Ovarian Cancer Chemotherapy: Targeted Drug Conjugate Systems

Abstract

This chapter discusses advances in ovarian cancer chemotherapy. Ovarian cancer is one of the deadliest diseases that affect women worldwide. Unfortunately, most women with ovarian cancer receive a diagnosis when the disease has progressed to stages 3 or 4, which makes recovery from the disease difficult. The likelihood of survival is increased in women with early-stage disease who are able to commence treatment early as a consequence of early detection. While the majority of the patients respond well to first-line treatment, i.e. cytoreductive surgery integrated with platinum-based chemotherapy, the rate of disease recurrence is very high and the available treatment options for recurrent disease are not curative. Thus, more potent ovarian cancer therapy options are therefore required. In the fight against ovarian cancer, targeted drug conjugate systems have become a potentially effective therapeutic approach. With the help of these systems, it is possible to administer chemotherapeutic agents to ovarian cancer while protecting healthy cells. To promote the clinical translation of these drug conjugate systems, it is important to develop and utilize improved pre-clinical tumor models that more accurately mimic ovarian tumors in humans during the preclinical phase of drug development. Additionally, targeted drug conjugate systems improve therapeutic efficacy by facilitating drug accumulation in the tumor and minimizing the incidence of adverse effects. In this chapter, different targeted drug conjugate systems that have been developed or are being developed for the treatment of ovarian cancer are discussed.

Full text

________________________________________________________________________
a Department of Pharmaceutical Sciences, Howard University, Washington, DC, USA.
*Corresponding author: E-mail: simeon.adesina@howard.edu;
Chapter 8
Print ISBN: 978-81-973195-7-0, eBook ISBN: 978-81-973195-3-2
Ovarian Cancer Chemotherapy: Targeted
Drug Conjugate Systems
Omotola D. Ogundipe a, Oluwabukunmi Olajubutu a
and Simeon K. Adesina a*
DOI: 10.9734/bpi/prrat/v1/8457E
Peer-Review History:
This chapter was reviewed by following the Advanced Open Peer Review policy. This chapter was thoroughly checked to
prevent plagiarism. As per editorial policy, a minimum of two peer-reviewers reviewed the manuscript. After review and
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ABSTRACT
This chapter discusses advances in ovarian cancer chemotherapy. Ovarian
cancer is one of the deadliest diseases that affect women worldwide.
Unfortunately, most women with ovarian cancer receive a diagnosis when the
disease has progressed to stages 3 or 4, which makes recovery from the disease
difficult. The likelihood of survival is increased in women with early-stage
disease who are able to commence treatment early as a consequence of early
detection. While the majority of the patients respond well to first-line treatment,
i.e. cytoreductive surgery integrated with platinum-based chemotherapy, the rate
of disease recurrence is very high and the available treatment options for
recurrent disease are not curative. Thus, more potent ovarian cancer therapy
options are therefore required. In the fight against ovarian cancer, targeted drug
conjugate systems have become a potentially effective therapeutic approach.
With the help of these systems, it is possible to administer chemotherapeutic
agents to ovarian cancer while protecting healthy cells. To promote the clinical
translation of these drug conjugate systems, it is important to develop and utilize
improved pre-clinical tumor models that more accurately mimic ovarian tumors in
humans during the preclinical phase of drug development. Additionally, targeted
drug conjugate systems improve therapeutic efficacy by facilitating drug
accumulation in the tumor and minimizing the incidence of adverse effects. In this
chapter, different targeted drug conjugate systems that have been developed or
are being developed for the treatment of ovarian cancer are discussed.
Keywords: Ovarian cancer; chemotherapy; targeted drug delivery system; drug
conjugate.

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1. INTRODUCTION - EPIDEMIOLOGY
Ovarian cancer is the most lethal of gynecological cancers globally [1 – 4].
Epidemiological data reveal that the incidence of ovarian cancer differs across
various regions worldwide. In the past, Central Europe used to have the highest
rate of incidence, however, from 2007 to 2017, South and East Asia experienced
the most significant percentage increase in incidence [5]. Globally, a total of
294,422 new cases of ovarian cancer and 198,412 deaths were recorded in 2019
in women with ages ranging from 50-69 years [6]. The countries with the highest
standardized incidence rates of ovarian cancer per 100,000 population were
Monaco (22.75), Brunei Darussalam (16.12), Pakistan (15.85), Seychelles
(15.66), American Samoa (15.60), United States Virgin Islands (14.13),
Greenland (13.57), United Kingdom (13.22), Samoa (13.12), and Ireland (12.84).
Conversely, the countries with the lowest standardized incidence rates of ovarian
cancer per 100,000 population were Niger (2.15), Chad (2.25), Mali (2.50),
Dominican Republic (2.53), Yemen (2.59), Central African Republic (2.66), Fiji
(2.95), the Democratic Republic of the Congo (2.98), Sudan (3.07), and Egypt
(3.27) [6].
In 2018, an estimated 300,000 new cases of ovarian cancer were diagnosed
worldwide, accounting for 3.4% of all cancer cases among women. It was
estimated that by the conclusion of 2023, approximately 19,710 women in the
United States received a diagnosis of ovarian cancer, with 13,270 of them sadly
succumbing to the illness [7]. There has been a gradual decline in incidence
observed in many countries in Europe, such as Denmark, Norway, and France,
as well as in North America, including the United States and Canada, where
historically, the incidence has been higher compared to less developed regions.
However, certain countries in these regions, such as Belarus, Poland, and the
Czech Republic, continue to experience a high incidence of ovarian cancer
compared to other parts of the world [8]. More recently, there has been a notable
increase in ovarian cancer rates in some Asian countries that previously had
lower rates, such as Japan and India [9]. The variations in ovarian cancer rates
across countries are a result of a combination of factors such as family and
reproductive history, the use of menopausal hormone therapy, and access to
sophisticated diagnostic equipment and care [10]. Notably, the widespread
adoption of oral contraceptives has significantly contributed to the decrease in
ovarian cancer cases seen in recent decades [11, 12].
Approximately 1 in 78 women will develop ovarian cancer in their lifetime, and a
woman’s lifetime risk of dying as a result of the disease is about 1 in 108 [3, 13].
Over the past three decades, there has been an increase in cancer survival rates
due to advances in screening, diagnosis, and therapy [14, 15]. However, the
overall 5-year relative survival rate for ovarian cancer in the United States is
50.8% [7]. This is attributed to its late diagnosis and high recurrence rate [13, 16,
17]. Non-specific symptoms associated with ovarian cancer which are very
difficult to distinguish from less serious abdominal symptoms include abdominal
pain, bloating, early satiety, and urinary urgency [4, 18, 19]. These symptoms, in
addition to the lack of routine screening tests for ovarian cancer, make the

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disease easily missed at the early stages, thereby making treatment challenging
[1, 4, 13, 15].
In the United States, ovarian cancer is more common among non-Hispanic White
women compared to Hispanic, Asian, or African American women [20]. However,
African American women continue to bear the largest and most disproportionate
burden of ovarian cancer of all racial and ethnic groups in the United States,
largely due to structural disparities in clinical trial participation and access to
cutting-edge therapies [15, 21]. From 1975 to 2015, there was a 13% rise in the
five-year relative survival rate for white women, whereas, for black women, it
decreased by 2% [22]. The most significant factor responsible for the disparity in
survival rate was attributed to adherence to treatment guidelines (36.4%)
followed by access to care (22.7%) and the presence of comorbidities (18.2%)
[23]. These reports are corroborated by the African American Cancer
Epidemiology Study (AACES), which is probably the largest cohort study of
African American women with epithelial ovarian cancer [24]. According to the
AACES report, 45% of the women evaluated earn < $25,000 annually, 51% have
a post-high school education, and 32% have no standard insurance. Additionally,
Montes de Oca et al. [25], in their study, reported that non-Hispanic African
American patients have a 26% higher risk of death from ovarian cancer
compared with non-Hispanic White patients. Over the past three decades, deaths
from ovarian cancer have narrowly dropped [1]. Also, the overall prognosis for
ovarian cancer, irrespective of race, is still poor [4]. Thus, many unmet needs in
ovarian cancer treatment require urgent attention [15].
1.1 Overview of Ovarian Cancer
The pair of ovaries in the adult female reproductive system (Fig. 1) serves the
essential roles of ovulation and the production of reproductive hormones [15, 26].
A normal ovary is made up of three major cell types, namely; the epithelial cells,
stromal cells, and germ cells. The epithelial cells form the epithelium that
envelops the ovary; the germ cells form the ova; and the stromal cells form the
ovarian connective and structural tissues. Each of these ovarian cell types can
produce benign and malignant tumors, with the tumor being named after the cell
type from which it arises [15, 27]. Accordingly, ovarian cancer is an umbrella
name for malignant ovarian tumors that can either be epithelial, germ cell, or
stromal tumors [20].
Ovarian cancer, like other types of cancer, can metastasize to other organs,
including the liver, lungs, and brain, through the blood and lymphatic vessels
[27]. Fig. 2 depicts the four main clinical stages of ovarian cancer. Early stage 1
disease is confined to the ovaries, however as the cancer progresses to
advanced stages (stages 2, 3, and 4), the cancer has spread to other body
organs. When diagnosed early, greater than 90% of ovarian cancer patients
survive for at least five years after treatment [4, 15]. Unfortunately, the majority of
ovarian cancer patients are diagnosed when the disease has spread to other
parts of the body, including the bowel, lymph nodes, liver, and lungs. Ovarian
cancer can also spread within the abdominal cavity, forming nodules on the

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surface of the peritoneum, including the omentum [27]. Ascites, a common
feature of advanced ovarian cancer, are caused by the buildup of fluid in the
peritoneal cavity. This occurs due to the obstruction of lymphatic vessels in the
diaphragm during the later stages of the disease [15, 27]. According to Ray et al.
[28], malignant bowel obstruction is a prevalent complication of recurrent ovarian
cancer and a significant contributor to mortality.
Fig. 1. (A) Anatomy of the female reproductive system (B) Anatomy of the
human ovary. Created with BioRender.com
Fig. 2. Ovarian cancer staging. Created with BioRender.com

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Approximately 90% of ovarian cancer cases are epithelial and are highly
heterogeneous at both cellular and molecular levels [18, 29, 30]. Five identified
subtypes of epithelial ovarian cancer include low-grade serous, high-grade
serous, endometrioid, clear cell, and mucinous carcinoma [16, 31]. The most
aggressive subtype, high-grade serous ovarian carcinoma (HGSOC) [32], is
responsible for the majority of ovarian cancer cases, making epithelial ovarian
cancer the most clinically important ovarian malignancy [15, 30, 31].
Low-grade serous ovarian carcinomas develop slowly, are confined to the ovary,
and resist conventional chemotherapy [27, 33]. The most common ovarian
cancer type, HGSOC, develops quickly and is rarely confined to the ovary.
HGSOC is believed to have initiated from the fallopian tube and metastasized to
the ovary [19, 20]. The shedding of invasive serous lesions known as ‘serous
tubal intraepithelial carcinoma (STIC)’ from the fallopian tube into the ovary has
been commonly reported as the origin of HGSOC [15, 31, 34, 35]. A microRNA
called miR-181a has been recently identified as being responsible for the
transformation of fallopian tube secretory epithelial cells to STIC by inhibiting
tumor suppressor genes Rb1 (retinoblastoma 1) and STING (stimulator-of-
interferon genes) [35]. The exact mechanism of this transformation is still
relatively unknown. While HGSOC originates from the epithelium of the fallopian
tube, the other major epithelial ovarian cancer histotypes originate from the
ovarian surface epithelium [2, 15].
High-grade serous ovarian carcinoma is primarily clinically distinguished by
alterations in TP53, the gene that encodes the tumor protein, p53 [19, 20]. In
normal cells, p53 is activated when there is deoxyribonucleic acid (DNA) damage
to stop cell cycle progression and allow damage repair. If the damage is
irreparable, p53 triggers the affected cells’ death by apoptosis [36]. Hence, the
mutation or loss of p53 function as the "keeper of the genome" leads to genomic
instability and the accumulation of toxic DNA lesions [15, 37]. TP53 mutations
drive oncogenesis by activating pathways such as the Ras/mitogen-activated
protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) pathways.
MAPK promotes cell survival and resistance to apoptosis through the activation
of PI3K [15, 27, 36].
Approximately 15–20% of women with HGSOC have germline mutations in
BRCA1 and BRCA2 proteins, which are involved in the repair of DNA double-
strand breaks through the process of homologous recombination [31]. The
efficient repair of DNA double-strand breaks is crucial for maintaining genomic
stability and preventing harmful mutations. Homologous recombination repair
(HRR) is error-free and very essential for maintaining genomic stability; thus,
BRCA1/2 proteins act as tumor suppressors. HGSOCs with mutations in
BRCA1/2 genes (BRCAness) typically have homologous recombination
deficiency (HRD) [15, 31, 36]. HGSOCs are characterized by BRCAness and
TP53 mutations, resulting in high copy number alterations. Copy number
aberrations and marked genomic instability present in HGSOC make its
treatment very challenging [27]. In addition, features of the ovarian tumor
microenvironment such as dense extracellular matrix, activated fibroblasts,

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tumor-associated macrophages, and cancer-associated adipocytes contribute to
the development of chemoresistance and metastasis of ovarian cancer to distal
organs [15, 19].
1.2 Treatment of Ovarian Cancer
1.2.1 Systemic chemotherapy
The primary treatment of ovarian cancer, in most cases, integrates cytoreductive
surgery with systemic chemotherapy [4, 16]. The standard chemotherapy for the
treatment of epithelial ovarian cancer was a single alkylating agent, such as
cyclophosphamide and melphalan, until cisplatin/carboplatin combination therapy
showed superior results over single agents [14, 15, 31]. The current standard
first-line chemotherapy for epithelial ovarian cancer is intravenously co-
administered carboplatin/cisplatin and paclitaxel, given every three weeks over
six cycles [16, 31]. Doxorubicin, gemcitabine, irinotecan, and etoposide, 5-
fluorouracil, among others, are also approved by the US Food and Drug
Administration (FDA) for the treatment of ovarian cancer [20, 38]. While most
ovarian cancer types are sensitive to chemotherapy, the majority of ovarian
cancer patients suffer relapse and die quickly [20, 39]. This is attributed to
resistance to chemotherapy and the inability to eliminate the disease completely
with the available standard treatment [15, 19, 40, 41].
Intraperitoneal chemotherapy, which involves the injection of chemotherapeutic
drugs into the intra-abdominal cavity, has similar benefits as intravenous
administration, but with more toxicities [4, 17]. Another technique called
hyperthermic intraperitoneal chemotherapy (HIPEC) is also used for systemic
chemotherapy of ovarian cancer [40]. HIPEC involves the injection of
chemotherapeutic drugs at high temperatures into the intra-abdominal cavity [31].
While HIPEC may be useful for patients with large residual lesions after primary
surgery, it is not recommended due to the risks, such as bowel perforation,
intraperitoneal hemorrhage, and death, involved with the procedure [40].
1.2.2 Targeted therapy
In addition to chemotherapy, other agents, such as bevacizumab and poly
(adenosine diphosphate ribose) polymerase (PARP) inhibitors, that target
specific cancer features are approved by the FDA for ovarian cancer treatment
[16, 31]. Bevacizumab is a monoclonal antibody that has been humanized
through recombinant technology. It is designed to target vascular endothelial
growth factor (VEGF), which is frequently overexpressed in ovarian cancer [14].
It is added as a third agent to platinum-based chemotherapy as the standard of
care for women at high risk of disease progression [4, 15, 16]. Additional
toxicities related to bevacizumab, when used, include delayed wound healing,
hypertension, and bowel perforation [4, 31].

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Pembrolizumab and nivolumab, two immune checkpoint inhibitors, have shown
promise in clinical trials with a limited number of ovarian cancer patients when
used in combination with PARP inhibitors or bevacizumab [42, 43]. However, the
response rate of ovarian cancer patients to immunotherapy is still limited, mainly
due to the inherently immunosuppressive tumor microenvironment in ovarian
cancer [14]. In addition, immunotherapy is not yet approved for use in the
treatment of ovarian cancer because of a lack of sufficient experimental evidence
of its effectiveness [15, 43].
1.2.2.1 Synthetic lethality
Most targeted therapy for cancer treatment targets specific genes that tumors
depend on for survival, but not all tumors have such targetable genes. Exploiting
synthetic lethal interactions between mutation genes holds promise for the
development of effective anticancer treatments [44]. Two genes are synthetic
lethal pairs if a cell is still viable with a single loss of either gene function, but a
simultaneous loss of both gene functions results in cell death [45]. A successful
example of targeted therapy that is based on synthetic lethality is the PARP
inhibitors such as olaparib, niraparib, rucaparib, and talazoparib [14, 40].
Olaparib, niraparib, and rucaparib are used as maintenance monotherapies for
recurrent epithelial ovarian cancer in women who have BRCA1 / BRCA2
mutations [14, 39, 40, 46]. In the United States and Europe, Olaparib is also used
as maintenance therapy regardless of BRCA mutation status [46], but patients
with BRCA mutation show more benefits [39].
BRCA1 and BRCA2 genes are involved in the repair of DNA double-strand
breaks through the process of homologous recombination [36]. Ovarian cancers
with BRCA1 / BRCA2 mutations depend on error-prone alternative pathways like
the base excision repair (BER) pathway to repair single-strand breaks in DNA
damage [47, 48]. PARP is a family of DNA-repairing enzymes significantly
involved in DNA damage repair via BER [47]. PARP inhibitors kill cancer cells via
synthetic lethality when given to patients who have BRCA1 / BRCA2 mutations
by blocking the BER pathway and causing an accumulation of toxic double-
strand breaks within cancer cells (Fig. 3) [15, 49, 50]. Thus, a combination of
PARP inhibition with loss-of-function mutations in additional pathways of DNA
damage repair, such as in cells having BRCAness, will lead to breaks in double-
stranded DNA that cannot be efficiently repaired in the homologous
recombination-deficient tumors [46, 50].
The use of PARP inhibitors has been reported to improve progression-free
survival but not overall survival [40]. In addition, the concurrent use of olaparib,
the first approved PARP inhibitor, with platinum-based chemotherapy is limited
by overlapping hematologic toxicities, which necessitates drug dose reduction
[31]. Furthermore, acquired drug resistance mechanisms such as BRCA
mutation reversions and ABCB1 fusions have been described for PARP inhibitor
treatment resistance in some patients [15, 51].

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Fig. 3. Mechanism of synthetic lethality with PARP inhibitors. Accumulation
of DNA double-strand breaks as a consequence of inhibition of DNA
damage repair by both the base excision and homologous recombination
repair pathways lead to cell death. Created with BioRender.com
1.3 Challenges of Ovarian Cancer Treatment
Treatment-induced hypertension caused by VEGF inhibitors (e.g. bevacizumab)
limits their use in hypertensive patients [52]. Also, a small proportion of ovarian
cancer patients can benefit from PARP inhibitors since only 5–10% of them carry
mutations in the BRCA1 / BRCA2 genes [53]. These limitations of targeted
therapies leave chemotherapy as the major option for the treatment of metastatic
or advanced ovarian cancer [15]. Irrespective of the route of administration,
systemic chemotherapy of ovarian cancer generally has a high rate of disease
recurrence [17]. The rates of disease recurrence in patients with early-stage and
advanced ovarian cancer are 25% and > 80%, respectively [4]. Available
treatment options for recurrent ovarian cancer are not curative [4, 41]; and the
patients usually do not live longer than two years after recurrence [4]. Patients
with recurrent disease are re-treated with the first-line platinum-based
chemotherapy or a sequence of single chemotherapeutic agents such as
paclitaxel, liposomal doxorubicin, topotecan, and gemcitabine, until subsequent
progression to advanced stages or unacceptable toxicity takes place [20, 39, 51].
In addition, multi-drug resistance also limits the therapeutic efficiencies of
existing chemotherapeutics for the treatment of ovarian cancer [20, 40]. One
known driver of chemoresistance in ovarian cancer is permeability glycoprotein
(P-gp), a major adenosine triphosphate binding cassette transporter that effluxes
drug molecules from the tumor microenvironment [41, 54]. Conventional anti-
cancer drugs rely on the diffusion of small drug molecules for entry into cancer
cells. As such, they are susceptible to P-gp efflux transporters [47]. This leads to
decreased intracellular accumulation of very potent cytotoxic drugs, resulting in a
sub-lethal concentration within the cancer cellular environment [55]. Thus, a
higher dose would be required to achieve the initially achieved cytotoxic effect in
subsequent administration. The most efficient approach for treating ovarian

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cancer, enhancing treatment effectiveness, and addressing resistance to
chemotherapy involves using a combination of two or more chemotherapy drugs
[20, 38]. The idea is that a broader cytotoxic effect can be achieved by
simultaneously administering multiple chemotherapeutic agents that work in
different ways, thereby decreasing the likelihood of resistance [38].
Systemic toxicity poses a concern when it comes to combination chemotherapy.
Chemotherapeutic drugs mostly damage cells that are actively dividing [56].
Although they are effective against cancer cells, they are also lethal to healthy
cells, reducing the maximum dose that a patient may safely take. The most
common strategy for addressing the non-specific toxicity of chemotherapeutic
drugs is by encapsulating them in nanoparticles for controlled drug delivery to
specific sites [14]. Another approach is the development of cytotoxic drugs as
targeted drug conjugates. Similar to nanoparticles, targeted drug conjugates
embody Paul Ehrlich’s “magic bullet” application in cancer therapy by selectively
killing cancer cells while sparing healthy cells [57 – 59]. In these systems, the
active drug is presented as a prodrug that remains inactive during its delivery to
the site of action and is activated by specific conditions in the targeted site [15,
60 – 62].
1.4 Targeted Drug Conjugates for the Treatment of Ovarian Cancer
Drug conjugates are compounds that are formed by chemically joining a drug
with another molecule or compound to enhance its therapeutic effect, increase its
selectivity, or improve its pharmacokinetic properties [63]. The other molecule
can be a protein, peptide, antibody, or other biological entity that specifically
targets a cell or tissue type or a chemical compound that improves drug stability,
and solubility or facilitates drug delivery to the target site [15, 63]. Targeted drug
conjugates are different from general drug conjugates because of the presence
of one or more targeting moieties in their design, and can be broadly categorized
into antibody-, peptide-, polymer-, and small molecule-drug conjugates,
depending on the molecules that are conjugated with the drug [64]. These
conjugate systems exploit one or more specific tumor microenvironment
conditions including, acidic pH, enhanced permeability and retention effect,
overexpression of glutathione, certain surface receptors, surface proteins, and
proteolytic enzymes for their activation and subsequent drug release. Table 1
highlights many target molecules that have been explored for the development of
targeted drug conjugates for the treatment of ovarian cancer [15].
Folate receptor-alpha (FR-α) is one of the most targeted antigens in the
development of targeted drug delivery systems for the treatment of ovarian
cancer [65]. This is because approximately 90% of patients with ovarian cancer
overexpress FR-α [66]. In addition, the expression of FR-α increases as the
disease progresses; making FR-α an excellent target for advanced disease [66].
FR-α is a cell membrane-bound receptor with a very high affinity for folate and its
derivatives, which are transported into the cell via endocytosis [15, 67]. As the
density of FR-α surges with cancer progression, it loses its polarized cellular
localization and becomes distributed over the cancer cell surface, making
numerous FR-α accessible drug-containing macromolecules in the blood
circulation [68].

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Table 1. Molecular targets and their reported overexpression in ovarian cancer
Target molecules
Reported overexpression
Reference
Folate receptor-α
60 – 100 %
[59]
Sortilin-1
52 – 100 %
[69]
Tumor-associated glycoprotein-72
88 %
[70]
Cluster of differentiation 70
70 %
[71]
Human epidermal growth factor receptor-2
Up to 50 %
[72]
Mesothelin
55 – 100 %
[59]
Trophoblast-antigen-2
47 – 89 %
[73]
Type II sodium–phosphate cotransporter
95 %
[59]
Mucin-16
70 – 90 %
[59]
Tissue factor
25 – 100 %
[59]
Cadherin-6
65 %
[74]
Wnt/β-Catenin signaling pathway
16 – 54 %
[75]
Lipolysis-stimulated lipoprotein receptor
50 – 70 %
[76]
Type-I 15-leucine–rich repeat-containing-membrane
protein (LRRC15)
16 % of HGSOC
[28]
Nectin-2
50 %
[77]
Gonadotropin-releasing hormone receptor
78 %
[78, 79]
Permeability glycoprotein
~ 0% chemo-naive cells; 8%
chemoresistant cells
[80, 81]
Nuclear factor erythroid 2-related factor 2
Kelch-like ECH-associated protein 1
95 %
72%
[82]
[82]
Cluster of differentiation-44
55 – 64 %
[83]
Ephrin receptor A2 (EphA2)
> 75%
[84]

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Table 2. Targeted drug conjugate systems in or through clinical development for the treatment of ovarian cancer
Conjugate (Cytotoxin)
Target antigen
Linker
Status
ClinicalTrials.gov identifier
Antibody-drug conjugate
LY4101174
Nectin-4
Unknown
Phase 1
NCT06238479
XB002 (Auristatin)
Tissue Factor
ZymeLink
Phase 1
NCT04925284
CUSPO6 (Exatecan
derivative)
Cadherin-6
Protease-cleavable
Phase 1
NCT06234423
STRO-002 (SC209)
FRα
DBCO-valyl-citrullinyl-p-amino
benzyl carbamate
Phase 1
NCT03748186
TORL-1-23 (MMAE)
Claudin-6
Valine-citrulline moiety [85]
Phase 1
NCT05103683
ASN004 (Auristatin moiety)
5T4
Dolaflexin
Phase 1
NCT04410224
Vobramitamab duocarmazine
(Duocarmycin analog)
B7-H3
Maleimido valine-citrulline type
Phase 1
NCT05293496
IMGN151 (DM21)
FRα
Cleavable peptide
Phase 1
NCT05527184
XMT-1592 (Auristatin F-HPA)
NaPi2b
Dolasynthen platform
Phase 1b
NCT04396340
Anetumab ravtansine (DM4)
Mesothelin
Reducible SPDB
Phase 1c
NCT02751918
Lifastuzumab vedotin (MMAE)
NaPi2b
Maleimidocaproyl-valyl-citrullinyl-
p-aminobenzyl carbamate
Phase 1c
NCT01363947;
NCT01995188
CDX-014 (MMAE)
TIM-1
Maleimidocaproyl-valyl-citrullinyl-
p-aminobenzyl carbamate
Phase 1t
NCT02837991
SC-003 (SC-DR002)
Dipeptidase 3
Protease-cleavable linker
Phase 1t
NCT02539719
SGN-15 (Doxorubicin)
Lewis Y
Hydrazone
Phase 2t
NCT00051584
HKT228 (DM4)
Cadherin-6
Sulfo-SPDB
Phase 1t
NCT02947152
SYD985 (Duocarmycin)
HER2
Valine-citrulline
Phase 1w
NCT04602117
LCB84 (MMAE)
TROP-2
β-glucuronidase-cleavable
Phase 1/2
NCT05941507
AZD5335 (Camptothecin
FRα
Cleavable
Phase 1/2
NCT05797168

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Conjugate (Cytotoxin)
Target antigen
Linker
Status
ClinicalTrials.gov identifier
moiety)
SKB264
TROP2
Unknown
Phase 1/2
NCT04152499
PRO1184 (Exatecan)
FRα
Cleavable hydrophilic
Phase 1/2
NCT05579366
AZD8205 (TOP1i)
B7-H4
Unknown
Phase 1/2a
NCT05123482
MORAb-202 (Eribulin)
FRα
Maleimido-PEG2-valyl-citrullinyl-p-
aminobenzyl carbamate
Phase 1/2
Phase 2
NCT04300556
NCT05613088
A166 (Duostatin-5)
HER2
Valine-citrulline
Phase 1/2c
NCT03602079
IMMU-132 (SN-38)
TROP2
pH-sensitive
Phase 1/2c
NCT01631552
Enapotamab vedotin (MMAE)
AXL receptor
tyrosine kinase
Maleimidocaproyl-valyl-citrullinyl-
p-aminobenzyl carbamate
Phase 1/2c
NCT02988817
CX-2009 (DM4)
CD166
Reducible SPDB
Phase 1/2c
NCT03149549
Dato-DXd (Exatecan
derivative)
TROP2
Lysosomal enzyme-cleavable
tetrapeptide
Phase 2
NCT05489211
Tisotumab vedotin (MMAE)
Tissue factor
Maleimidocaproyl-valyl-citrullinyl-
p-aminobenzyl carbamate
Phase 2c
NCT03657043
Mirvetuximab Soravtansine
(DM4)
FRα
Sulfo-SPDB
Phase 2
Phase 3c
Phase 3
NCT05041257
NCT04296890
NCT04209855
XMT-1536 (Auristatin F-HPA)
NaPi2b
Dolaflexin platform
Phase 3
NCT05329545
Small molecule-drug conjugate
EC1456 (Tubulysin B
hydrazide)
Folate receptor
Disulfide
Phase 1c
NCT03011320

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Conjugate (Cytotoxin)
Target antigen
Linker
Status
ClinicalTrials.gov identifier
Peptide-drug conjugate
TH1902 (Docetaxel)
Sortilin
Ester bond
Phase 1
NCT04706962
BT5528 (MMAE)
EphA2
Cleavable linker
Phase 1/2
NCT04180371
BT8009 (MMAE)
Nectin-4
Valine-citrulline
Phase 1/2
NCT04561362
Nanoparticle-drug conjugate
ELU001 (Exatecan)
FR-α
Protease-cleavable
Phase 1/2
NCT05001282
CRLX101 (Camptothecin)
None
Ester bond
Phase 1/2c
NCT00333502
EP0057 (Camptothecin)
None
Ester bond
Phase 2
NCT04669002
Polymer-drug conjugate
PLX038 (SN-38)
None
Phenyl ether bond, cleavable
Phase 2
NCT05465941
CT-2103 (Paclitaxel)
None
Ester bond
Phase 2c
NCT00045682
MMAE: Monomethyl auristatin E; FRα: folate receptor-α; NaPi2b: type II sodium–phosphate cotransporter; TROP2: trophoblast cell surface antigen 2;
HER2: human epidermal growth factor receptor 2; TOP1i: topoisomerase 1 inhibitor; B7-H4: B7 homolog 4; B7-H3: B7 homolog 3; CD166: cluster of
differentiation 166; TIM-1: transmembrane protein T-cell immunoglobulin mucin-1; DBCO: dibenzocyclooctyne; PEG: poly(ethylene glycol); SPDB:
succinimidyl 4-(pyridin-2-yl)disulfanyl; cCompleted; tTerminated; wWithdrawn. Sources: ClinicalTrials.gov; adcreview.com; NCI's Drug Dictionary

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It should be noted that FR-α is also expressed in normal cells, although to a
lesser extent (100 – 300 times) compared to cancer cells [68]. This expression in
normal cells is limited to the apical surfaces of the organs expressing the
receptors except for the kidney [15, 67, 86]. These sites are inaccessible to FR-
α-targeted drug conjugates administered parenterally because intercellular
junctions prevent such molecules from crossing the epithelium [68]. As a result of
this specific orientation, FR-α-targeted therapeutics cannot bind to folate
receptors on normal cells but only to those on malignant cells [87, 88]. Also, it
has been reported that folic acid retains its ability to bind to the folate receptor
after conjugation with drugs or other carrier systems [88]. It is thus capable of
eliciting receptor-mediated endocytosis of FR-α-targeted drug conjugates for
selective drug delivery to cancer cells [15].
Mirvetuximab soravtansine (Elahere™) is an antibody-drug conjugate comprising
of an anti-FR-α monoclonal antibody that is linked with DM4, a maytansinoid
microtubule inhibitor, through a gluthathione-reducible disulfide linker [89]. The
anti-FR-α monoclonal antibody present in mirvetuximab soravtansine targets and
binds to FR-α, a cell surface antigen that is commonly overexpressed in epithelial
ovarian cancer [15, 66]. The specific binding of the monoclonal antibody with FR-
α facilitates receptor-mediated internalization of mirvetuximab soravtansine,
followed by cleavage of the disulfide linker and subsequent drug release in the
tumor [59]. It received approval in the USA in November 2022 for the treatment
of adult patients who have FR-α positive, platinum-resistant epithelial ovarian,
fallopian tube, or primary peritoneal cancer and have undergone up to three prior
systemic treatment regimens [89]. Other drug-conjugate systems that have been
or are being clinically developed for the treatment of ovarian cancer are
highlighted in Table 2 [15].
2. ANTIBODY-DRUG CONJUGATES (ADCS)
An antibody-drug conjugate (ADC) is a drug conjugate system comprising a
cytotoxic agent that is conjugated through a linker with an antibody that targets
specific tumor-associated antigens (Fig. 4) [57, 90]. Extensive reviews on ADCs
for targeted cancer therapy have been done elsewhere [57, 58, 91, 92], and the
readers are referred to them. Chimeric or humanized antibodies, approximately
150kDa in size and belonging to the immunoglobulin G1 class, are generally
used to make ADCs [57, 91]. The Fab region, which is responsible for antigen
recognition by these antibodies, is also used for the design of smaller antibody
fragments-drug conjugates [15, 57].
ADCs facilitate the targeted delivery of cytotoxic drugs to cancer cells by
selectively binding to a specific antigen that is either exclusively expressed or
overexpressed on the surface of cancer cells while having low expression in
healthy tissues [59]. ADCs possess unique characteristics as they are
biocompatible proteins with high molecular weight that exhibit extended plasma
circulation and efficient accumulation in solid tumors through the enhanced
permeability and retention (EPR) effect [15, 57]. EPR effect is the preferential
accumulation of macromolecules in tumors relative to healthy tissues due to

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leaky vasculature and a defective lymphatic drainage system present within the
tumor microenvironment. These two characteristics—leaky vasculature and a
faulty lymphatic drainage system—are unique to cancers and distinguish them
from healthy tissues, thereby allowing for selective drug delivery to cancer cells
[15, 93 – 95]. The leaky tumor blood vessels increase tumor vascular
permeability to circulating macromolecules, which are also not efficiently
removed from the tumor microenvironment by the defective lymphatic drainage
system, thus allowing the macromolecules to passively accumulate in the tumor.
In particular, the medulla of the ovary (Fig. 1B) comprises abundant blood and
lymphatic vessels [96]. Rapid angiogenesis in the ovarian tumor will therefore
present higher tumor vascular permeability, making ovarian cancer prone to
targeting by the EPR effect [15].
Fig. 4. Representation of an antibody-drug conjugate. Created with
BioRender.com
2.1 Linker
The primary function of the linker between the monoclonal antibody and the
cytotoxic drug in an antibody-drug conjugate (ADC) is to facilitate the selective
release of the cytotoxic drug within the tumor environment [97, 98]. The linker
should have good plasma stability such that the ADC can undergo prolonged
circulation without nonspecific drug release and ultimately accumulate in the
tumor where selective drug release is facilitated [15]. Linker stability is essential
to prevent the premature release of the cytotoxic payload, which could cause off-
target toxicity. It has been reported that whether the ADC is internalized or not,
the drug release is dependent on the type of linker used, which may be cleavable
or non-cleavable [15, 91, 97].
Cleavable linkers utilize characteristic tumor properties such as acidic pH, redox,
and proteolytic enzymes for the selective release of the cytotoxic drug from the
antibody-drug conjugate [97]. The utilization of pH-sensitive linkers is based on
the pH gradient between the acidic tumor microenvironment and the general

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blood circulation (pH = 7.4) [63]. The observed acidity in the tumor
microenvironment is a result of energy production by anaerobic glycolysis, a
process that leads to the production of lactic acid [15, 99]. Several drug
conjugates have been designed using acid-sensitive linkers that contain
hydrazone [63]. An example is Mylotarg®, an ADC comprising gemtuzumab
ozogamicin conjugated to calicheamicin through an acyl hydrazone linkage [100].
Hydrolysis of the hydrazone in the lysosome (pH ~4) induces the selective
release of calicheamicin, which causes cytotoxic double-strand breaks, within the
cancer cells [101]. The disadvantage of ADCs that are designed using acid-labile
linkers that contain hydrazones, imines, or acetals, is low plasma stability [15, 91,
99] which could cause non-specific drug release and systemic toxicity. Mylotarg®
was marketed in the US for the treatment of acute myeloid leukemia from 2000
until 2010 when it was withdrawn due to multiple toxicity reports [100]. The
instability of hydrazone-containing linkers is believed to have played a role in this
[15, 97].
Redox-sensitive linkers, which include disulfide bonds, utilize elevated levels of
glutathione within the intracellular environment compared to the plasma [97].
Drugs that are linked by disulfide bonds exhibit resistance to reductive cleavage
in the bloodstream due to the comparatively lower concentration of glutathione in
the blood (5 µmol/L) as compared to the cytoplasm (1-10 mmol/L) [15, 57]. This
differential in reductive potential between the plasma and cytosol facilitates the
selective release of the cytotoxic drug in the reductive intracellular environment.
Additionally, glutathione concentration in cancer cells is approximately 1000-fold
higher than that observed in normal cells [102]. Thus, the site-specific release of
drugs in cancer cells is enabled by the use of glutathione-cleavable linkers due to
low levels of glutathione in healthy tissues. Succinimidyl 4-(pyridin-2-yl) disulfanyl
(SPDB), a glutathione-sensitive cleavable disulfide linker used in mirvetuximab
soravtansin, prevents cleavage of the ADC in the bloodstream where the
glutathione level is low, and on the other hand facilitates cleavage in cancer
thereby enhancing it is targeting efficacy [15, 59].
Enzyme-sensitive linkers utilize proteases, predominantly cathepsin B, that are
present in the lysosomes of tumor cells to identify and cleave particular peptide
sequences within the linker [97]. Cathepsin B is constitutively expressed in all
tissues for cellular housekeeping functions [103], and it is localized to the
lysosome [104]. Cathepsin B overexpression, as seen in ovarian cancers, is
often accompanied by its migration to the plasma membrane where it is secreted
into the extracellular environment [15, 104]. Cathepsin B in blood circulation is
not active due to the plasma pH and the presence of protease inhibitors in the
plasma [105, 106]. Normal tissues have very low expression of cathepsin B and
the enzyme has often been targeted for enzyme-triggered tumor-specific drug
delivery [107 – 109]. Maleimidocaproyl-valyl-citrullinyl-p-aminobenzylcarbamate
(Fig. 5) is a chemically modified form of the cathepsin B-cleavable dipeptide,
valine-citrulline, that is utilized in Tisotumab vedotin to link monomethyl auristatin
E (MMAE) to an anti-tissue factor antibody [110]. Following the cleavage of the
valine-citrulline dipeptide by cathepsin B, the p-aminobenzyl carbamate (PABC)
derivative of MMAE is released. This is followed by a spontaneous 1,6-

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elimination of PABC, leaving the free drug molecule and carbon dioxide as the
release products [15, 111]. The stability of valine-citrulline in the plasma is higher
compared to acid-based linkers, owing to the presence of protease inhibitors.
However, upon internalization, valine-citrulline is rapidly hydrolyzed by lysosomal
cathepsin B [91].
Fig. 5. Representation of the chemical structure of Tisotumab vedotin [110].
The self-immolation of the p-aminobenzyl carbamate (PABC) group
following the cleavage of valine-citrulline by cathepsin B results in the
release of the free drug and carbon dioxide (CO2)
For ADCs that use non-cleavable linkers, the linker is part of the payload [112].
The release of the cytotoxic drug from such ADC is contingent upon the
degradation of the ADC within the lysosome after its internalization [97]. Such
ADCs are stable in blood circulation, have longer half-lives, and have fewer
instances of non-specific drug release [91]. Chemical components such as
maleimidocaproyl and succinimidyl thioether are frequently used as non-
cleavable linkers in the synthesis of ADCs [57, 63].
2.2 Mechanism of Action of Antibody-drug Conjugates
Most ADCs are designed to target specific internalizing antigens, such as surface
receptors, with subsequent internalization of the ADCs, intracellular cleavage of
the linker, and subsequent direct release of the drug in the tumor cells to elicit
cytotoxicity (Fig. 6) [15, 92, 98]. Non-internalizing ADCs, on the other hand, are
designed to selectively release cytotoxic drugs in the tumor extracellular space
through the cleavage of the linker by proteolytic enzymes or redox conditions in
the tumor microenvironment [57, 98]. The liberated drug could then enter the

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tumor cells by mechanisms such as diffusion and pinocytosis [57]. Some ADCs,
in addition to killing cells that express the targeted antigen, also kill neighboring
cells that may not express that antigen by “bystander effect” [15, 91]. This
happens when the cytotoxic drug molecules are either expelled from the target
antigen-expressing cells following internalization and degradation of the ADC or
are released from non-internalizing ADCs following the cleavage of the ADC
linker within the tumor microenvironment [91]. Further, ADCs also kill tumors by
the activation of the immune response through antibody-dependent cellular
toxicity or complement-dependent cytotoxicity by tumor-infiltrating immune cells
[15, 59, 91, 113].
2.3 Antibody-drug Conjugates Developed for Ovarian Cancer
The first FDA-approved ADC for human use was gemtuzumab ozogamicin
(Mylotarg) for acute myeloid leukemia in 2000 [114]. More than two decades
later, the first ADC for ovarian cancer, Mirvetuximab soravtansine, was approved
by the FDA [89]. More than 150 ADCs have now been evaluated in clinical trials
[76]; however, the number of clinically tested ADCs for the treatment of ovarian
cancer is still limited. Approximately 30 ADCs have been clinically evaluated for
the treatment of ovarian cancer since 2003 (Table 2) [15]. Out of these, four
(clinicaltrials.gov identifiers: NCT02837991; NCT02539719; NCT00051584;
NCT02947152) were terminated, and one (clinicaltrials.gov identifier:
NCT04602117) was withdrawn from clinical development. Despite this low
representation, significant efforts are being made in the preclinical development
of novel ADCs for the targeted chemotherapy of ovarian cancer [15].
Fig. 6. Schematic representation of the mechanisms of action of ADCs. The
cleavage of ADCs with cleavable linkers starts in the early endosome. The
cleavage of ADCs with non-cleavable linkers, on the other hand, is a
complex proteolytic process involving cathepsin B and plasmin and occurs
in lysosomes [91]. Created with BioRender.com

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While most ADCs in clinical development for ovarian cancer (MIRV, IMGN151,
PRO1184, MORAb-202, and STRO-002) target the FR-α antigen, there is a
continuous search for newer target antigens to expand the targeting
effectiveness of ADCs [15]. The clinical development of a new ADC, LY4101174,
for ovarian cancer and other advanced solid tumors began in March 2024
(clinicaltrials.gov identifier: NCT06238479). LY4101174 targets nectin-4, a
member of the calcium ion-independent immunoglobulin-like cellular adhesion
molecules that are involved in cell migration [115]. Many solid tumors, such as
pancreatic and ovarian cancers, overexpress nectin-4, which is linked to a poor
prognosis [15, 115, 116]. Kanda et al. [76] identified the lipolysis-stimulated
lipoprotein receptor (LSR) as a new tumor antigen of epithelial ovarian cancer.
The overexpression of LSR has been linked with the proliferation and metastasis
of different cancer types. Approximately 70% of serous ovarian carcinoma
overexpress LSR, and high LSR expression has been correlated with poor
prognosis in these cancer subtypes [15, 76]. Kanda et al. [76] also demonstrated
that while LSR is widely expressed in epithelial ovarian cancer patient tissues
and cell lines, LSR expression in normal tissues is very low, making LSR a good
candidate for an antibody-based therapy against epithelial ovarian cancer. They
prepared an anti-LSR mAb and reacted it with maleimidocaproyl-valyl-citrullinyl-
PABC-MMAE to yield the LSR-ADC with a drug-to-antibody ratio of 2.8. The
LSR-ADC was efficiently internalized within 1h, and subsequent trafficking to the
lysosomal compartment was confirmed by immunofluorescence [76]. The LSR-
ADC selectively inhibited the proliferation of LSR-expressing ovarian cancer cell
lines (NOVC-7C and OVCAR3) compared to LSR-negative ES2 cell lines [76].
However, the in vivo cytotoxicity of the LSR-ADC in OVCAR3 and primary
patient-derived xenograft models was not the same, although both tumors are
highly LSR-expressing. At a dose of 3 mg/kg, significant tumor growth
suppression by LSR-ADC was observed in the OVCAR3 and primary patient-
derived xenograft models after day 7 and day 21, respectively [76]. This
observed slower inhibitory effect of LSR-ADC on the primary patient-derived
xenograft models raises concerns about the direct extrapolation of preclinical
animal studies to clinical models [15].
LRRC15, a type-I 15–leucine-rich repeat-containing membrane protein, is
another novel ADC target in ovarian cancer [28]. The functional association of
LRRC15 with the regulation of cell-cell and cell-extracellular matrix interactions
has been established [28]. These are believed to be achieved through LRRC15
interaction with various extracellular matrix proteins such as fibronectin, laminin,
and collagen IV, facilitated by its extracellular leucine-rich repeats [15]. Ray et al.
[28] demonstrated that LRRC15 is highly over-expressed in ovarian cancer cells
compared to normal ovarian cells; and significantly promotes adhesion to
mesothelial cells and extracellular matrix proteins, implicating LRRC15 as a
potent driver of omental metastasis. They targeted LRRC15 with ABBV-085, an
antibody-drug conjugate consisting of an anti-LRRC15 humanized IgG1 antibody
linked with MMAE through a protease-cleavable valine-citrulline linker. ABBV-085
showed a dose-dependent reduction in cell viability for LRRC15-expressing
OVCAR5 NTC cells but not in cells where LRRC15 has been knocked down [28].
They also showed that therapeutic targeting of LRRC15 led to suppression of

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both tumorigenesis and metastatic spread in xenograft models of ovarian cancer
[15, 28]. ADCs targeting other antigens including, trophoblast-antigen-2 [73], type
II sodium–phosphate cotransporter (NaPi2b) [117], cluster of differentiation 70
[71], Wnt signaling receptors [118, 119], and nectin-2 [120], have also shown
promising activities against ovarian cancer in vitro and in vivo. The common
denominator for these antigens is their overexpression in ovarian cancer cells
with little or no expression in normal cells [15].
One limitation of many developed ADCs is that the drug-to-antibody ratio for
most of them is limited to between 3 and 4 [121]. A higher drug load is essential
to retard the development of chemotherapeutic resistance by cancer cells.
However, increasing the drug load can alter the targeting ability of the antibodies
that are used in designing the ADCs, or lead to an increase in the molecular size
of the ADCs, causing rapid clearance by the reticuloendothelial system [15, 121,
122]. This seems to not be a problem for XMT-1536, a NaPi2b-targeting ADC
comprising of a humanized antibody (Rebmab200) conjugated with 10 to 15
auristatin F-hydroxypropyl amide payload molecules using a flexible poly-l-
hydroxymethylethylene hydroxymethylformal platform called Dolafexin [117, 121].
The Dolafexin platform is a linker platform with high hydrophilicity and
polyvalency and allows for the preparation of antibody-drug conjugates with high
drug-antibody ratios [15, 121]. Compared with another NaPi2b-targeting ADC
that has a drug-antibody ratio of 3.5, XMT-1536 showed superior antitumor
activity in both ovarian cancer and non–small cell lung cancer primary patient-
derived xenograft models [117]. This superior activity was attributed to the higher
drug-antibody ratio of the XMT-1536. It is currently in phase 3 clinical trials for
platinum-resistant ovarian cancer and metastatic non-small cell lung cancer
(clinicaltrials.gov identifier NCT05329545) [15].
Other challenges of ADCs include the risk of antibody-induced immunogenicity
[123], and alterations in antigen recognition by the ADC antibody [92]. To
address these, antibody fragments or formats that can simultaneously target
multiple antigens are now being employed in the development of ADCs [15, 92,
124]. Overall, ADCs are the foremost drug conjugate systems that have made
considerable clinical success in ovarian cancer-targeted chemotherapy.
Preclinical evaluation of monoclonal antibody immunogenicity and ADC
resistance mechanisms is critical to optimizing ADC development and improving
clinical benefit [92]. For more detailed information on ADCs for the treatment of
ovarian cancer, readers are referred to the reviews referenced at [59], [90], [114],
and [124].
3. SMALL MOLECULE-DRUG CONJUGATES
Small molecule ligands (with molecular weight < 0.5 kDa) [99] are fast-becoming
attractive alternatives to antibodies for cancer-targeted drug conjugates owing to
their non-immunogenicity, tunable synthesis, and better cell penetration due to
their low molecular weights [65, 125,126]. Folate and glutamic acid urea
derivatives designed for targeting FR-α and prostate-specific membrane
antigens, respectively, are probably the most used small molecule ligands for the

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selective delivery of cytotoxic drugs to tumors [15, 65, 81, 98]. The use of small
molecules for the development of drug conjugates has been reviewed in detail by
Zhuang et al. [126] and the reader is referred to it. Typically, small molecule-drug
conjugates (SMDCs) are drug conjugate systems that contain a therapeutic
agent that is covalently attached to a small molecule targeting ligand through a
cleavable linker (Fig. 6). A spacer is usually inserted between the targeting ligand
and the cleavable group in the linker for enhanced target binding or improved
cleavage rate and plasma stability of the SMDCs [15, 126].
FR-α-targeted SMDCs have been widely investigated for the treatment of
different types of cancer [65]. EC1456 is an FR-α-targeted small molecule drug
conjugate consisting of folic acid covalently attached to tubulysin B hydrazide
through a disulfide linker (Fig. 7) [15]. It also contains a hydrophilic spacer, 1-
amino-1-deoxy-glucitolyl-γ-glutamate residues, separated by d-Glu residues and
terminated with d-Cys, between the folic acid targeting ligand and the cleavable
disulfide linker [127]. The importance of the hydrophilic spacer is to prevent non-
FR-α-mediated cellular uptake by other FR-α-expressing cells [127].
Tubulysins are a family of tetrapeptide products that cause cell death by
disrupting microtubule dynamics [15, 128]. They are highly potent against many
cancer cell lines, including multidrug-resistant cells; but are not selectively toxic
to cancer cells [127, 128]. The preclinical assessment of EC1456 exhibited a
dose-dependent response and showed approximately 1000-fold specificity in FR-
α-expressing cells [127]. A phase one study of EC1456 in ovarian cancer
patients undergoing cytoreductive surgery (ClinicalTrials.gov Identifier:
NCT03011320) was completed in 2018 but the outcome has not been released.
The major limitation of SMDCs is their low molecular weights, which makes them
undergo rapid renal clearance, and hence do not accumulate in solid tumors by
the EPR effect [15, 126].
Fig. 7. Representation of the chemical structure of EC1456 consisting of
folic acid as the targeting ligand for FR-α, a hydrophilic spacer, reducible
disulfide bridge, and tubulysin B hydrazide as the cytotoxic drug. Adapted
from Ref. [127].

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4. AFFIBODY-DRUG CONJUGATES
Affibody molecules are a class of engineered affinity proteins [129, 132] (Altai et
al., 2018; Ding et al., 2021). They are small non-immunoglobulin proteins (~7
kDa) made up of 58 amino acids folded into a three-helix structure [129 – 133].
Affibodies offer several advantages over the conventional monoclonal antibodies.
These include rapid extravasation and enhanced penetration into the tumors due
to the small size, high selectivity and stability, and ease of production [134].
Affibodies can be easily engineered and modified to optimize their binding affinity
and pharmacokinetic profiles. Additionally, affibodies elicit relatively less toxic
and reduced immunogenicity. HER2-specific affibody molecules including
ZHER2:2891 and ZHER2:342 have been investigated for use in tumor imaging for
diagnostic purposes and in the targeted delivery of drugs for several
malignancies including breast cancer, colorectal cancer, and ovarian cancers
[129 – 131].
A reported limitation of affibodies is their short biological half-lives [135]. This is
because they are of small size and as a result are rapidly eliminated from
circulation. Affibodies lack cysteine residues, allowing the incorporation of
cysteine for site-specific modifications for desired chemical conjugation such as
thiol-mediated chemistry [132, 136]. Affibodies coupled with cytotoxic payloads,
radiotracers, or imaging probes have been developed via modification of affibody
C-terminal or N-terminal with additional cysteine residue [136].
Several strategies have been documented to improve the half-life of affibody
molecules. One such approach involves the fusion of affibody molecules to the
albumin-binding domain (ABD). For example, ABD035, which has a high affinity
for human serum albumin, was discovered to prolong the half-life of affibody
molecules when fused with them [137]. Following administration, the affibody-
ABD fusion binds to the abundant serum albumin in circulation, increasing the
size of the complex by 66 - 67 kDa, a molecular weight large enough to evade
renal filtration, thereby extending their plasma half-life [138]. The short half-live
can also be circumvented by developing affibody-drug conjugates into
nanoparticles as described above.
Affibody-drug conjugate (AffiDC) (Fig. 8) is another notable application of
affibody in the targeted delivery of cytotoxic agents in cancer treatment. They are
promising as cytotoxic drug carriers because they exhibit high selectivity and
specificity toward their target of interest [132]. Like other drug conjugates, AffiDC
can be fabricated by conjugating a drug of interest with the affibody carrier via
suitable linkers. Xia et al. [135] designed an affibody and conjugated it to MMAE
through a maleimido valine-citrulline type linker to form an amphiphilic affibody-
drug conjugate. When dispersed in water, the conjugate self-assembled into
nano micelles due to its amphiphilic nature. The nano-aggregation prolonged the
plasma circulation of the conjugate by 8 hours following intravenous
administration. A recent investigation conducted by Yin et al. [138] examined
various drug conjugates designed using an affibody targeting HER2, coupled
with an ABD to improve the affibody’s half-life. These conjugates were linked to

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one of three cytotoxic tubulin polymerization inhibitors (MMAE, MMAF, or DM1)
via a maleimidocaproyl linker, and evaluated for anti-tumor effect. Among these
conjugates, ZHER2-ABD-mcMMAF demonstrated notable cytotoxicity in SKOV3
ovarian cancer xenografts inhibiting tumor growth and prolonged survival rates.
The study attributed this cytotoxic effect to the targeted delivery of the
therapeutic agent facilitated by affibody interaction with HER2. This assertion
was supported by the results obtained for the control group where tumor growth
persisted without any notable regression [138]. Altai et al. [129] also prepared an
AffiDC by conjugating ZHER2:2891 with a maytansine derivative (MC-MDI) via
maleimide-thiol chemistry. The in vitro cytotoxicity data showed that the AffiDC
was effective and prolonged the survival of mice bearing HER2-positive SKOV3
xenograft [129].
Fig. 8. Representation of an affibody-drug conjugate. Created with
BioRender.com
5. APTAMER DRUG CONJUGATES
Aptamers are chemically synthesized oligonucleotides (5 - 30 kDa) that bind to
target molecules with specificity and affinity that is equal to that of antibodies but
with little or no immunogenicity. They are being increasingly used for cancer
targeting [105, 139, 140]. Aptamer-drug conjugates (ApDCs) may be prepared by
covalently linking chemotherapeutic agents to aptamers via suitable linkers or by
non-covalent coupling of therapeutic agents to aptamers (Fig. 9). An example of
ApDC developed via non-covalent conjugation is a conjugate developed by
physical intercalation of doxorubicin with A10, a prostate-specific membrane
antigen (PSMA)-targeting aptamer with an inherent drug intercalation site [141,
142].

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Fig. 9. Representation of an aptamer-drug conjugate. Created with
BioRender.com
In addition to their use in targeted delivery of chemotherapeutics, aptamers are
employed for specific delivery of nucleic acid therapeutics, proteins,
photosensitizers, and photothermal agents [142]. Li et al. [105] prepared an
aptamer, NucA, to target nucleolin protein, which facilitates cancer proliferation
and metastasis [143]. Nucleolin is mainly found in the nucleus but is also found
on the cell surface of various cancers including ovarian cancer [105]. The
covalent linkage of paclitaxel to NucA using a valine-citrulline-p-aminobenzyl
carbonyl linker rendered the hydrophobic drug water-soluble. The NucA-
paclitaxel conjugate was also reported to facilitate the selective accumulation of
paclitaxel in ovarian tumor tissue compared with normal tissues in SKOV3 and
OVCAR3 xenograft models of ovarian cancer [105]. This resulted in enhanced
anticancer activity and reduced toxicity of paclitaxel in animal models [15, 105].
Similarly, Henri and colleagues [140], also prepared an aptamer that specifically
targets epithelial cell adhesion molecule (EpCAM) on ovarian cancer cell surface
and conjugated it with doxorubicin. The aptamer-doxorubicin conjugate
demonstrated in vitro cytotoxicity similar to free doxorubicin in ovarian cancer
cells [140]. While aptamers are promising targeting moieties for drug conjugates
in cancer therapy, there is concern regarding how much drug can be conjugated
to them without losing targeting capacity [15, 139]. As the drug loading increases,
the targeting ability of the aptamer may be compromised due to the reduction in
the size of the aptamer relative to the drug load. Additionally, the steric hindrance
caused by the drug has the potential to obstruct the aptamer, leading to a loss of
its targeting efficacy. Insufficient drug loading may also result in ineffective drug
delivery [139].
6. PEPTIDE-DRUG CONJUGATES
Peptide-drug conjugates (pDCs) are drug delivery systems that are formed by
the covalent attachment of drug(s) to a peptide sequence through a suitable
linker (Fig. 10) [64]. They are now gaining more attention as a means of cancer

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targeting owing to their advantages over the well-known antibody-drug
conjugates [63, 99, 144]. Peptide-drug conjugates have simpler designs, cheaper
synthesis, decreased immunogenicity, and offer a multifunctional approach to
cancer targeting [15, 99]. The average molecular weight of a monoclonal
antibody and that of a peptide used in cancer targeting is 150 kDa and 0.5 - 5
kDa, respectively [99, 144]. The smaller size of peptides enables them to better
penetrate primary tumor and metastatic tumor sites than larger-sized antibodies
[64]. Both the N-terminus and the C-terminus of the amino acid residues present
in a given peptide provide attachment sites for drugs, linkers, and other targeting
moieties. This has made pDCs extensively studied for targeted delivery of drugs
to cancers [15, 99, 107 – 109]. Readers are referred to references [144] and
[145] for detailed reviews on pDCs for general cancer targeting.
Fig. 10. Representation of a peptide-drug conjugate. Created with
BioRender.com
Similar to ADCs, the linker used for the design of pDCs can be cleavable or non-
cleavable. Two categories of peptides employed in the design of pDCs can be
identified and these include cell-targeting peptides and/or cell-penetrating
peptides [99, 144]. Cell-penetrating peptides (CPPs) mainly transport cytotoxic
payloads across the cell membrane into the cytoplasm by energy-independent
transmembrane mechanisms [15, 145]. Oligoarginine is a cell-penetrating
peptide that has been reported to facilitate intracellular delivery of paclitaxel by
rendering it water-soluble and evading p-glycoprotein-mediated efflux [146]. HIV
transactivators of transcription peptides and transportan are other examples of
CPPs that have been used to improve the internalization of anticancer agents
[64]. The use of CPPs is, however, limited due to their low selectivity [144]. Most
CPPs cannot target and bind to specific cell types and may enter cells
indiscriminately [15, 147].

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Cell-targeting peptides, on the other hand, can selectively bind with specific
receptors that are overexpressed on the cancer cell surface, and facilitate
receptor-mediated endocytosis of the conjugated cytotoxic drugs [148]. Peptides
that can bind specifically with somatostatin, epidermal growth factor, and
gonadotropin-releasing hormone (GnRH) receptors on ovarian cancer cell
surface have been commonly used as targeting peptides for the design of
peptide-drug conjugates developed against ovarian cancer [15, 144, 148].
Schuster et al. [79] prepared GnRH-drug conjugates by covalently linking
paclitaxel and daunorubicin with a GnRH analog, GnRH III, via cathepsin-B
cleavable dipeptides. The conjugates exhibited significant growth inhibition in
GnRH-receptor-overexpressing A2780 ovarian cancer cells compared with
pancreatic cancer cells that express GnRH receptors at low levels [15].
Compared with ADCs, only a few pDCs have been tested clinically for the
treatment of cancer. Melphalan flufenamide (melflufen) is a peptide-drug
conjugate that is made up of a lipophilic dipeptide formed by an ester linkage of
melphalan with para-fluoro-L-phenylalanine. Following administration, melflufen
rapidly penetrates cell membranes because of its high lipophilicity and is quickly
hydrolyzed into the more hydrophilic melphalan by aminopeptidases in
aminopeptidase-positive tumor cells [15, 149]. This results in the specific release
and accumulation of melphalan in the tumor cells. Melphalan is an alkylating
agent that induces the cross-linking of DNA strands leading to cell death. The
delivery of melphalan as melflufen thus allows for improved efficacy and reduced
off-target toxicity [133]. In 2021 melflufen (ClinicalTrials.gov Identifier:
NCT04534322) received accelerated FDA approval for the treatment of multiple
myeloma but was withdrawn from the US market following multiple deaths in a
phase 3 clinical trial the same year [15, 150].
A novel peptide-drug conjugate, TH1902, is currently undergoing a phase one
clinical trial in patients with advanced solid tumors, including ovarian cancer
(ClinicalTrials.gov Identifier: NCT04706962). TH1902 is a sortilin-targeted
peptide-drug conjugate comprising two docetaxel molecules linked to the
peptide, TH19P01, through an ester linkage [15, 69]. SORT1 is a key scavenger
receptor that plays a dual role in endocytosis and receptor trafficking, facilitating
the transfer of many peptides and proteins, including proneurotrophins, from the
cell surface to specific intracellular locations [69, 151]. SORT1 is associated with
cancer cell proliferation, migration, and invasion, and its expression is
significantly higher in ovarian cancer compared to healthy ovarian tissue [15,
151]. In a preclinical investigation conducted by Currie et al. [69], TH1902
reduced ovarian cancer cell growth and induced more SORT1-dependent cell
death than unconjugated docetaxel. This was a result of TH1902's potential to
leverage SORT1's ligand internalization ability.
While it is possible to generate high-affinity human monoclonal antibodies
against almost any protein target, isolating small ligands to target proteins of
pharmacological interest is not always feasible [98]. Also, the problem of fast
clearance of small peptides, either by the kidney or enzymatic degradation
leading to non-specific drug release, is a major limitation of pDCs [15, 99]. A

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detailed review of the efforts made to improve plasma stability and circulation of
peptides including cyclization, peptide stapling, and conjugation of peptides with
macromolecules with sizes above the renal filtration threshold (>50 kDa) has
been published [99]. One example of such stabilized peptides is the ‘bicycle’
peptide, which has an average of 15 amino acids with 3 cysteine residues in its
sequence [15, 99]. Covalent linking of the cysteine residues results in the rigid
‘bicycle’ conformation of this peptide [99]. BT5528 is a bicyclic pDC consisting of
an EphA2-targeting peptide covalently linked to MMAE through a cleavable linker
[152]. EphA2 is a receptor tyrosine kinase that is involved in cancer spread and
survival and is overexpressed in > 75% of ovarian cancer cases [15, 84]. High
anti-tumor activity in pre-clinical animal models has been reported for BT5528
without the adverse effect of bleeding associated with earlier EphA2-targeting
antibody-drug conjugate [152]. A Phase 1/2 clinical study of BT5528 patients with
EphA2-expressing cancers, including ovarian cancer, is currently ongoing
(ClinicalTrial.gov Identifier: NCT04180371) [15]. BT8009 is another bicyclic pDC
consisting of a nectin-4-targeting peptide covalently linked to MMAE through a
valine-citrulline cleavable linker. It is currently used as a monotherapy or in
combination with pembrolizumab in an ongoing phase 1/2 clinical trial in patients
with advanced solid tumors including ovarian cancer, non-small-cell lung cancer,
and triple negative breast cancer (ClinicalTrial.gov Identifier: NCT04561362).
Additionally, elastin-like polypeptides (ELPs), which are synthetic derivatives of
tropoelastin, are recently gaining attention in cancer therapy [153]. The basic
structural unit of ELPs consists of linearly repeating pentapeptides. These
pentapeptides consist of the amino acid sequence (Val-Pro-Gly-X-Gly)n, where
the variable X can be any amino acid except for proline [154]. ELPs are
biocompatible, degradable, temperature-responsive, have tunable structures,
and can be used to improve the physical properties and in vivo fate of anticancer
agents [15, 153]. For example, gemcitabine-conjugated ELPs developed by
Ramamurthi et al. [154] showed significant cytotoxicity in ovarian cancer cell
lines. Also, the pH-sensitive hydrazone linker used in the design of the ELPs
facilitated the in vitro release of gemcitabine in the acidic tumor
microenvironment. Moreover, the block architecture of ELPs enables them to
undergo self-assembly into drug-encapsulating nanoparticles; with the drugs
being chemically conjugated to the ELPs before self-assembling or physically
adsorbed to the self-assembled ELPs [153]. Self-assembling pDCs have been
reported to passively target and enhance the accumulation of loaded drugs in
ovarian cancer via the EPR effect [15, 133, 155,156].
7. NANOPARTICLE-DRUG CONJUGATES
The term ‘nanoparticles’ refers to small molecules in the nanometer size range
that are made from a variety of materials including inorganic materials, naturally-
occurring polymers, and synthetic polymers (Fig. 11) [15, 93]. Various ovarian
cancer chemotherapeutics have been developed as polymeric nanoparticles
[155], micelles [157], and liposomes [158]. These nanoparticle platforms offered
the advantages of enhancing the water-solubility of hydrophobic drugs, active
targeting of cancer cell surface receptors, prolonged blood circulation, tissue

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penetration, and enhanced tumor accumulation [14, 159]. Also, as a result of
their nano-size range, they are not susceptible to plasma membrane-bound
transporters that efflux small drug molecules from cancer cells [15, 160]. While
so much effort has been directed towards the development of nanoparticle drug
delivery systems, the nanoparticle-based chemotherapeutics that have been
approved for the treatment of ovarian cancer - Doxil® (liposomal doxorubicin),
Genexol-PM® (polymeric micellar paclitaxel formulation), and Abraxane®
(albumin-bound paclitaxel nanoparticle) - are those based on conventional
methods of drug encapsulation [14, 15, 161, 162]. These conventional
nanoparticles have been reported to improve the toxicity profiles, but not the
therapeutic efficacy of the drugs incorporated in them [163]. Additionally, since
the drugs are simply encapsulated within the nanocarriers, they are susceptible
to ‘burst-release’ in blood circulation causing off-target toxicity in healthy cells
[163].
Fig. 11. Different types of nanoparticles. Created with BioRender.com
Nanoparticle-drug conjugates (NpDCs) can be defined as drug delivery systems
in which active drug molecules are covalently attached to natural or synthetic
materials to form a nano-sized ‘prodrug’ that is activatable by target-specific
conditions [164]. To improve the safety and effectiveness of cytotoxic drugs, it
may be best to chemically conjugate them with nanoparticles using suitable
linkers that are selectively degraded in the tumor microenvironment [15]. This
approach has been used for the selective delivery of highly potent anticancer
drugs to ovarian cancer cells without ‘burst release’. Qi et al. [163] covalently
conjugated MMAE to a triblock copolymer of methoxy poly (ethylene glycol)-
block-poly(carbobenzyloxy-L-lysine)-block-poly(N-[N-(2-aminoethyl)-aminoethyl]
aspartamide) through a disulfide linker. The triblock copolymer can self-assemble
in aqueous solutions into polymeric nanoparticles [15]. Further complexation of
methoxy poly (ethylene glycol)-block-poly(glutamic acid) with the nanoparticle
produced ‘stealth’ nanoparticle-MMAE conjugate by conferring a steric
hydrophilic barrier on the MMAE-conjugated nanoparticle (Fig. 12a). This
approach enables longer blood circulation of the nanoparticle by evading the
reticuloendothelial system, leading to passive tumor accumulation by the EPR
effect [15, 64]. The polymer coat of the MMAE-conjugated nanoparticle was

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designed to be degraded in the acidic tumor microenvironment, escape the endo-
lysosome, and selectively deliver the drug component in the cytoplasm where the
reduction of the disulfide linker by high intracellular glutathione concentrations
triggers the release of the cytotoxic MMAE [15]. In vitro studies show that the
MMAE-conjugated nanoparticle gradually released MMAE over a period of time
in the presence of exogenous glutathione but remained stable over 7 hours at pH
7.4 without glutathione [15]. This shows that the conjugate system can circulate
longer in the plasma (pH 7.4) without releasing the incorporated drug until it
reaches the tumor site. In addition, the conjugate exhibited cytotoxicity
comparable to free MMAE in OVCAR8 cell lines and demonstrated no toxicity in
animal models at a dose of 3 mg/kg [15, 163].
Fig. 12. Representation of a nanoparticle-drug conjugate where (a) the drug
is conjugated to a self-assembling polymeric backbone, and (b) the drug is
conjugated to the surface of a stealth nanocarrier through a cleavable
linker. Created with BioRender.com
The conjugated drug in NpDCs can also be covalently attached to the surface of
nanoparticles instead of self-assembling (Fig. 12b). Recently, Wu et al. [165]
developed a small (6.4 nm) targeted nanoparticle-drug conjugate (EC112002)
comprising a stealth C’Dot nanocarrier that is linked to multiple folic acid and
exatecan molecules via non-cleavable and cathepsin B-cleavable dipeptide
linkers, respectively (Fig. 12b) [15]. A C’Dot nanocarrier is a PEGylated silica
nanoparticle in which one to two Cy5 fluorescent dyes molecules are covalently
attached to the silica network [165]. EC112002 contains approximately 13 folic
acid molecules linked to the C’Dot via DBCO-azide click chemistry [165].
Approximately 21 molecules of exatecan, a topoisomerase 1 inhibitor, are also
covalently linked to the C’Dot by click chemistry [15]. The folic acid enables FRα-
mediated endocytosis and lysosomal trafficking of EC112002 in the tumor cells

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where cathepsin B-cleavage of the dipeptide linker releases free exatecan to
elicit its cytotoxic effect. EC112002 was stable in human plasma for over 48h and
released about 80% of the drug after 24h in vitro in the presence of exogenous
cathepsin B at pH 5.0. An IC50 range of 160pM to 17.6nM was established for
EC112002 in 3D platinum-resistant ovarian cancer models. EC112002
demonstrated dose-dependent and FR-α-expression-dependent cytotoxicity in
vivo and was tolerated in animal models at doses up to 0.48 mg/kg [15, 165].
Compared with ADCs, only a few NpDCs have been clinically developed.
ELU001, a C’Dot drug conjugate that is similar in design to EC112002, is
currently undergoing a phase 1/2 clinical trial in patients who have advanced,
recurrent, or treatment-resistant FRα-expressing tumors, including ovarian
cancer (ClinicalTrials.gov identifier: NCT05001282). In another development, the
initial phase of the clinical development of CRLX101, a self-assembled
cyclodextrin-based nanoparticle-drug conjugate of camptothecin was completed
(ClinicalTrials.gov identifier: NCT00333502) [15]. CRLX101 was administered as
monotherapy to 29 patients with relapsed platinum-resistant ovarian cancer
[166]. The study reported that CRLX101 was generally well-tolerated by the
patients except for nausea, fatigue, and anemia. The patients received a median
of 3 treatment cycles and showed a clinical benefit rate of 68% and an overall
response rate of 11% [15, 166]. The polymeric nature of the nanoparticle-drug
conjugate enabled it to accumulate preferentially in tumor tissues by the EPR
effect, such that intact conjugate was still present in the tumor up to 48h after
intravenous administration in animal models [167]. The conjugate system was
reported to exhibit a sustained slow release of camptothecin in the tumor while
limiting unwanted toxicity in healthy cells [168]. Another phase 2 clinical trial to
evaluate the safety and efficacy of CRLX101 (under the code name, EP0057), in
combination with olaparib in women with advanced ovarian cancer is ongoing
(ClinicalTrials.gov Identifier: NCT04669002) [15].
8. POLYMER-DRUG CONJUGATES
Polymer-drug conjugates (PDCs) are probably the commonest macromolecules
that are used for EPR-based passive targeting of cancer [169, 170]. By definition,
PDCs are drug conjugate systems in which active drugs with or without targeting
moieties are covalently attached to a polymeric backbone (Fig. 13a) [15, 171].
Conjugation to water-soluble polymers is one strategy that has the potential to
boost the clinical utility of chemotherapeutic drugs. For example, the formulation
and administration of many chemotherapeutic drugs are complicated by the fact
that they are poorly water-soluble. A significant increase in aqueous solubility can
be achieved without the use of organic solvents or surfactants through the
process of conjugation to water-soluble polymers [15, 64]. Second, the
conjugated system's biodistribution and pharmacokinetics can be modulated by
linking it to a hydrophilic polymer carrier [38]. Several PDCs have been used to
improve the stability of plasma-labile drugs [38], provide ultra-sustained drug
delivery [172], EPR-based passive targeting [173] and combined active/passive
targeting [174, 175] in human ovarian cancer cells (Table 3) [15].

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Fig. 13. Representation of: (a) polymer-drug conjugate (b) linear polymer, (c) cross-linked linear polymer, and (d) a 5th-
generation dendritic polymer. Created with BioRender.com

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Table 3. Examples of polymer-drug conjugates developed for targeting ovarian cancer.
Polymer
Anticancer
agent(s)
Linker
Targeting
strategy
Study model
Summary
Reference
Polylysine
dendritic
polymer
Cisplatin
pH-sensitive
EPR effect
SKOV-3 cells
Exhibited increased tumor uptake,
accumulation, and anticancer activity
compared with the free drug
[177]
HPMA
copolymer
Doxorubicin
GFLG
tetrapeptide
EPR effect
A2780 &
resistant
A2780/AD
cells
Conjugate decreased tumor size by
28X and 18X in the sensitive and
resistant cells, respectively,
compared to the free drug.
[178]
PolyHPMA
Gemcitabine
Paclitaxel
GFLG
tetrapeptide
EPR effect
A2780 cells
Conjugates showed moderate
stability at pH 7.4 and fast drug
release in the presence of
exogenous cathepsin B at pH 6.0.
[38]
PolyHPMA
Gemcitabine
Paclitaxel
GFLG
tetrapeptide
EPR effect
A2780
xenografts
Increased Mw of the conjugates
resulted in enhanced drug
exposure to tumor cells by
prolonging the blood circulation time.
[179]
PolyMPC
Doxorubicin
Hydrazone
EPR effect
SKOV-3
xenografts
Drug loading was ~19%; Tolerated
maximum conjugate dose was >
twice free drug dose; Reduced
systemic toxicity and improved drug
accumulation in tumor cells.
[173]
PolyHPMA
Epirubicin
GFLG
tetrapeptide
EPR effect
A2780
xenografts
Four-fold increase in the drug half-
life attributable to the conjugate’s
molecular weight (106 kDa)
[180]

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Polymer
Anticancer
agent(s)
Linker
Targeting
strategy
Study model
Summary
Reference
PolyHPMA
Gemcitabine
Paclitaxel
GFLG
tetrapeptide
EPR effect
A2780
xenografts
Conjugates ~ 100kDa in size had the
best antitumor activity compared to
those with Mw of 200 kDa and 300
kDa.
[181]
Bi-(mPEG-
PLGA)
Cisplatin
Paclitaxel
Ester bonds
EPR effect
SKOV3 cells
& xenografts
Reported a synchronous and
sustained in vitro release of both
drugs over 2.5 months; a single
injection of the conjugate in mice
showed enhanced efficacy and
reduced side effects compared with
multiple injections of the free drug
combination.
[172]
PolyHPMA
Aminohexyl-
geldanamycin
Docetaxel
GFLG
tetrapeptide
EPR effect
& αvβ3
integrins
targeting
A2780 cells
Targeting of αvβ3 integrins
significantly improved tumor
regression
[174]
Pullulan
Doxorubicin
Primary amide
bonds
EPR effect
& folic acid
receptor
targeting
A2780 cells
Exhibited moderate stability at pH
7.4 and gradually increasing in vitro
drug release at acidic pH. In vitro,
the cytotoxicity of the conjugate (IC50
0.036 mg/L) was greater than free
doxorubicin (IC50 0.15 mg/L).
[182]

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Polymer
Anticancer
agent(s)
Linker
Targeting
strategy
Study model
Summary
Reference
HPMA
copolymer
Paclitaxel
Hydrazone
EPR effect
& CD44
targeting
SKOV3 cells
Hyaluronic acid-modified conjugate
demonstrated 50X higher in vitro
cytotoxicity towards CD44-
overexpressing cells compared to
unmodified conjugate.
[183]
PolyHPMA
Doxorubicin
GFLG
tetrapeptide
EPR effect
& P-gp
inhibition
A2780 &
resistant
A2780ADR
cells
Early cleavage of the hydrazine
linker in an acidic tumor environment
inhibited P-gp resulting in enhanced
doxorubicin cytotoxicity in resistant
A2780ADR cells.
[175]
Zosuquidar
Hydrazone
MPC: methacryloyloxyethylphosphorylcholine; HPMA: N-(2-hydroxypropyl) methacrylamide; GFLG: glycyl phenylalanyl leucyl glycine; mPEG-PLGA:
methoxylpoly(ethylene glycol)-poly(lactide-co-glycolic acid; P-gp: permeability glycoprotein

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Recent reviews on the structure and design of PDCs can be found in references
[170] and [171], and the readers are referred to them. The polymers selected for
the design of PDCs should have suitable functionalities such as the carboxyl,
hydroxyl, amino, or thiol functional groups suitable for covalent bonding with
drugs and targeting ligand molecules. They should also be biodegradable or
degraded to components that are completely excreted from the body after drug
release [15, 170]. Ideally, such polymers and their metabolites should not elicit
toxicity or immune response; be easily synthesized using reproducible methods;
have uniform molecular-weight distribution, and be water-soluble [176]. For the
general synthesis of PDCs, the drug may be conjugated to a pre-formed polymer
or a polymer-intermediate for subsequent polymerization. The latter method
circumvents the problem of uncontrolled conjugation of drugs to the polymer
backbone that may occur with the former method, resulting in controlled drug
loading [15, 170]. Polymers that have been used for the synthesis of PDCs can
be broadly classified as linear and branched polymers (Fig. 13b, 13c, & 13d).
Such linear polymers include poly (N-(2-hydroxypropyl) methacrylamide)
(HPMA), poly (malic acid) (PMA), and poly (ethylene glycol) (PEG), and
branched polymers include poly(amidoamine) (PAMAM) and poly(ethyleneimine)
(PEI) polymers [15, 170].
Linear, water-soluble synthetic non-biodegradable polymers, such as N-(2-
hydroxypropyl) methacrylamide (HPMA) polymers, have been mostly employed
in the synthesis of PDCs because of their wide molecular weight range,
biocompatibility, non-immunogenicity, and relative ease of incorporating one or
more drug molecules and targeting agents [15, 38, 169, 184]. First-generation
HPMA-based PDCs were non-biodegradable with macromolecular sizes below
40kDa. Since their sizes fall below the renal threshold, they were suboptimal due
to rapid renal elimination [185]. For example, PK-1, a conjugate of doxorubicin
and a first-generation HPMA copolymer was synthesized with a molecular weight
of 28kDa to facilitate renal elimination of the conjugate. PK-1 showed limited
effectiveness when evaluated in Phase 2 clinical trials [15, 185]. This is
attributable to the rapid elimination of the conjugate and its inability to fully exploit
the EPR effect. Second-generation HPMA-based PDCs comprised high
molecular weight multiblock copolymers of HPMA that contain enzyme-
degradable sequences to make the PDCs biodegradable [38]. Such conjugates
were shown to have longer blood circulation times, higher tumor accumulation,
and no adverse effects in A2780 human ovarian carcinoma xenografts,
compared with the low molecular weight PDCs [15, 38, 185].
Dendrimers are another polymer-based system utilized in the synthesis of PDCs.
Dendrimers are well-defined, three-dimensional, multi-branched macromolecules
with a central core surrounded by building units of several layers known as
generations [186 – 189]. They have attracted notable attention in drug delivery
owing to their unique properties and versatility including biocompatibility,
polyvalency, solubility, and monodispersity [15, 190]. In addition, their nanometer
size makes them applicable in cancer passive targeting via the EPR effect,
exploiting the tumor microenvironment, as well as in active targeting. Dendrimers

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afford versatility in drug delivery as drugs can be encapsulated within the inner
core or conjugated to the surface of the dendrimers [15, 190 – 192].
Different types of dendrimers including polyamidoamine (PAMAM),
glycodendrimers, poly amidoamine-organosilicon (PAMAMOS), polyester,
polypropylene imine, and peptide dendrimer have been evaluated [192, 193].
Yellepeddi et al. [194] developed biotinylated PAMAM dendrimers loaded with
cisplatin. The formulation reduced the toxicity associated with cisplatin and
exhibited increased intracellular uptake, accumulation, and in vitro cytotoxicity
compared to the free drug [15]. Also, Lee et al. [195] modified the surface of a
dendrimer encapsulating a doxorubicin-containing gold nanoparticle with
hyaluronic acid, facilitating the active targeting of CD44. The nanoformulation
facilitated enhanced cellular uptake and cytotoxicity in SKOV-3 xenograft models,
compared to free doxorubicin [195]. The major concern with the use of
dendrimers in drug delivery is toxicity, which has been reported to be dependent
on the generation of dendrimers, size, and surface charge/functionality [15, 196,
197]. For example, positively charged dendrimers unlike those with neutral or
anionic charge may cause cell disruption and lysis [193, 196].
Polymer-drug conjugates containing various degradable linkers (acid-sensitive,
enzyme-cleavable, hydrolysis-sensitive) have been described in the literature for
ovarian cancer targeting and treatment (Table 3) [15]. A lot of these studies used
GFLG, a tetrapeptide-specific substrate for cathepsin B enzyme that is
overexpressed in many solid tumors, including ovarian cancer. Proteolytic
enzymes, such as cathepsin B, possess extensive active sites that can bind with
multiple amino acid residues [184]. Hence, the peptide linker's length plays a
crucial role in drug attachment. Typically, a peptide linker composed of four
amino acid residues is involved in the interactions that govern the creation of the
enzyme-substrate complex, leading to the eventual release of the drug [15, 184].
Furthermore, the incorporation of oligopeptide linkers at the termini of polymer
chains serves to mitigate steric hindrance effects that may impede the formation
of enzyme-substrate complexes [184]. Another cathepsin B peptide substrate,
Val-Cit, which is very popular in ADCs development [97], is known to exhibit
widespread sensitivities to a variety of cathepsins and could induce non-specific
drug release causing off-target toxicity in normal cells [15, 112]. GFLG, on the
other hand, is more specific for cathepsin B and is stable in the plasma [198 –
200]. Challenges with the use of GFLG include hydrophobicity and very long
cleavage times, which may lead to slower drug release and a consequent
reduction in cytotoxic efficacy [15, 201].
Pechar et al. [111] covalently attached doxorubicin with HPMA polymer using
Val-Cit-PABC, Val-Cit, and GFLG linkers and compared the in vitro cathepsin-B-
mediated drug release and in vivo cytotoxicity of the three HPMA-doxorubicin
conjugates in sarcoma S-180 mice models. The GFLG-containing conjugates
exhibited a ‘linear’ drug release (~20 % at 48h) while the Val-Cit-PABC-
containing conjugates exhibited a very fast initial drug release (~30 % at 8h)
followed by a gradual ‘linear’ drug release (~55 % at 48h) in the presence of
exogenous enzyme at pH 6.0 [15, 111]. The Val-Cit-PABC-containing

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conjugates, however, showed degradation at this pH in the absence of cathepsin
B, releasing about 17 %w/w of doxorubicin in 48h. The Val-Cit-containing
conjugates (not containing the self-immolative PABC), on the other hand, only
released <5 %w/w of the drug at pH 6.0 in the presence of the cathepsin B.
Despite differences in the in vitro drug release profiles, there was no significant
difference in the inhibition of tumor growth between the conjugates containing
GFLG or Val-Cit-PABC linkers [15, 111]. This similarity in effect is thought to be
due to the similar pharmacokinetics of the PDCs, resulting in similar
accumulation in the tumor tissue and exposure to a similar dose of
chemotherapeutics. Additionally, complex enzymatic activity may lead to similar
drug release rates from the conjugates in a living organism. Although the Val-Cit-
PABC linker showed higher drug release within 48 hours in vitro, the GFLG linker
demonstrated a linear release property that may result in increased release over
a longer incubation period, leading to similar cumulative drug release in the
tumor tissue [15, 111]. A similar sustained slow drug release exhibited by GFLG-
containing conjugates was also reported for CRLX101 which was discussed in
the previous section. In contrast to GFLG-, and Val-Cit-PABC-containing
conjugates, the conjugate that contains just Val-Cit without PABC is not cleaved
by cathepsin B and exhibited insignificant effects on tumor growth (Pechar et al.,
2022). This study may prove the importance of the self-immolative PABC spacer
in drug-conjugated systems that contain Val-Cit as the linker [15].
Although a large macromolecular size that can exploit the EPR effect has been
the selling point of PDCs, the molecular weight of a polymer-drug conjugate must
be optimized for it to be most effective [181]. An increase in the size of PDCs of
gemcitabine and paclitaxel from <50 kDa to ~100 kDa resulted in higher drug
loading, improved tumor accumulation, and antitumor activity [15, 38, 179 – 181].
Further increase in molecular weight, however, resulted in decreased antitumor
activity [181]. This is attributed to the complexity of water-soluble polymers that
bear hydrophobic drugs (e.g. paclitaxel) at their terminal side chains. The
hydrophobic moieties can undergo hydrophobic interactions leading to
conformational changes in the macromolecules which subsequently impact water
solubility, tumor penetration, enzymatic drug release, and antitumor activity [181].
Additionally, the architecture of PDCs impacts cellular internalization [15, 184].
Linear HPMA copolymer-meso-tetra (4-carboxyphenyl) porphyrin conjugate
exhibited higher internalization rates and light-induced cytotoxicity than meso-
tetra (4-carboxyphenyl) porphyrin attached to hyperbranched amine-terminated
PAMAM dendrimer [184]. Complex architectures may therefore impede the
enzyme-substrate complex formation and slow-down drug release, and ultimately
decrease cytotoxic activity [15, 184].
Considerable efforts have been made by researchers in the development of
PDCs for cancer targeting and treatment. Poly (L-glutamic acid)-paclitaxel
conjugate (Xyotax®) was the first PDC to advance to phase 3 clinical trials, where
it was tested in patients with advanced non-small cell lung cancer [202]. The FDA
did not approve Xyotax® even though it was given fast-track status. PLX038 is a
long-acting PEG-SN-38 conjugate that is currently undergoing phase 2 clinical
trials for the treatment of metastatic platinum-resistant ovarian, primary

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138
peritoneal, and fallopian tube cancer (ClinicalTrials.gov identifier:
NCT05465941). PLX038 contains four moieties of SN-38 (a topoisomerase 1
inhibitor) attached to PEG40kDa-DBCO via phenyl ether cleavable linker that
cleaves slowly [203, 204]. PLX038 prolonged the half-life of SN-38 to
approximately 5 days in humans [204]. In terms of the pharmacokinetics of SN-
38, this is a major improvement. Its in vivo effectiveness is limited by its short
half-life of approximately 12 hours [204].
In addition to monotherapy, PDCs have been used for combination drug delivery
and have shown promising results in ovarian cancer targeting. Combination
chemotherapy using two drugs with distinct mechanisms of action, serves as a
good strategy for reducing the development of chemoresistance [15, 38, 172,
174, 179, 181]. PDCs that are fabricated as nanoparticles, for instance,
CRLX101, have shown effectiveness in patients with advanced solid tumors,
including ovarian cancer [167, 168]. Also, the use of polymer platforms,
Dolaflexin and Dolasynthen, in the ADCs, XMT-1536 and XMT-1592,
respectively, have enabled the synthesis of novel ADCs with higher drug loading
compared to conventional ADCs [121]. The clinical translation of PDCs is still
very limited as no PDC has been approved for cancer treatment yet [15, 205].
The major limiting factors responsible for this include safety concerns over
cumulative polymer accumulation throughout the body [38], structure complexity,
and lack of batch-to-batch synthetic reproducibility [15, 181]. An ideal PDC for
ovarian cancer treatment should be rationally designed to circulate longer in the
blood without releasing the active drug, sufficiently accumulate in the tumor
microenvironment, be internalized whether by fluid-phase, adsorptive or receptor-
mediated endocytosis, and efficiently release the drug in the cancer cells [15,
111, 205]. It is also important that a higher drug loading and optimal release
characteristics are achieved to minimize the development of chemoresistance. In
addition, the polymer carrier should be completely cleared from the body once
the drug payload is released [205].
9. CONCLUSION
Drug conjugate systems are promising effective treatment options for advanced,
recurrent, or platinum-resistant ovarian cancer. This article is distinct from other
published reviews on drug conjugate systems for the treatment of ovarian cancer
in that it discusses the progress and limitations of targeted drug conjugate
systems, including antibody-drug conjugates, in ovarian cancer treatment [15].
The overexpression of different molecules that can serve as therapeutic targets
in ovarian cancer (Table 1) opens up great opportunities to selectively deliver
highly potent cytotoxic drugs to cancer cells with little or no systemic toxicity.
While a lot of efforts have been made by researchers in the area of targeted drug
conjugate systems, only Mirvetuximab Soravtansine, an antibody-drug conjugate
system carrying DM4 as the cytotoxic payload, has been approved for the
treatment of FR-α-overexpressing ovarian cancer that is resistant to first-line
chemotherapy [15]. Other drug conjugate systems, including polymer-, peptide-,
small molecule-, and nanoparticle-drug conjugates, are not as successful as

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ADCs in terms of clinical development. In addition to the active targeting to
overexpressed target molecules in ovarian cancer, EPR-based passive targeting
is the mechanism of targeted macromolecule drug conjugate systems, especially
polymer- and nanoparticle-drug conjugates, that have been developed for
ovarian cancer treatment [15]. The paucity of patient-based experimental data on
the EPR effect limits the extrapolations from studies in pre-clinical models to
clinical patients. To promote the clinical translation of these drug conjugate
systems, it is important to develop and utilize improved pre-clinical tumor models
that more accurately mimic ovarian tumors in humans during the preclinical
phase of drug development.
COMPETING INTERESTS
Authors have declared that no competing interests exist.
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Biography of author(s)
Omotola D. Ogundipe
Department of Pharmaceutical Sciences, Howard University, Washington, DC, USA.
She obtained her Bachelor of Pharmacy (BPharm) and Master of Science (MSc) in Pharmaceutics from
Obafemi Awolowo University, Nigeria. She graduated with a Ph.D. in Pharmaceutical Sciences from
Howard University, Washington, DC, USA. Her work has focused on nanotechnology applications in
drug delivery. Her research focuses on developing innovative approaches to precision medicine in
cancer treatment. Her doctoral project involved redesigning existing chemotherapeutics as targeted
polymer-drug conjugates to prevent adverse side effects and improve therapeutic outcomes in ovarian
cancer. She is currently a postdoctoral fellow at the National Cancer Institute, National Institutes of
Health, USA, studying the molecular mechanisms of chemoresistance in cancer and how to use
combinatorial and targeted approaches to enhance therapeutic effectiveness and address
chemoresistance issues. She also serves as a member of the American Association of Pharmaceutical
Scientists Newsmagazine editorial content committee and has 7 scholarly publications in peer-reviewed
journals.
Oluwabukunmi Olajubutu
Department of Pharmaceutical Sciences, Howard University, Washington, DC, USA.
She is a Doctoral student in the Department of Pharmaceutical Sciences, Howard University,
Washington, DC, USA, and a recipient of the Edward Alexander Bouchet Doctoral Scholars Fellowship.
Her research involves developing novel targeted drug delivery systems for cancers and she works in the
laboratory of Dr. Simeon K. Adesina. Before joining Howard University, she earned her Master of
Science (MSc) in Pharmaceutics and Bachelor of Pharmacy degree from Obafemi Awolowo University,
Ile-Ife, Nigeria, in 2022 and 2016, respectively. She is currently a visiting graduate research trainee at
the University of Texas MD Anderson Cancer Center, Department of Translational Molecular Pathology
where she focuses on understanding the molecular basis of drug resistance in cancer and exploring
different approaches to overcome cancer treatment resistance.

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Simeon K. Adesina
Department of Pharmaceutical Sciences, Howard University, Washington, DC, USA.
He completed his Ph.D. at the Department of Pharmaceutical Sciences, College of Pharmacy, Howard
University after obtaining the B. Pharm. (Distinction) and M.Sc. (Pharmaceutics) degrees from the
Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife in Nigeria. His research interests include
nanotechnology for drug delivery and theranostic applications (with a bias for cancers and HIV), the
design and development of stimuli-sensitive polymeric drug delivery systems, the design and
development of targeted delivery systems and targeted drug conjugates, such as peptide drug
conjugates, for the treatment of cancers and other disease states. He is also interested in concurrent
and sequential active targeting of tumors to achieve improved therapeutic efficacy and reduction in side
effects. He is a registered pharmacist in the USA.
___________________________________________________________________________________
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DISCLAIMER
This chapter is an extended version of the article published by the same author(s) in the following journal.
Biomedicine & Pharmacotherapy, 165(115151), 2023. DOI: https://doi.org/10.1016/j.biopha.2023.115151
Peer-Review History:
This chapter was reviewed by following the Advanced Open Peer Review policy. This chapter was thoroughly checked to
prevent plagiarism. As per editorial policy, a minimum of two peer-reviewers reviewed the manuscript. After review and
revision of the manuscript, the Book Editor approved the manuscript for final publication. Peer review comments,
comments of the editor(s), etc. are available here: https://peerreviewarchive.com/review-history/8457E