientists worldwide. These new drug delivery routes for
peptides also provide the advantage of self- administration
[88]. Considerable effort should be made for the develop-
ment of non-invasive drug delivery approaches such as oral,
transdermal, nasal, ophthalmic, and inhalational. Computer
modelling and drug design approaches should be applied to
predict the pharmacokinetics of peptides for better druggabil-
ity [89]. The structural uniqueness of peptides helps in
reaching the target site and prevents peripheral toxicity. Re-
nal elimination of peptide molecules is inversely proportion-
al to the molecular weight. As shown in the literature,
molecules with less than 50 kDa are preferably removed by
the kidney. Glomeruli pore size of about 8 nm can easily re-
move the peptide molecules that are below 50 kDa [90].
Modification of the peptide molecular weight up to the opti-
mum level is a challenging effort to reach up to desired phar-
macokinetic in terms of circulation time and half-life. As dis-
cussed by Patel et al., conjugation of peptides to polymers
such as polysialic acid, PEG, and starch derivatives showed
reduced renal clearance [90]. Turecek et al. also observed
that PEGylation of erythropoietin and human growth hor-
mone improved the half-life by about 14 and 400 times, re-
spectively [91].
Another approach for increasing the molecular weight of
peptides is to fuse the peptides with serum/circulating pro-
teins. It decreases the rate of clearance by reducing glomeru-
lar filtration. Plasma binding of therapeutic peptides reduces
its clearance significantly [92].
Conjugation of peptides with fatty acids leads to the de-
velopment of lipopeptides, and lipopeptides have a better
ability to interact with circulating albumin, further resulting
in improved circulation time. In a study, Poon et al. showed
that binding of insulin with myristic acid increases the ac-
tion duration of insulin [93].
The same concept of improved circulation time by slow
clearance was also supported by Guja et al. in their study.
The investigator showed that binding of semaglutide (gluca-
gan-like peptide) with fatty acid improved the half-life up to
168 compared to the initial half-life of 3-6 h [94].
4.7. Intensification of Plasma Protein Binding
Intensification of plasma protein binding resulted in in-
creased binding to membrane or serum proteins and de-
creased renal clearance [95, 96].
4.8. Large Polymer Conjugation
Renal clearance can be reduced by increasing hydrody-
namic or molecular volume by conjugating with large poly-
mers, resulting in a bulkier molecule. Hydroxyethyl starch,
polysialic acid, and polyethylene glycol are the commonly
used polymers for peptide conjugation [81].
4.9. Blending to Plasma Proteins
Blending to plasma proteins like albumin and immuno-
globulin (IgG) reduces renal clearance, resulting in high
MW [53]. Elimination and renal clearance can be reduced
by binding to the Fc receptor and covalent linkage to albu-
min [97].
5. PEPTIDE-DRUG CONJUGATE FOR CANCER DI-
AGNOSIS AND TREATMENT
The general peptide-drug conjugate for cancer diagnosis
and treatment is summarized in Fig. (3).
Fig (3). Schematic diagram to represent the general peptide-drug
conjugate for cancer diagnosis and treatment. (A higher resolution /
colour version of this figure is available in the electronic copy of
the article).
8 Current Cancer Drug Targets, хххх, Vol. хх, No. хх Malviya et al.
Fig. (4). Schematic representation of drug-linker-peptide formulation development and selective cancer cell targeting. (A higher resolution /
colour version of this figure is available in the electronic copy of the article).
As mentioned in the literature, the number of diagnosed
cancers might rise to 27.5 million by 2040 [98]. Radiation
therapy is used as curative therapy. High energy damages
the genetic material of cells and prevents their growth. As
discussed by Chau et al., five drug-antibodies conjugates
have been approved by USFDA and European regulatory
agencies, and many more are under clinical studies [99].
High molecular weight is a major limitation that prevents
the diffusion of monoclonal antibodies into tumour cells. Im-
munogenicity, non-selectivity, high cost of production, and
time-taking process are the limitations of monoclonal anti-
bodies to be used as therapeutic agents for cancer therapy.
The use of small peptides eliminates the drawbacks associat-
ed with monoclonal antibodies [98]. Less immunogenicity,
low molecular weight, non-toxic metabolites, and good pene-
tration ability lead to a significantly better therapeutic effect
of peptides than monoclonal antibodies. Energy-dependent
and energy-independent processes are responsible for the
penetration of peptides into tumour cells [98]. Cell-penetrat-
ing peptides showed low cellular specificity, hence the limit-
ed application. Cellular targeting peptides become an ideal
carrier for drug targeting. N terminal of the peptides is not in-
volved in receptor recognition; therefore, it becomes an ide-
al site for modification. Drug conjugation with peptides can
be achieved at multiple sites and easily gain higher drug con-
centration in conjugates [4]. High payload loading improves
the therapeutic effect of peptide conjugates. Selective drug
targeting has been identified as a major challenge in the de-
signing of effective anti-cancerous formulation develop-
ment. The drug-linker-peptide formulation development and
targeting into cancer cells is represented in (Fig. 4).
Peptides and monoclonal antibodies are of staggering in-
terest in the biomedical community for cancer therapy and
diagnosis. A large number of clinical investigations also elic-
it that industries are continuously investing in the develop-
ment of peptide therapeutic agents. As shown in different
works of literature, more than 600 peptides/monoclonal anti-
bodies are in clinical studies within the United States [88,
89].
Peptide conjugates may alter half-life or selective tissue
distribution or both, based on conjugating molecules. The
conjugate formation also improves the localization of thera-
peutic active molecules into target tissues [100]. Peptides
generally consist of ˂50 amino acids and are stabilized by di-
sulphide bonds. It makes sense to use specificity to bind a re-
ceptor for receptor targeting in many disease models. A se-
lective peptide can preferably bind to a protein receptor site
and inhibit the interaction of another peptide, hence pre-
venting the oncogenic protein interaction [2]. The amino
acid sequence in a peptide chain can be easily altered to im-
prove the interaction between peptide and protein receptors
due to easy biological techniques.
Peptide modulated delivery should be strengthened in
the future to control the disaster associated with the disease.
Peptide-based therapy optimization can be proved as a po-
Advancement and Strategies for the Development of Peptide-Drug Conjugates Current Cancer Drug Targets, хххх, Vol. хх, No. хх 9
tent weapon against the war on cancer [101]. Classical thera-
pies of cancer have serious limitations, including side effects
associated with peripheral toxicity. Tumour identification
characteristics of active therapeutic agents are the ultimate
goal of the novel treatment approaches [102].
Antibodies are used as an imaging agent in tumour detec-
tion. The half-life of antibodies ranges from 1 week to 3
weeks, and these properties lead to significant background
noise during tumour imaging. A fragmented engineered pep-
tide chain of antibodies is now developed and preferred for
the detection of tumour cells. Modification in the pharma-
cokinetics of antibodies leads to better tumour cells contrast
ratio. Smaller peptide fragmentation also leads to a higher
rate of renal clearance, hence lowering down the lag time be-
tween detection and administration [101, 1].
Accumulation of drug-protein conjugates in cancer cells
is represented in (Fig. 5).
Fig. (5). Accumulation of drug-protein conjugates in cancer cells.
(A higher resolution / colour version of this figure is available in
the electronic copy of the article).
By using polymeric nanoparticles, it may be possible to
achieve targeted delivery of drugs to specific cells, im-
proved delivery of hydrophobic drugs, and their controlled
release [103]. The protein nanoparticle conjugates were ef-
fectively taken up by cells and accumulated specifically in
cancerous cells, based upon the interaction with some specif-
ic protein receptors in caveolae and caveolae-mediated trans-
cytosis on tumor cells [104, 105].
The currently approved protein-nanoparticle conjugate
has improved the therapeutic index of the drugs mainly by
improving the drug efficacy and reducing drug toxicity. Due
to the addition of targeting ligands, the functionality of tar-
geting ligands becomes more complex. There is a need to
precisely design nanoparticles to achieve targeted function
[106].
The targeted delivery of nanoparticle-ligand conjugate in-
to cancer cells is represented in (Fig. 6). Bombesin is a pep-
tide obtained from the skin of the Bombina frog. The half-
life of Bombesin analogues was found to be 0.5 to 1.5 h.
Conjugation of Bombesin with Technetium-99m (99mTc) im-
proved the half-life up to 6h. 99mTc labelled Bombesin ana-
logue was found to be useful in the detection of cancer
[100].
Liolios et al. also showed that 99mTc labelling of
Bombesin analogue showed improved pharmacokinetics and
enhanced cellular targeting. The contrast ratio between tu-
mour cells and normal cells was improved for ease of diag-
nosis [108].
As discussed by He et al., conjugation of FITC with CS-
NIDARAC peptide results in selective targeting into tumour
cells for a better diagnosis. Labelled peptide quickly cleared
from the non-tumour tissues after 2 h [108]. The outcomes
of Dijkgraaf et al. research also supported the outcomes of
He et al. Dijkgraaf et al. showed that labelling of RGD pep-
tide with NODAGA chelator and Al18F, 68Ga, or 111In al-
so improved the selective tumour cell distribution. Labelled
peptides are easily eliminated from the body after 2h, espe-
cially through renal clearance [109]. Some other researchers
also showed that conjugation with peptide molecules could
be used to alter the pharmacokinetics of molecules. Conju-
gated peptides showed better cellular internalization by tu-
mour cells [109, 110].
Conjugation with relatively higher molecular grafts dra-
matically changed the pharmacokinetics of conjugates even
though it retarded their selectivity towards the tumour cells.
In a study, it was also observed that 124I labelled ApoPep-1
was selectively distributed into tumour cells and used to
identify apoptosis [111].
In another study, Lee et al. observed that labelled
molecules were selectively bio-distributed into unhealthy
neurons, specifically due to Parkinson’s [112].
The exploitation of the pharmacokinetic profile of pep-
tide/protein can be easily achieved by conjugation, which im-
proves the characteristics in terms of tumour detection and
targeting with inhibited systemic exposure [1]. For tumour
detection, the size of the peptide should be smaller, and
clearance should be higher. For better therapeutic effect, pep-
tides should have a longer circulation time (half-life) and se-
lective tumour targeting.
Peptide ligand activates the receptors and becomes a ma-
jor area of attraction for targeted cancer therapy. These re-
ceptors are overexpressed in tumour tissues compared to
healthy cells. When active therapeutic agents are conjugated
with peptide ligand, they become the promising carriers for
cancer cell targeting [105, 113]. Modulation in conjugation
structure improves cellular internalization, selective deliv-
ery, and cell death (Fig. 7). In the context of the delivery sys-
tem, novel drug delivery systems such as niosomes, lipo-
somes, and nanoparticles are preferred over the conventional
delivery system.
10 Current Cancer Drug Targets, хххх, Vol. хх, No. хх Malviya et al.
Fig. (6). Schematic diagram to show the nanoparticle ligand binding to the overexpressed receptor at cancer cells. (A higher resolution /
colour version of this figure is available in the electronic copy of the article).
Fig. (7). Process of protein-drug ligand binding to cellular recep-
tors and subsequent cell death. (A higher resolution / colour ver-
sion of this figure is available in the electronic copy of the article).
The drug is loaded into the particulate delivery system,
and the particle surface is decorated with peptide ligands
[113]. It enhances the per particle concentration of the drug
into tumour cells. A schematic diagram to develop liposom-
al-peptide conjugate for targeted delivery of the drug into
cancer cells is represented in (Fig. 8).
A schematic diagram to present engineered liposomal
formulation conjugated with antibody epitope for targeted
cancer therapy is shown in Fig. (9).
Integrins receptors are transmembrane receptors overex-
pressed in tumour cells. αvβ3 is an important target receptor
among integrin receptors identified as a valuable resource
for cell adhesion, migration, and internalization [114]. An ex-
tracellular matrix consisting of a tripeptide (arginine-g-
lycine-aspartic acid motif) is used for αvβ3 targeting. A
cyclic form of this tripeptide is the preferred form for conju-
gation with the drug carrier system. GnRH-R receptor signal
blocking in tumour cells with peptide antagonists shows an-
tiproliferative effect [115]. Drafting of peptide ligand conju-
gate is a suitable means by which peptide receptors of tu-
mour cells can be easily targeted by the drug. Generally, pep-
tides are considered safe, show no or very little immuno-
genicity, and produce fewer toxic metabolites [115]. Peptide
backbone modification, including cyclization, methylation,
or change in amino acid sequence, eliminates the limitations
associated with small peptide molecules, such as short half-
life due to fast clearance and in vivo proteolytic degradation.
Lipidation of the peptide is a novel approach for improving
the characteristics of peptides for systemic retention. It in-
cludes attachment of the small fatty acid moiety to the pep-
tide chain, which provides a protective effect and hence sys-
temic retention [116]. Based on this concept, two products
are marketed viz. Ozempic (semaglutide) and Victoza (lirag-
lutide); both are glucagon-like peptide-1 receptor agonists
and are used in the treatment of diabetes.
Peptide molecules can be helpful in the diagnosis of can-
cer and targeting chemotherapeutic agents and radionucli-
Advancement and Strategies for the Development of Peptide-Drug Conjugates Current Cancer Drug Targets, хххх, Vol. хх, No. хх 11
Fig. (8). Representation of liposomal surface modification using peptide ligand for selective cancer targeting. (A higher resolution / colour
version of this figure is available in the electronic copy of the article).
Fig. (9). Engineered liposomal formulation using antibody epitope and infrared radiation-induced targeted management of cancer cells. (A
higher resolution / colour version of this figure is available in the electronic copy of the article).
12 Current Cancer Drug Targets, хххх, Vol. хх, No. хх Malviya et al.
Fig. (10). Representation of the cellular internalization of peptide linked nanoparticles (selective targeting) and non-targeted nanoparticles
(no-targeting). (A higher resolution / colour version of this figure is available in the electronic copy of the article).
des. In cancer management, peptides can be used to target
unhealthy tissues, improve cell permeability or pore forma-
tion, and antimicrobial effect [2]. Pore-forming peptides are
part of the human defence system and are found in humans.
They are cationic; therefore, they easily bind to the anionic
microbial cell membrane that further leads to cell death.
Pore-forming peptides cause necrosis or apoptosis. NRC-3
and NRC-7 are peptides obtained from Pleuronectes ameri-
canus. Treatment of human breast cancer cells with these
two proteins showed the improved anti-cancerous effect of
cisplatin [116].
Buforins are peptides obtained from the Bufo bufo gar-
garizans, which showed an anti-cancerous effect against cer-
vical carcinoma and leukaemia [116]. NRC-3, NRC-7, and
Buforins are pore-forming peptides that have significant po-
tential against human cancerous cells. In a study, Lim et al.
designed a peptide CPP derived from HIV and observed that
this peptide has an anticancerous effect against HeLa cells
and human colon cancer cells [117]. It was also observed
that CPP-conjugated doxorubicin was effective against
drug-resistant human breast cancer cells [118]. Tumour tar-
geting peptides are markers especially expressed on the re-
ceptors found in tumour cells. RGD is a peptide that selec-
tively binds to integrin (present over cell membrane) [119].
In a study, RGD (a peptide) was fused at the surface of lipo-
somes containing doxorubicin and showed improved effica-
cy against human melanoma cells [117]. NGR is another tu-
mour targeting protein. When delivered with doxorubicin, it
showed enhanced activity against human fibrosarcoma.
NGR is selectively bound to CD13 cells overexpressed in
the tumour cell membrane [118, 119]. Peptides having the
cellular penetrating ability have been used for the manage-
ment of cancer therapy. In a study, such peptides were conju-
gated with Tat peptide and internalized within the human
breast cancer cells, leading to the release of pro-apoptotic
peptides and inhibition of cell growth. It also showed inhibi-
tion of melanoma cells, lung cancer cells, and cervical can-
cer cells [120-122]. (Fig. 10) represents the difference in the
behavior of cellular internalization of peptide-linked nano-
particles (cellular targeting) and non-targeted nanoparticles.
The fate of peptide ligand coated nanoparticles in tumor
cells is represented in (Fig. 11).
Pentapeptide-containing biopolymers are temperature
sensitive and have been used to deliver antibodies, proteins,
and DNA into solid tumours [123]. Meyer et al. also showed
two folds more accumulation of pentapeptides into solid tu-
mours [124].
PEGylation involves the conjugation of small peptides
with polyethylene glycol. It increases the half-life of the pep-
tide by reducing renal clearance. In individuals, PEG may
lead to the production of antibodies against them. In a study,
Schellenberger et al. developed 864 amino acid-long pep-
tide, i.e., STEN, which mimics the PEG and is less immuno-
genic [125, 126]. In a study, glucagon-like peptide-2 ana-
logue was conjugated with XTEN, and an improved half-life
of the peptide was observed in animals [127]. Conjugation
of the peptide with the drug also improves the peptide solu-
bility. In a study, Xiao et al. conjugated the betaine with
CG-T20 and CG-GPRT and observed that the solubility of
both proteins was improved significantly [128].
Mitogen-activated protein kinases are found to be overex-
pressed in tumour cells. They trigger the signals for cellular
events that lead to the uncontrolled growth of cells. Some
Advancement and Strategies for the Development of Peptide-Drug Conjugates Current Cancer Drug Targets, хххх, Vol. хх, No. хх 13
Fig. (11). Mobilization of peptide ligand coated nanoparticles in tumour cell. (A higher resolution / colour version of this figure is available
in the electronic copy of the article).
therapeutic peptides have the capabilities to inhibit these ki-
nases and prevent cell proliferation [129]. Extracellular sig-
nal-regulated kinase inhibitors have a potential therapeutic
effect against tumour cells.
In humans, four cardiac peptides viz. atrial natriuretic
peptide (ANP), vessel dilator peptide, long-acting natriuretic
peptide (LANP), and kaliuretic peptide are found and
showed significant anticancerous activity against various
cancer cells. Inhibition of epidermal growth factors is a ba-
sic phenomenon behind their anticancer effect [130, 131].
Other peptides having an inhibitory effect against prostate
cancer are vessel dilator and kaliuretic peptides. They act by
inhibiting Ras [132].
JNK1/2 is another class of MAPKs, which is overex-
pressed in various types of cancers. Conjugation of Tat pep-
tide with JNK peptide inhibitors showed an inhibitory effect
on mammary cancer cells [133].
Inhibition of the cell cycle by therapeutic peptides is a
simple and progressive approach to control the proliferation
of cancer cells. In a study, it was shown that the movement
of the G1 to S phase cycle in the cell could be inhibited by
tumour suppressor protein p16 by binding to Cdk4/6. In tu-
mour cells, p16 is observed to be muted and induces apopto-
sis [134]. In a study, CT20 peptide was encapsulated into
nanoparticles and showed an inhibitory effect against human
breast cancer and colon cancer cells [135]. A synthetic pep-
tide RRM-MV containing 18 amino acids showed an inhibi-
tory effect against human squamous carcinoma and mouse
melanoma [136]. IL-12 is a cytokine that has inhibitory ac-
tivity against different types of cancers. RRM based bioac-
tive peptide was designed, and it showed properties of IL-2
[137]. P53 is a muted protein generally found in human can-
cer cells; at higher concentrations, it promotes the apoptosis
of cells. Different peptides/peptide derivatives have been uti-
lized to inhibit the expression of P53, resulting in inhibition
of colony formation in cells [138-140]. The use of che-
motherapeutic agents for cancer therapy is a trademark for
clinicians. Cytotoxic drugs affect cancer cells with healthy
cells. Application of chemotherapeutic drug locally or target-
ing of drug to specific tissues after administration prevent
the toxic effect of a drug to healthy tissues [141].
X-rays and gamma rays are, in general, electromagnetic
rays used for cancer therapy. They act by destroying genetic
material, hence preventing cell proliferation. Generation of
secondary malignancies is the drawback of using radiation
therapy [142]. Overexpression of cell surface protein of tu-
mour cells allows a new approach for the targeting of a che-
motherapeutic agent into malignant cells. In this approach,
chemotherapeutic agents are bound with molecules that have
target potential towards overexpressed cell surface proteins
for efficient delivery. Tumour selectivity can be directly
achieved by using antibodies, proteins, and peptides [143].
Peptide drug conjugate formation, selective binding at tu-
mour cells, and internalization are shown in (Fig. 12).
Studies also showed that a single peptides molecule
could target multiple receptors to treat more than two diseas-
es. For example, a hybrid peptide dopastatin can be used to
treat neuroendocrine disorders with tumour pathology [42].
Monoclonal antibodies have been used as magic bullets to
treat cancer. However, the excessive molecular mass of anti-
bodies limits their potential applications. The most sensitive
tool to identify neuroendocrine tumours is the binding of a
radiolabeled ligand to tumour receptors. Radiolabeling of so-
matostatin with Y90 is an effective method for the selective
identification of the tumour and also showed a reduction in
the tumour cells growth [144, 145].
In vitro autoradiography is an interesting tool used to pre-
dict receptor data for improved cancer therapy. This in vitro
method showed overexpression of somatostatin receptors.
Further study is required to investigate the overexpression of
14 Current Cancer Drug Targets, хххх, Vol. хх, No. хх Malviya et al.
Fig. (12). Representation of peptide-drug conjugate formation, their selective binding at the overexpressed cellular receptor, and subsequent
internalization. (A higher resolution / colour version of this figure is available in the electronic copy of the article).
other peptide receptors in distinguishing tumour cells. It will
surely be useful for selective targeting of active therapeutic
peptides into tumour cells. The strong focus of clinical scien-
tists on nuclear medicine will open diverse strategies for tu-
mour cell detection and treatment [145].
Tumoral receptors have the ability to prefer binding with
peptide/peptide analogue. This results in the radiotherapeu-
tic drug targeting and diagnosis of peptide molecules. Li-
gand receptor interaction becomes important when the recep-
tor helps in the internalization, e.g., G protein-coupled pep-
tide receptor. G protein-coupled receptor itself internalize in-
to the cells with ligand (agonist) attached to it [146]. In-DT-
PA-[d-Phe1]-octreotide is a commercially available peptide
that is developed by “Octreoscan, Mallinckrodt, Inc., St.
Louis, MO” and rapidly internalized in a receptor-specific
and temperature-dependent manner [147]. Ectopic overex-
pression of receptors in tumour cells provides a chance for
selectivity.
Despite all the advantages of using nanoparticles as
agents for targeted drug delivery, nanoparticles do have
some limitations. For instance, their small size and large sur-
face area may lead to particle aggregation, which makes
their handling quite difficult in liquid and dry forms. Be-
sides physical limitations, they do have some physiologic
limitations as well. For example, their small size limits the
drug loading capacity and may lead to the burst release of
the drug. Polymer degradation may also be affected by parti-
cle size [148, 149].
6. PATENTS BASED ON PEPTIDE/PEPTIDE DRUG
CONJUGATE FOR CANCER THERAPY
Table 1 summarizes various patents based on the utiliza-
tion of peptide/peptide analogue for cancer therapy
[150-174].
Table 2 summarizes various patents based on the utiliza-
tion of peptide/peptide analogue which binds with HLA
molecule for cancer therapy [175-179].
7. CLINICAL STUDIES OF PEPTIDE/PEPTIDE ANA-
LOGUE FOR CANCER THERAPY
Nowadays, one of the most prominent reasons for death
worldwide is cancer. It is increasing rapidly and may even
exceed deaths by cardiovascular diseases. Despite recent ad-
vancements in treatment procedures, cancer still contributes
significantly to global morbidity and mortality [180]. Cancer
mortality is set to rise above that of cardiovascular diseases.
In 2018, The International Agency for Cancer Research’s lat-
est cancer statistics show that there were approximately 18.2
million new cancer cases and 9.5 million cancer deaths
worldwide [181].
Although there are many conventional antitumors in use
currently, their therapeutic impact is still not satisfactory and
may not meet the clinical demands. As a result, new thera-
pies with high specificity and low toxicity are required
[182]. The increase in efficacy and safety of anti-cancerous
drugs is mainly due to the alteration and development of an-
Advancement and Strategies for the Development of Peptide-Drug Conjugates Current Cancer Drug Targets, хххх, Vol. хх, No. хх 15
Table 1. Patent based on the utilization of peptide/peptide analogue for cancer therapy.
S.
No. Work Done References
1.
Inventor proposed that peptide or peptide analogue of the biologically obtained peptide such as a mammalian gastrin-releasing peptide, neu-
romedin B, neuromedin C, amphibian bombesin, or litorin can be used to treat human cancer by cell inhibition. These peptides have 8 to 10
amino acids and can be effective against colon, prostatic, pancreatic, lung and breast cancer in humans.
[150]
2.
Inventors used HYD1 peptides and their fragments or variants as anticancer agents for the treatment of myeloma. Peptides and their frag-
ments or analogues were able to improve the anticancerous properties of chemotherapeutic agents. Peptides easily bound to β1 integrin re-
ceptor and showed cell growth inhibition. Immobilized peptides can remove circulating tumour cells from the blood. Inventors also showed
that immobilized peptide was able to detect circulating tumour cells within the blood by using specificity towards receptor binding.
[151]
3.
In this patent, inventors isolated or purified specific peptide-based molecules and used them as anti-tumour agents. Peptides have acetyl
group at N-terminal and an amine group at C-terminal. The peptide was linked with lipid carrier or liposomes or nanocapsule. The peptide
was a synthetic part of the human androgen receptor and was used to treat prostate and breast cancer. Peptide analogue can be used in the
development of tumour diagnosis, assay, and treatment.
[152]
4.
Inventors showed that some peptide and their mixture have antitumor activity. The peptide has almost 80% identical amino acid sequence
as SEQIDNO5, SEQIDNO7, SEQIDNO8 or their modifications. Formulation composition has significant anticancerous properties against
breast cancer.
[153]
5. In the invention, peptide analogue associated with melanoma was selected and showed effective treatment and diagnostic strategy against
melanoma. Melanoma peptide analogue also showed better immunogenicity. [154]
6. Inventors have shown that peptides obtained from syndecan 1 can be used to control the growth of the tumour. Peptides hinder the interac-
tion between α4β6 and HER2 and prevent tumour tissue invasion. [155]
7. In the patent, peptide molecules are selected as the target and are used to diagnose and treat colorectal cancer. The peptide also helps in
recognition of tumour cells. [156]
8.
In the patent, inventors discovered specific peptides having affinity to target blood vessels of tumour cells. In the invention, it was pro-
posed that conjugation of radioactive component and anti-tumour drug doxorubicin with discovered peptide can diagnose tumour cells and
selectively treat only tumour tissues. It was also disclosed that drug-peptide conjugates were entrapped into liposomes for administration.
[157]
9.
In the invention, peptides (peptide A and peptide B) were identified which had anti-inflammatory activity. Both the peptides were stable
during circulation. The inventor disclosed that the administration of peptides with chemotherapeutic agents (gemcitabine, fluorouracil, leu-
covorin, etc) could treat pancreatic cancer.
[158]
10. The inventor discovered a peptide with the ability to selectively uptake cancer cells. Anticancerous agents conjugated to identified peptide
were able to deliver drug specifically to tumour cells and prevent peripheral toxicity. [159]
11.
Inventors isolated a peptide used for breast cancer targeting. They also prepared anticancer drug conjugate with target peptide as micropar-
ticulate drug delivery systems. Targeting of anticancer drugs into the breast cancer cells was achieved by using peptide as targeting
molecules and liposomes as delivery carriers.
[160]
12. Inventor disclosed a tumour-targeting peptide that comprised of a motif that is connected with C-terminal or N-terminal of amino acid. A
peptide can penetrate selectively into tumour vessels and is helpful for the diagnosis and treatment of the tumour. [161]
13. Inventors disclosed that peptide combinations have the ability to bind specifically to the neuropeptides present over the cellular membrane
and show anticancer activity. [162]
14. Inventors showed that oral administrable composition, consisting of apolipoprotein helix resembling peptides with amino acid pair and
other molecules, can be utilized for the treatment of cancer. [163]
15. It was shown that tumour infiltering T lymphocytes can recognize specific peptides and can be used for the vaccination with improved im-
munogenicity for the treatment and diagnosis of melanoma. [164]
16.
It was shown that administration of chemotherapeutic agents with some peptides having anti-inflammatory activity is a suitable method for
the treatment of pancreatic cancer. It was also disclosed that peptides have amino acid sequence Lys-Phe-Arg-Lys-Ala-Phe-Lys-Arg-Phe-
Phe.
[158]
17.
In the patent, inventors developed chimeric peptide which has the capability to target cancer cells. Targeting is achieved by interaction with
overexpressed EGFR present over cancer cells. Targeting was achieved by using chimeric peptides with EGF receptor binding peptides and
cytotoxic peptides.
[165]
18. It was disclosed that peptides obtained from syndecan 1 can inhibit α4β6 interaction with HER2. Inhibition of interaction results in the pre-
vention of tumour growth. [155]
19. Inventors showed that forkhead box M1 is overexpressed in cancer patients from Japan. Peptides obtained from the forkhead box M1 acti-
vate the human killer T cells and are helpful in cancer immunotherapy. [166]
20. It was disclosed that peptides that can bind MHC class I polypeptide sequence A anticancer agents can be combined with peptides for tar-
geted delivery into cancer cells. [167]
21. Inventors disclosed a peptide that has taken by specific cancer cells. Conjugation of a peptide with anticancer drugs provides a means for
drug targeting into cancer tissues. The mentioned peptide can be selectively used for the diagnosis and imaging of cancer and tumour cells. [168]
22.
It is shown in the patent that tumour-associated antigen peptides were used as vaccines for the anti-tumour effect. Antigen derived from the
Uroplakin, prostate-specific antigen, prostate acid phosphate, and Teratocarcinoma-derived growth factor can be used as a vaccine against
the tumour.
[169]
(Table 1) contd....
16 Current Cancer Drug Targets, хххх, Vol. хх, No. хх Malviya et al.
S.
No. Work Done References
23. Invention showed that overexpression of CDH3, EPHA4, and other molecules can be used as a target site for the treatment of cancer. A pep-
tide having a specific amino acid sequence was also related to the expression of cytotoxic T cell. [170]
24. Inventor disclosed a peptide derived from surviving which belonged to MHC Class I- restricted T-cell epitopes. The peptide can recognize
tumour cells and can be used for the diagnosis and treatment of cancerous cells. [171]
25.
Inventors showed a library of the peptides to identify colon carcinoma cells (HT29) based on differentiation. A peptide consisting of 9 ami-
no acids and disulphide linkage can bind on the cell surface of HT29 cells and easily internalize within the cells. A peptide can be used for
the detection and treatment of colon cancer cells.
[163]
26. Inventors disclosed a tumour vascular homing protein having a molecular weight between 1 to 100 kDa. The mentioned protein can be easi-
ly fused with the anti-cancerous drug (alkylating agent) to reduce the solid tumour load in the patient. [172]
27. Inventors disclosed a peptide ligand that has an affinity towards G-protein coupled receptors. Disclosed protein has an affinity to treat skin
cancer, tumour progression, and tumour size reduction. [173]
28. It was reported that a receptor-bound peptide selectively moved into the tumour of blood vessels and cells. Drug conjugation with the pep-
tide can be used for the targeting of tumour cells. Conjugation of a peptide with an antitumor agent can be used for the treatment of cancer. [174]
Table 2. Patent based on the utilization of peptide/peptide analogue which binds with HLA molecule for cancer therapy.
S.
No. Work Done References
5.
In this patent, inventors derived a peptide consisting of 15 to 20 amino acids from Telomerase reverse transcriptase protein and showed
that it can be used for antitumour immunotherapy. The peptide is capable of binding with HLA class II and stimulating various responses
associated with CD4. Modified peptides also showed resistance against proteolysis and improved immunogenicity.
[175]
6.
Investigators showed that HLA class I molecules are overexpressed on the cellular surface of hepatocellular carcinoma. Investigators select-
ed peptides having 8 to 50 amino acids sequences. Peptides were derived from serine and phosphoserine. Peptides can bind selectively to
HLA molecules and hence show selectivity towards the carcinoma cells. The prepared composition can be easily administered as a vaccine
for the selective treatment and diagnosis of hepatocellular carcinoma.
[176]
7. In the invention, peptides were isolated, which have the potential to bind with HLA antigen. Peptides were derived from the tumour-associ-
ated antigens and have potential against cancer cells when administered in the form of a vaccine. [176]
8. In the invention, epitope peptide was derived from survivin and they have properties to bind HLA molecule. Survivin is a good inhibitor of
apoptosis. The peptide can identify tumour cells. [171]
9.
Inventors isolated peptides that can bind HLA antigen. Selective binding to HLA leads to tumour targeting of a peptide. Selective tumour-
targeting eliminates the chance of peripheral toxicity. Inventors showed that peptide can be easily targeted for breast cancer, cervical can-
cer, colorectal cancer, and prostate cancer.
[159]
10.
In the invention, the inventor showed that specific peptides HLAA*0201 are overexpressed on ovarian cancer tissues. Overexpressed pep-
tides can stimulate an immune response in ovarian cancer and other proliferative diseases. Peptides are also used in the diagnosis of
ovarian cancer and other proliferative diseases. Inventors also disclosed that peptide can be utilized for the targeting of cancer cells.
[177]
11.
It is shown in the patent that specific peptides HLA A*0201, B*0301, B*0702, and B*2705 are expressed over cancer cells. These proteins
can be used for the detection and diagnosis of cancer. Expressed proteins can be easily used as target sites for the treatment of colorectal
cancer.
[178]
12. Inventor isolated peptides or fragment of peptides that were obtained from SEQ ID NO-45. SEQ ID NO-45 can bind HLA antigen and fur-
ther promote cytotoxic T lymphocytes. The selectivity of a peptide can be utilized to target cancer for diagnosis and treatment. [179]
Fig. (13). Graphical representation to show the increase in the num-
ber of peptides in clinical trials each year. (A higher resolution /
colour version of this figure is available in the electronic copy of
the article).
ticancer drugs and also due to the discovery of a new drug
delivery system. This new strategy deals with proteins and
peptides receptors present on tumour cells for cancer thera-
py. There are various peptide drugs with various clinical
trials underway. Over the past year, peptides have become
promising therapeutic agents in cancer therapy [182]. The
graph illustrates (Fig. 13) the data in the 1970s, 1980s,
1990s, and 2000s; it was 1.2, 4.6, 9.7, 16.8 per year, respec-
tively. In the clinical and preclinical development, there are
hundreds of peptide applicants in the process.
Several synthetic drugs and vaccines which are based on
a peptide are currently in clinical trials. The information re-
lated to the clinical trial is updated by national institutes of
health (NIH) and available on the website of the clinical
trial, i.e. clinicaltrials.gov [183]. In total, 792 studies be-
tween 1995 and 2019 were identified and researched for can-
Advancement and Strategies for the Development of Peptide-Drug Conjugates Current Cancer Drug Targets, хххх, Vol. хх, No. хх 17
cer, peptide, and other keywords. Vaccination based on pep-
tide was used as a self-sustaining adjuvanted therapeutic ap-
proach or used along with chemotherapy, radiation therapy,
or immunotherapies as another form of treatment. These
types of studies include patients with blood cancer, brain tu-
mours, non-small cell lung cancer (NSCLC), cancer of the
breast, prostate carcinoma, melanoma, ovarian carcinoma,
cervical cancer, hepatocellular carcinoma, and biliary tract
cancer [183-187].
For example, vaccination with Wilm’s (WT1) tumour 1
peptide and drug OK-432 in combined form in pediatric
solid tumour patients proved to be safe for these children.
CIGB -300 (an amidated disulfide cyclic undecapeptide)
was combined with the TAT cell-penetrating peptide via Be-
ta-alanine spacer, inhibiting phosphorylation mediated by
CK-2 and leading to apoptosis of cancer cell in non-small
cell lung cancer (NSCLC) patient [188]. Along with this, in
the gynecological cancer patient, a modified peptide vaccine
(WT1 9-mer peptide vaccine) was also used to activate
myeloid dendritic cells and it has been shown that it is asso-
ciated with T lymphocytes activation that is cytotoxic [182].
Besides, in a Phase I study, the WT1 pulse dendritic vaccine
was used to treat patients with cancer whose pancreas was re-
sected surgically. After this, the peptide vaccine (WT1) was
tested in gynaecological cancer patients in phase II of clini-
cal study [188-190].
LY6K-177 is a peptide vaccine which is emulsified with
Montanide ISA 51 was tested in a patient of gastric carcino-
ma as a phase I clinical study, and it has been shown that it
can also be used for patient with advanced gastric carcinoma
(50% of a gastric cancer patient had stable disease while con-
traction effect has been shown in 16% of the patient) [191].
GV1001 is a cancer vaccine which is based on peptide
and derived from Htert. It was given to cancer patient with
non-resectable pancreas that are in Phase I/II Dose Augmen-
tation Study. GV1001 was able to induce T cells which are
types of CD4+ and CD8+, to interact with cells with profes-
sional antigens presenting cells, and then engulf tumour
cells and tissues which have been dead [192]. Additionally,
in the case of a blood cancer patient, GV1001 may be a can-
didate vaccine [193]. Furthermore, numerous immunothera-
peutic modalities in cancer patients involve a peptide that is
derived from short TAA that can bind to class I or II
molecules of MHC directly. In many cases, for a standard
treatment regimen, vaccination is combined with therapy
with a chemical agent, radiation therapy, and targeted anti-
cancer agents [194-196].
The best example of the use of peptides in cancer treat-
ment is the use of LHRH agonists (luteinizing hormone-re-
leasing hormone) as a treatment for prostate cancer. Since
then, for more efficacious and more convenient treatment of
prostate cancer patient, many agonists of LHRH have been
developed in form of depots such as buserelin, goserelin,
and triptorelin [197]. These types of peptides decrease the
production of testosterone due to a decrease in FSH and LH
hormone, which is the result of the downregulation of
LHRH receptors in the pituitary. This has provided a novel
method for prostate cancer as an androgen deprivation thera-
py. Parallel to this, the antagonist of LHRH also inhibits LH
and FSH in a dose-related fashion as it blocks LHRH recep-
tors competitively. This action resulted in therapeutic im-
provement over agonist of LHRH [197]. Nowadays, many
potent antagonists of LHRH such as cetrorelix are available
for clinical use in patients and thus became the first LHRH
antagonist with marketing approval. Thereafter some new
generation antagonist of LHRH gets approval for human use
such as Abarelix and Degarelix. The extended-release formu-
lation of cetrorelix is being developed by zentaris Gmbh and
is under the test of phase 1 and phase 2 clinical trials in can-
cer patients of prostate and BPH [198]. Another clinical trial
focuses on peptides that have been derived from extracellu-
lar matrix proteins, coagulation cascade proteins, growth fac-
tors, and type 1 thrombospondin domain. Recently, an-
giotensin has been found to stop tumour growth of lung can-
cer in mice by inhibiting the formation of blood vessels
[199]. Clingitide from Merck (antiangiogenic agent) is an
RGD peptide derivative. Being an inner salt of a cyclized
RGD pentapeptide, it is αv integrins selective, which are im-
portant in angiogenesis. For glioblastoma and refractory
brain tumours treatment of children, it is under phase II trial
currently. ATN-161 is another peptide for cancer that is un-
der early phase II trials. It inhibits integrins involved in the
progression of tumours. L-glutamine L- tryptophan (a dipep-
tide) has shown antiangiogenic properties that are made in
thymus gland normally. Although it has recently proven to
be ineffective against AIDS-Kaposi’s sarcoma in a Phase III
trial, it remains promising for other forms of cancer
[197-202].
In phase I study, various drugs have been evaluated with
ACPs in solid tumours such as bevacizumab, plitidepsin,
and cyclodepsipeptide. Agonist of LHRH, which is under
phase II clinical study, possesses anticancer activity for
LHRH receptor-positive carcinomas like cancer of prostate
and ovary. Before this, a new approach was developed in the
form of a Personalized Peptide Vaccination (PPV) that stim-
ulated the immune response [202]. Similarly, based on their
anticancer immunological effect and safety profile for me-
tastatic breast cancer patient, among 31 PVVs, approxima-
tely 19 mixed peptides were selected and tested in a phase II
clinical study. In contrast, other peptides such as
gp100:209-217/imiquimod/ montanide and E39 peptide/GM
-CSF vaccine plus E39 booster have been approved for high-
-risk melanoma and ovarian cancer, respectively, such as
peptide boronate bortezomib [202].
A reversible 26S proteasome inhibitor (peptide boronate
bortezomib) that degenerates various intracellular proteins
and has anticancer and antiproliferative activities can be
used as therapy for multiple myeloma. For the treatment of
resistant multiple myeloma, bortezomib with enhanced tar-
geted delivery has been developed. Because of their adverse
reactions and drawbacks like peripheral neuropathy, hemato-
toxicity, poor penetration, and decreased bioavailability, it
has been used with nanoparticles [203-208]. Data obtained
from the “clinicaltrials.gov” regarding clinical trials on pep-
tide drug conjugates for anticancerous activity is sum-
marized in Table 3.
18 Current Cancer Drug Targets, хххх, Vol. хх, No. хх Malviya et al.
Table 3. Common anti-cancerous peptide-drug conjugates and associated clinical trials.
Vehicle of Peptide Targeted Receptor Chemotherapy Drug Conjugation Ongoing Clinical Trials Phase
SST SSTR1-5 CPT - -
DRDDS Folate Receptor Dablh (SM) Epethilial Ovarian Cancer 3
Polyglutamic Acid - Ptx (SM Non-small Lung Cancer 3
Ge11 ErbB1 (EGFR) SeNPs, PEG - -
LHRH LHRH CLIP71 (Lytic Peptide) Advanced, LHRH Receptor Expressing Solid Tumors (73) 1
OCTREOTIDE SSTR2/5 PTX - -
Irgd Integrin ανβ3/ανβ5 PTX - -
RGD Integrin ανβ3 CPT - -
Table 4. Peptides in preclinical trials of cancer.
Preclinical Stage Drug Cancer Types
I/II/III HER-2/neu immunodominant peptide Lung, breast, or ovarian cancer
I/II/III Mucin-1 Breast or colon cancer
I/II/III HPV-16 E7 peptide Cervical cancer
I/II/III Ras oncoprotein peptide Colorectal and pancreatic carcinomas
II GV-1001 Liver cancer and NSCLC (non-small-cell lung cancer)
III GV-1001 Pancreatic cancer
Ib NGR peptide-targeted hTNF in combination with doxorubicin Refractory/resistant solid tumours
Apart from this, the conjugates of peptide and drugs
(PDCs) are also used as a platform for targeted cancer treat-
ment. Peptides can offer the versatility required for a suc-
cessful approach to cancer drug discovery. Conjugated pep-
tide drugs (PDCs) are a new targeted treatment with en-
hanced tumour penetration and selectivity. The construction
of PDCs and ADCs (antibody-drug conjugates) only differ
by the homing device [206]. At present, Lu-dotatate I is the
only therapeutic Peptide drug conjugate on the market, but
many others are at various stages of the chain. The first
FDA-approved peptide drug conjugate is Lu-dotatate and it
is used for the treatment of gastroenteropancreatic neuroen-
docrine tumours (GEP-NETs. Before this year, two ad-
vanced PDCs were issued: TH1902 and TH1904. TH1902 is
a peptide drug conjugate that is used for the treatment of tri-
ple-negative breast carcinoma and ovarian malignancy
[206]. Similarly, for the treatment of ovarian cancer,
TH1904 is also used. TH1902 are TH1904 both target sor-
tilin 1(SORT 1) receptor that is overexpressed in many can-
cers, including triple-negative breast cancers, ovarian carci-
noma, lung cancer, colorectal, skin, and pancreatic cancer
[207]. PDCs are a common term for many different conju-
gates using different types of peptides. For example, bicy-
cle-toxin conjugates and peptide dendrimer conjugates both
have shown promise as drug delivery systems. These conju-
gates provide deeper penetration in the tumour, rapid extra-
vasation, and slower renal clearance [208].
Currently, there are multiple BTCs in the clinical study
from bicycle therapeutics which include BT1718, BT5528,
and BT8009 - all target for specific tumours. BT1718 is a bi-
cycle therapeutics-derived BTC currently in Phase I/IIa spon-
sored by Cancer Research UK. The target of this BTC is
type 1 membrane matrix metalloprotein (MMP-14), which is
overexpressed in multiple tumours. BTC such as BT5528 is
in phase I/II study which targets Ephrin type-A receptor 2
(EphA2) which is overexpressed in several tumours [208].
BT8009 is another BTC under clinical study that targets
Nectin-4 which is overexpressed in several cancers, includ-
ing lung, breast, bladder, and pancreatic [209, 210]. Differ-
ent peptides that are in preclinical trials (data obtained from
clinicaltrials.gov) for cancer treatments are tabulated below
(Table 4).
Peptide medications have been an emerging tool in the
treatment of cancer, displaying not only positive therapeutic
effectiveness but also major economic benefits. However,
there are also numerous barriers to the therapeutic implemen-
tation and promotion of peptide products. Few key scientific
difficulties are the comprehensive and complicated process-
es in the preclinical and clinical studies, such as the need for
continuous practical verification and modification of candi-
date peptides [210]. These techniques also guarantee better
therapeutic performance and safety of peptides in the clini-
cal study than comparable products in developed markets.
However, pre-clinical cancer experiments are constrained by
the lack of tumour specificity [210]. Tat's conjugation to a
p53-activating peptide is an example used to diagnose mice
with injected human cancer tissue with the best effects. Both
RGD and NGR peptides have been used to treat a variety of
tumour molecules and are being studied in various stages of
human clinical trials [208, 210]. Data were collected for the
peptide analogue used for cancer treatment from the “clini-
caltrials.gov” and are summarized in Table 5 and Table 6.
Advancement and Strategies for the Development of Peptide-Drug Conjugates Current Cancer Drug Targets, хххх, Vol. хх, No. хх 19
Table 5. Details of peptide and their analogues in Phase I and II clinical trials.
Peptide Name Therapeutic Use Clinical Develop-
ment Phase Clinical Trial Site
GD (Cilengtide, Delta 24-RGD, Delta 24-RGD
4C, RGD-K5)
Cancer:
Brain
Ovarian
Head and Neck
Prostate
Lung
Melanoma
Phase I
Phase II,
Phase I
Phase I and II
Phase I
Phase I and II
Phase II
M.D. Anderson and others
Erasmus Medical Center and others
University of Alabama at Birmingham
Merck, Chang Gung Memorial Hospital
University of Michigan Cancer Center
Merck, University Hospital Mannheim
M.D. Anderson
18F-DCFPyL PET Prostate Cancer Early Phase I
University of Wisconsin Carbone Cancer
Center
Madison, Wisconsin, United States
WT-1 analog peptide vaccine
Leukemia
Lung cancer
Malignant mesothelioma
Primary peritoneal cancer
Phase I
Lee M. Krug
Memorial Sloan Kettering Cancer Center
United States, New York
WT 1 or NY-ESO -1 vaccine and nivolumab
Ovarian cancer
Primary peritoneal cancer
Recurrent ovarian cancer
Phase I
Department of Nuclear Medicine, Innsbruck
Medical University, Australia
Erasmus University Rotterdam, Netherlands
Department of Nuclear Medicine, Universi-
ty Hospital Freiburg, Germany
177Lu-DOTA-EB-TATE Neuroendocrine tumors Phase I Peking Union Medical College Hospital
Beijing, Beijing, China
Melan-A ELA + Montanide
Melan-A ELA + NY-ESO-1b + MAGE-A10 +
Montanide
Melan-A -ELA + NY-ESO-1b + MAGE-A10
peptide + Montanide + CpG
Melanoma Phase I
Oncology Department, Lausanne University
Hospital (CHUV) and University of Lau-
sanne
Lausanne, Vaud, Switzerland
Division of Oncology at the Geneva Univer-
sity Hospital
Geneva, Switzerland
MART-1 antigen Melanoma (Skin) Phase I Mayo Clinic, Rochester, Minnesota, United
States
Drug: 177Lu-DOTATATE 25.9 GBq activity
Drug: 177Lu-DOTATATE 18.5 GBq activity Neuroendocrine Tumors Phase II Irst Irccs
Meldola, FC, Italy
Satoreotide trizoxetan 5-20 μg
Drug: Satoreotide trizoxetan 30-45 μg
Gastro-Enteropancreatic Neuroen-
docrine Tumor Phase II
UCLA Medical Center
Los Angeles, California, United States
Medical University of Innsbruck
Innsbruck, Austria
University Clinic for Radiology and Nu-
clear Medicine
Vienna, Austria
Galinpepimut-S
Pembrolizumab
Acute Myelogenous Leukemia
Ovarian Cancer
Colorectal Cancer
Phase II
St. Joseph Heritage Healthcare
Santa Rosa, California, United States
Innovative Clinical Research Institute
(ICRI)
Whittier, California, United States
Rocky Mountain Cancer Centers
Denver, Colorado, United States
Table 6. Details of peptide and their analogues in Phase III and IV clinical trials.
Peptide Name Therapeutic Use Clinical Development Phase Clinical Trial Site
Magainin2 Cancer: Bladder
Anti-microbial: Diabetic foot, ulcers
Pre-clinical
Phase III MacroChem Corporation
β-defensin Anti-microbial:
Inflammatory, Biomarker Phase IV Eastern Virginia Medical School/Merck
Interferon alpha-2b Gastro-intestinal neuroendocrine tumors Phase III
Jules Bordet Institute
Brussels, Belgium
UZ Leuven
Leuven, Belgium
[68Ga]-DOTANOC PET/CT Gastroenteropancreatic neuroendocrine tumors Phase III AP-HM
Marseille, France
Chromogranin A Non-functioning pancreatic endocrine tumor Phase IV Asan Medical Center
Novartis
20 Current Cancer Drug Targets, хххх, Vol. хх, No. хх Malviya et al.
CONCLUSION
The development of peptide-based drug conjugates in
cancer therapy is not only full of challenges and possibilities
like narrow therapeutic index and low bioavailability but al-
so presents terrific promises and potential. A large number
of drugs have not been FDA-approved because of their poor
physico-chemical characteristics. Exploration of techniques
aimed at improving the properties is critical to the success of
peptides. Enhancement of the ADME profile can be a means
of hastening the development of peptides into successful
drugs. In-silico ADME tools are used as a guide to design
peptides with drug-like properties while sustaining target po-
tency. Transporters play a vital role in the uptake of peptides
for enhanced oral absorption and penetration inside the cell
membrane. Peptide-based vaccines have various advantages
such as convenience and inexpensiveness, easy administra-
tion, specificity in targeting tumor tissues but not normal tis-
sues, and few or no side effects. Peptides can be used direct-
ly as cytotoxic agents in a variety of ways, or they can act as
carriers of cytotoxic chemicals and radioisotopes by target-
ing cancer cells preferentially. For the treatment of breast
and prostate cancers, peptide-based hormone therapy has
been extensively explored and used. Different strategies
were discussed within this review to prolong the half-life
time of peptides. The addition of hydrophilic/lipophilic units
represents an effective strategy for enhanced oral drug deliv-
ery. Peptide drug modification is to be based on the knowl-
edge of the influence of proteolytic enzymes within sys-
temic circulation as well as renal clearance of the drug. Vari-
ous approaches have been discussed to prolong plasma half-
life. Targeted chemotherapy is widely used as an excellent
tool to reduce problems related to conventional chemothera-
py. Various cancer vaccines using cytotoxic drugs and an-
ti-angiogenic peptides are under clinical trials. As a result of
tremendous development, it is now possible to make pep-
tide-based anti-cancer drugs more affordable to patients.
The manuscript also concludes the mechanism of cancer de-
velopment and drug targeting, molecular docking in protein
binding, modulation of pharmacokinetic and pharmacody-
namic conjugates, different drug conjugates for the diagno-
sis and treatment of cancer, and patents related to peptide
drug conjugates. It also summarizes the details of the clini-
cal trials of peptide drug conjugates.
CONSENT FOR PUBLICATION
Not applicable.
FUNDING
None.
CONFLICT OF INTEREST
The authors declare no conflict of interest, financial or
otherwise.
ACKNOWLEDGEMENTS
The authors are thankful to Galgotias University, India,
for their support in completing the study.
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