Drug Conjugates Research Articles

Enhanced efficacy of combined VEGFR peptide–drug conjugate and anti-PD-1 antibody in treating hepatocellular carcinoma

This study aimed to design a VEGFR-targeting peptide–drug conjugate with the ability to decrease tumor burden and suppress tumor angiogenesis, and to further evaluate the therapeutic effect of anti-PD-1 antibody in HCC therapy. A VEGFR-targeting peptide VEGF125 − 136 (QR) was conjugated with a lytic peptide (KLU) to form a peptide–drug conjugate QR-KLU. And the efficacy of QR-KLU in combination with anti-PD-1 antibody for HCC therapy in vivo and in vitro were evaluated. QR-KLU inhibited the proliferation and migration of mouse HCC cell line (Hepa1–6) cells under normoxic and hypoxic conditions in a dose-dependent manner. In the subcutaneous Hepa1–6 tumor model, QR-KLU combined with the anti-PD-1 antibody substantially inhibited tumor growth, promoted tumor necrosis, and prolonged the survival time of tumor-bearing mice. QR-KLU substantially inhibited hypoxia-induced expression of VEGF, promoted tumor vascular normalization, and increased cluster of differentiation 8+ (CD8+) T cell infiltration in the tumor. In addition, QR-KLU and anti-PD-1 antibody demonstrated a strong synergistic effect in promoting the activation of intratumoral CD8+ T cells, reducing the expression of immune-inhibitory factors, and increasing the expression of immune-stimulatory factors. This study proposed a novel approach for enhancing the efficacy of anti-PD-1 antibody using a VEGFR-targeting peptide–drug conjugate in HCC therapy.

Recent Advances in the Linkers of Drug Conjugates.

Drug conjugates have emerged as a pivotal research focus in the field of targeted cancer therapy. They represent a widely explored prodrug strategy that significantly enhances the therapeutic index of drugs while minimizing side effects. The stability and selective cleavage of the linker within drug conjugates are critical for the therapeutic efficacy and targeted treatment achieved by these conjugates. In this review, we have categorized the linkers based on their cleavage mode and summarized the chemical properties, advantages, and limitations of various types of cleavable linkers. Particularly, examples have been provided to illustrate their specific potential for development.

Exploiting the potential of rivastigmine-melatonin derivatives as multitarget metal-modulating drugs for neurodegenerative diseases

The multifaceted nature of the neurodegenerative diseases, as Alzheimer's disease (AD) and Parkinson's disease (PD) with several interconnected etiologies, and the absence of effective drugs, led herein to the development and study of a series of multi-target directed ligands (MTDLs). The developed RIV-IND hybrids, derived from the conjugation of an approved anti-AD drug, rivastigmine (RIV), with melatonin analogues, namely indole (IND) derivatives, revealed multifunctional properties, by associating the cholinesterase inhibition of the RIV drug with antioxidant activity, biometal (Cu(II), Zn(II), Fe(III)) chelation properties, inhibition of amyloid-β (Aβ) aggregation (self- and Cu-induced) and of monoamine oxidases (MAOs), as well as neuroprotection capacity in cell models of AD and PD. In particular, two hybrids with hydroxyl-substituted indoles (5a2 and 5a3) could be promising multifunctional compounds that inspire further development of novel anti-neurodegenerative drugs.

Conjugation of anti-HIV gp41 monoclonal antibody to a drug capable of targeting resting lymphocytes produces an effective cytotoxic anti-HIV immunoconjugate.

HIV-infected cells persisting in the face of suppressive antiretroviral therapy are the barrier to curing infection. Cytotoxic immunoconjugates targeted to HIV antigens on the cell surface may clear these cells. We showed efficacy in mouse and macaque models using immunotoxins, but immunogenicity blunted the effect. As an alternative, we propose antibody drug conjugates (ADCs), as used in cancer immunotherapy. In cancer, the target is a dividing cell, whereas it may not be in HIV. We screened cytotoxic drugs on human primary cells and cell lines. An anthracycline derivative, PNU-159682 (PNU), was highly cytotoxic to both proliferating and resting cells. Human anti-gp41 mAb 7B2 was conjugated to ricin A chain or PNU. The conjugates were tested in vitro for cytotoxic efficacy and anti-viral effect, and in vivo for tolerability. The specificity of killing for both conjugates was demonstrated on Env+ and Env- cells. The toxin conjugate was more potent and killed more rapidly, but 7B2-PNU was effective at levels achievable in patients. The ricin conjugate was well tolerated in mice; 7B2-PNU was toxic when administered intraperitoneally but was tolerated intravenously. We have produced an ADC with potential to target the persistent HIV reservoir in both dividing and non-dividing cells while avoiding immunogenicity. Cytotoxic anti-HIV immunoconjugates may have greatest utility as part of an "activate and purge" regimen, involving viral activation in the reservoir. This is a unique comparison of an immunotoxin and ADC targeted by the same antibody and tested in the same systems.IMPORTANCEHIV infection can be controlled with anti-retroviral therapy, but it cannot be cured. Despite years of therapy that suppresses HIV, patients again become viremic shortly after discontinuing treatment. A long-lived population of memory T cells retain the genes encoding HIV, and these cells secrete infectious HIV when no longer suppressed by therapy. This is the persistent reservoir of HIV infection. The therapies described here use anti-HIV antibodies conjugated to poisons to kill the cells in this reservoir. These poisons may be of several types, including protein toxins (immunotoxins) or anti-cancer drugs (antibody drug conjugates, ADCs). We have previously shown that an anti-HIV immunotoxin had therapeutic effects in animal models, but it elicited an anti-drug immune response. Here, we have prepared an anti-HIV ADC, which would be less likely to provoke an immune response, and show its potential for use in eliminating the persistent reservoir of HIV infection.

Abstract C019: A novel SDC1-targeted therapeutic antibody inhibits macropinocytosis and induces anti-tumor immunity in pancreatic cancer

Abstract Given that the mutated KRAS oncogene (KRAS*) dominates the genetic landscape of pancreatic ductal adenocarcinoma (PDAC), the development of KRAS* inhibitors represents a significant breakthrough in PDAC therapy. However, emerging evidence suggests that PDAC may eventually overcome its dependency on KRAS* and develop resistance to KRAS* inhibitor treatment. Our laboratory is dedicated to uncovering novel, accessible therapeutic targets that govern the mechanisms essential for KRAS*- driven PDAC cell survival. Our recent work has identified Syndecan1 (SDC1), a major heparan sulfate proteoglycan, as a critical mediator of KRAS* activity, promoting nutrient salvaging and fueling cancer cell growth, even in cases where PDAC cells have evaded KRAS* targeted therapy. Our finding positions SDC1 as a promising new therapeutic target for PDAC therapy. In our pursuit of new therapeutic approaches that can directly and specifically target SDC1 activity, we have successfully developed a monoclonal antibody against SDC1 (22B mAb), which exhibits remarkable sensitivity and specificity for human SDC1. Our results indicate that 22B mAb exerts substantial inhibition of PDAC cell growth in vitro and desirable tumor inhibitory effects in vivo in murine PDAC tumors and human PDAC cell-derived xenograft tumors. Interrogation of mechanism of actions further demonstrates that 22B elicits both direct effect in inhibiting macropinocytosis to block nutrient salvage of PDAC cells and indirect effect in inducing antibody-dependent cellular cytotoxicity (ADCC) to eliminate tumor cells. Notably, our 22B mAb synergizes with KRAS* inhibitors, chemotherapy, or immunotherapy, resulting in significantly enhanced therapeutic effects. In summary, our 22B mAb represents the first in class of anti-SDC1 antibody that not only directly targets the PDAC cells but also elicits immune cell-mediated killing. Additionally, our antibody holds the potential for developing new anti-PDAC therapeutic strategies, including antibody drug conjugates with cytotoxic or radionuclides payloads, for SDC1 targeted therapy/theranostics in PDAC. Thus, our newly developed 22B therapeutic antibody provides an alternate strategy for PDAC treatment and opens up new research horizons in therapeutic targeting of SDC1 in other malignancies characterized by aberrant SDC1 expression. Citation Format: Zecheng Yang, Madelaine S Theardy, Shuaitong Chen, Yongkun Wei, Mitsunobu Takeda, Xiaofei Wang, Jun Yao, Jennifer Li, Jangho Park, Yangxi Zheng, Long T Vien, Laura Bover, Haoqiang Ying, Wantong Yao. A novel SDC1-targeted therapeutic antibody inhibits macropinocytosis and induces anti-tumor immunity in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C019.

Use of stable isotope labeled (SIL) antibodies in cassette dosing to improve pharmacokinetics screening efficiency of ADCs with novel cytotoxic payloads

Stable isotope labelling by amino acids in cell culture (SILAC) is an established technique used in quantitative mass spectrometry (MS)-based proteomics. SILAC is also used to generate stable isotope labelled (SIL) antibodies for internal standards (IS) used in LC-MS/MS bioassays to improve quantitative robustness. Total antibody (TAb) is measured to evaluate pharmacokinetics (PK) of antibody drug conjugate (ADC) candidates measured by either ligand binding (LBA) or LC-MS/MS. Herein, we describe an application of SILAC, where multiple SIL combinations of an antibody are used for cassette dosing and PK evaluation. Our preclinical studies demonstrate SILAC-labelled ADC therapeutics did not alter antibody PK. Furthermore, with cassette dosing SIL antibodies exhibited comparable exposure to discretely administered unlabelled test articles in rats. In addition, SIL antibodies were conjugated to cytotoxic payloads to create SIL ADCs and cassette dosed in a cynomolgus monkey PK study and SIL ADCs yielded comparable PK results to discrete dosed unlabelled ADCs. In conclusion, SIL antibodies used with a cassette dosing strategy increases PK screening throughput of ADC candidates in preclinical species. Additionally, cassette dosing strategy further facilitates the responsible use of laboratory animals to achieve the three-Rs (Replacement, Reduction, and Refinement).

Pharmacovigilance study of the association between peripheral neuropathy and antibody–drug conjugates using the FDA adverse event reporting system

Antibody–drug conjugates (ADCs) are among the fastest-growing classes of anticancer drugs, making it crucial to evaluate their potential for causing peripheral neuropathy. We analyzed data from the FAERS database (January 1, 2014, to June 30, 2023) using disproportionality and Bayesian methods. We identified 3076 cases of ADC-associated peripheral neuropathy. Our study revealed significant signals for all ADCs (ROR 1.82, 95% CI 1.76–1.89). ADCs with tubulin-binding payloads showed significant peripheral neuropathy signals (ROR 2.31, 95% CI 2.23–2.40), whereas those with DNA-targeting (ROR 0.48, 95% CI 0.39–0.59) and topoisomerase 1 inhibitor (ROR 0.56, 95% CI 0.48–0.66) payloads exhibited non-significant signals. Signals for peripheral sensory neuropathy were 4.83, 2.44, 2.74, and 2.21 (calculated based on IC025) for brentuximab vedotin, trastuzumab emtansine, enfortumab vedotin, and polatuzumab vedotin, while signals for peripheral motor neuropathy were 5.31, 0.34, 2.27, and 0.03, respectively. The median time to onset for all ADCs was 127 days (interquartile range 40–457). Tisotumab vedotin had the highest hospitalization rate at 26.67%, followed by brentuximab vedotin at 25.5%. Trastuzumab emtansine had the highest mortality rate ,with 80 deaths (11.96%) among 669 cases. Based on FAERS database, only ADCs with tubulin-binding payloads exhibited significant peripheral neuropathy signals. Brentuximab vedotin and enfortumab vedotin showed similar profiles for peripheral sensory neuropathy and motor neuropathy. Given the delayed time to onset and potentially poor outcomes, ADC-related peripheral neuropathy warrants significant attention.

Unveiling the mysteries of HER2-low expression in breast cancer: pathological response, prognosis, and expression level alterations

BackgroundThe novel anti-HER2 antibody drug conjugates (ADCs) can effectively improve the long-term survival of patients with HER2-low expression breast cancer. However, pathological responses to neoadjuvant therapy (NAT) within HER2-low expression breast cancer, the relationship between pathological response and prognosis and the transformation of HER2 status are all now poorly understood.MethodsThe patients with HER2-0 and HER2-low expression breast cancer receiving NAT at Harbin Medical University Cancer Hospital between Jan. 2014 and Nov. 2018 were retrospectively explored. HER2 low expression refers to the IHC 1 + or 2 + and FISH negative. The Kappa test was utilized for analyzing the consistency rate of HER2 expression. To evaluate disease-free survival (DFS) and overall survival (OS), this research employed both the Kaplan-Meier analysis and the Cox regression.ResultsIn this study, 178 patients with HER2-0 and 344 patients with HER2-low expression breast cancer were included. In comparison with the HER2-0 group, it is shown that patients in the HER2-low group have more possibility to be younger compared to those 50 years old (P < 0.014), have more premenopausal patients (P < 0.001), a higher proportion of hormone receptor (HR) positive patients (P < 0.001), and less proportion of stage III V patients (P < 0.034). When NAT was finished, the pCR rate became 23.6% in the HER2-0 group while 22.1% in the HER2-low group, and there was also a higher pCR rate in HR- patients in comparison with that in HR + patients (P < 0.01). Considering HER2 expression inconsistency, the overall HER2 inconsistency rate was 30.4% (Kappa = 0.431, P < 0.01). Among patients initially diagnosed as HER2-0, 34% (N = 61) were re-diagnosed as HER2-low after NAT. After stratification by HR expression status, HR+/HER2-0 patients transformed to HER2-low after NAT in 37%, and 32% of HR- patients changed from HER2-0 to HER2-low. In this survival analysis, there were both better DFS rates (P = 0.009) and OS rates (P = 0.026) in the HR-/HER2-low patients in comparison with the HR-/HER2-0 patients, while the HER2-0 and HER2-low patients in the HR + group had no significant survival difference. Additionally, for non-pCR patients, there was better DFS (P = 0.029) and OS (P = 0.038) in the HER2-low group in comparison with that of the HER2-0 group, while no significant survival difference exists between pCR patients.ConclusionAfter HR stratification, there are unique clinical characteristics and prognostic outcomes in HER2-low expression breast cancer, which indicates the potential to become a specific molecular subtype of breast cancer. The significant instability of HER2-low expression status between primary tumor and residual invasive disease suggests that multiple detections of HER2 status should be emphasized in NAT strategies.

Preclinical Characterization of ARX517, a Site-specific Stable PSMA-Targeted Antibody Drug Conjugate for Treatment of Metastatic Castration-Resistant Prostate Cancer.

Metastatic castration-resistant prostate cancer (mCRPC) is an advanced disease in which patients ultimately fail standard of care androgen-deprivation therapies and exhibit poor survival rates. The prostate-specific membrane antigen (PSMA) has been validated as a mCRPC tumor antigen with over-expression in tumors and low expression in healthy tissues. Using our proprietary technology for incorporating synthetic amino acids (SAAs) into proteins at selected sites, we have developed ARX517, an antibody drug conjugate (ADC) which is composed of a humanized anti-PSMA antibody site-specifically conjugated to a tubulin inhibitor at a drug-to-antibody ratio of 2. After binding PSMA, ARX517 is internalized and catabolized, leading to cytotoxic payload delivery and apoptosis. To minimize premature payload release and maximize delivery to tumor cells, ARX517 employs a non-cleavable PEG linker and stable oxime conjugation enabled via SAA protein incorporation to ensure its overall stability. In vitro studies demonstrate that ARX517 selectively induces cytotoxicity of PSMA-expressing tumor cell lines. ARX517 exhibited a long terminal half-life and high serum exposure in mice, and dose-dependent anti-tumor activity in both enzalutamide-sensitive and -resistant CDX and PDX prostate cancer models. Repeat dose toxicokinetic studies in non-human primates demonstrated ARX517 was tolerated at exposures well above therapeutic exposures in mouse pharmacology studies, indicating a wide therapeutic index. In summary, ARX517 inhibited tumor growth in diverse mCRPC models, demonstrated a tolerable safety profile in monkeys, and had a wide therapeutic index based on preclinical exposure data. Based on the encouraging preclinical data, ARX517 is currently being evaluated in a Phase 1 clinical trial ([NCT04662580]).

Effectiveness of trastuzumab deruxtecan rechallenge in a patient with HER2-positive metastatic breast cancer: a case report.

Trastuzumab deruxtecan (T-DXd), a high-payload antibody drug conjugate, has been reported to exert potent antitumor effects and has recently shown promising efficacy against human epidermal growth factor receptor 2 (HER2)-positive adenocarcinoma. Despite its high efficacy, interstitial lung disease (ILD) is a severe adverse event (AE) associated with T-DXd. This report describes a patient who was successfully treated with a dose-reduced T-DXd challenge after recovery from ILD. Little disease progression was observed during the treatment interruption period; thus, the effect of T-DXd was considered to have been maintained. T-DXd may induce ILD, and re-administration under careful observation is considered an important option for treating patients with HER2-positive breast cancer.

In-depth characterization of a cysteine-linked ADC disitamab vedotin by multiple LC-MS analysis methods and cutting-edge imaged capillary isoelectric focusing coupled with native mass spectrometry

The characterization of cysteine-linked antibody‒drug conjugates (ADCs) can be more challenging than that of monoclonal antibodies (mAbs) and lysine-linked ADCs because the interchain disulfide bonds are reduced for payload conjugation, and the chains are noncovalently bonded to each other. Furthermore, payload conjugation and disulfide bond reduction/scrambling may introduce additional charge heterogeneity to biomolecules. This study illustrates an innovative workflow employing multiple separation techniques and tandem high-resolution mass spectrometry for comprehensive and in-depth characterization of disitamab vedotin, a recent-generation cysteine-linked ADC, including reversed-phase liquid chromatography (RPLC), ion exchange chromatography (IEX) and image capillary isoelectric focusing (icIEF). RPLC was employed for reduced chains analysis, subunit analysis and peptide mapping. IEX and icIEF were used for charge heterogeneity analysis. The innovation of the integrated methodology emphasizes the importance of cutting-edge icIEF-MS online coupling under near-native conditions to reveal the heterogeneity of disitamab vedotin.

Self-Assembly Hypoxic and ROS Dual Response Nano Prodrug as a New Therapeutic Approach for Glaucoma Treatments.

Glaucoma is an irreversible blinding eye disease characterized by retinal ganglion cell (RGC) death.Previous studies have demonstrated that protecting mitochondria and activating the CaMKII/CREB signaling pathway can effectively protect RGC and axon. However, currently treatments are often unsatisfactory, and the pathogenesis of glaucoma requires further elucidation. In this study, a ROS-responsive dual drug conjugate (OLN monomer) is first designed that simultaneously bonds nicotinamide and oleic acid. The conjugate self-assembled into nanoparticles (uhOLN-NPs) through the aggregation of multiple micelles and possesses ROS scavenging capability. Then, a polymer with a hypoxic response function is designed, which encapsulates uhOLN-NPs to form nanoparticles with hypoxic and ROS responses (HOLN-NPs). Under hypoxia in RGCs, the azo bond of HOLN-NPs breaks and releases uhOLN-NPs. Meanwhile, under high ROS conditions, the thioketone bond broke, leading to the dissociation of nano-prodrug. The released nicotinamide and oleic acid co-scavenge ROS and activate the CaMKII/CREB pathway, protecting mitochondria in RGCs. HOLN-NPs exhibit a significantly superior protective effect on R28 cells in glutamate models of glaucoma. The accumulation of HOLN-NPs in retinal RGCs lead to significant inhibition of RGC apoptosis and axonal damage in vivo. Notably, HOLN-NPs provide a new therapeutic approach for patients with neurodegenerative disease.

A novel mertansine conjugate for acid-reversible targeted drug delivery validated through the Avidin-Nucleic-Acid-NanoASsembly platform

In targeted cancer therapy, antibody-drug-conjugates using mertansine (DM1)-based cytotoxic compounds rely on covalent bonds for drug conjugation. Consequently, the cytotoxic DM1 derivative released upon their proteolytic digestion is up to 1000-fold less potent than DM1 and lacks a bystander effect. To overcome these limitations, we developed a DM1 derivative (keto-DM1) suitable for bioconjugation through an acid-reversible hydrazone bond. Its acid-reversible hydrazone conjugate with biotin (B-Hz-DM1) was generated and tested for efficacy using the cetuximab-targeted Avidin-Nucleic-Acid-NanoASsembly (ANANAS) nanoparticle (NP) platform.NP-tethered B-Hz-DM1 is stable at neutral pH and releases its active moiety only in endosome/lysosome mimicking acidic pH. In vitro, the NP/Cetux/B-Hz-DM1 assembly showed high potency on MDA-MB231 breast cancer cells. In vivo both B-Hz-DM1 and NP/Cetux/B-Hz-DM1 reduced tumor growth. A significantly major effect was exerted by the nanoformulation, associated with an increased in situ tumor cell death. Keto-DM1 is a promising acid-reversible mertansine derivative for targeted delivery in cancer therapy.

A single-chain fab derived drug conjugate for HER2 specific delivery

Despite the development of antibody-drug conjugates, the fragment Fab-based drug conjugates offer some unique capabilities in terms of safety, clearance, penetration and others. Current methods for preparing Fab drug conjugates are limited by the availability and stability of Fab proteins, leaving reports on this rare. Here, we found that a single-chain scaffold of Fab enables stabilization of the paired structure and supports high-yield expression in bacteria cytoplasm. Furthermore, we conjugated anti-neoplastic agent SN38 to the C-terminus by sortase A ligation and generated a homogenous Fab conjugate with the drug-to-Fab ratio of 1. The resulting anti-HER2 Fab-SN38 conjugate demonstrated potent and antigen-dependent cell-killing ability with the aid of its special cathepsin-triggered cyclization-promoted release mechanism. In vivo, Fab-SN38 can prevent growths of HER2-positive tumors in athymic mice and be well tolerated to the treatment at 7 mg/kg per dose. Anti-tumor activity, high dose tolerance and penetration advantage observed in this study would merit Fab conjugate investigation in target chemotherapy.

201P Efficacy of antibody drug conjugate (ADC) by mRNA expression of targeted genes in advanced solid tumors: SCRUM-Japan MONSTAR-SCREEN-2

201P Efficacy of antibody drug conjugate (ADC) by mRNA expression of targeted genes in advanced solid tumors: SCRUM-Japan MONSTAR-SCREEN-2

437TiP An open-label, multicenter, phase II study to evaluate the safety and efficacy of BB-1701, a novel antibody drug conjugate (ADC) targeting HER2, in previously treated patients (pts) with HER2+ or HER2-low unresectable or metastatic (M) breast cancer (BC)

437TiP An open-label, multicenter, phase II study to evaluate the safety and efficacy of BB-1701, a novel antibody drug conjugate (ADC) targeting HER2, in previously treated patients (pts) with HER2+ or HER2-low unresectable or metastatic (M) breast cancer (BC)

669P CBX-12-101: Final results of a phase I study of CBX-12, a peptide drug conjugate (PDC) in patients (pts) with metastatic solid tumors

669P CBX-12-101: Final results of a phase I study of CBX-12, a peptide drug conjugate (PDC) in patients (pts) with metastatic solid tumors

1994P Updated efficacy profile of the double antibody drug conjugate (DAD) phase I trial: Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) in ≥ second line in metastatic urothelial carcinoma (mUC)

1994P Updated efficacy profile of the double antibody drug conjugate (DAD) phase I trial: Sacituzumab govitecan (SG) plus enfortumab vedotin (EV) in ≥ second line in metastatic urothelial carcinoma (mUC)

787P First-in-human, phase I study of CBP-1008, a first-in-class bi-specific ligand drug conjugate (Bi-XDC), in patients with advanced solid tumors

787P First-in-human, phase I study of CBP-1008, a first-in-class bi-specific ligand drug conjugate (Bi-XDC), in patients with advanced solid tumors

Advancing Ovarian Cancer Therapeutics: The Role of Targeted Drug Delivery Systems.

Ovarian cancer (OC) is the most lethal reproductive system cancer and a leading cause of cancer-related death. The high mortality rate and poor prognosis of OC are primarily due to its tendency for extensive abdominal metastasis, late diagnosis in advanced stages, an immunosuppressive tumor microenvironment, significant adverse reactions to first-line chemotherapy, and the development of chemoresistance. Current adjuvant chemotherapies face challenges such as poor targeting, low efficacy, and significant side effects. Targeted drug delivery systems (TDDSs) are designed to deliver drugs precisely to the tumor site to enhance efficacy and minimize side effects. This review highlights recent advancements in the use of TDDSs for OC therapies, including drug conjugate delivery systems, nanoparticle drug delivery systems, and hydrogel drug delivery systems. The focus is on employing TDDS to conduct direct, effective, and safer interventions in OC through methods such as targeted tumor recognition and controlled drug release, either independently or in combination. This review also discusses the prospects and challenges for further development of TDDSs. Undoubtedly, the use of TDDSs shows promise in the battle against OCs.