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Open Access Article

International Medical Research Frontier. 2025; 9: (4) ; 15-19 ; DOI: 10.12208/j.imrf.20250039.

Polypeptide-drug conjugates: a new direction in targeted therapy
多肽偶联药物:下一代靶向治疗的方向

作者: 张薛龙, 姚彧远 *, 徐翀 *, 吴君臣 *

中国药科大学 江苏南京

*通讯作者: 姚彧远,单位:中国药科大学 江苏南京;徐翀,单位:中国药科大学 江苏南京;吴君臣,单位:中国药科大学 江苏南京;

发布时间: 2025-12-15 总浏览量: 69

摘要

多肽偶联药物(PDCs)作为新一代靶向治疗平台,通过共价键将具有靶向功能的肽段、细胞毒性载荷和连接子结合,构成了一个精准的药物递送系统。与抗体偶联药物(ADCs)相比,PDCs凭借其更小的分子尺寸、组织穿透性、合成简便性、生产成本及设计灵活性方面展现出显著优势。然而,PDCs的临床转化仍面临诸多挑战,主要包括多肽固有的代谢不稳定性、血液循环半衰期短、口服生物利用度低等问题。文章就PDCs的组成、临床应用进展、提高治疗效果的策略进行了综述,旨在为开发效果更佳的PDCs类抗肿瘤药物提供理论依据和研究思路。

关键词: 多肽偶联药物;靶向治疗;连接子

Abstract

Peptide-drug conjugates (PDCs), as a new generation of targeted therapeutic platforms, form a precise drug delivery system by covalently linking targeting peptides, cytotoxic payloads, and linkers. Compared to antibody-drug conjugates (ADCs), PDCs demonstrate significant advantages in terms of smaller molecular size, tissue penetration, ease of synthesis, production cost, and design flexibility. However, the clinical translation of PDCs still faces several challenges, including inherent metabolic instability of peptides, short half-life in systemic circulation, and low oral bioavailability. This article reviews the composition of PDCs, progress in clinical applications, and strategies to enhance therapeutic efficacy, aiming to provide a theoretical basis and research insights for the development of more effective PDC-based anticancer drugs.

Key words: Peptide-drug conjugates; Targeted therapy; Linkers

参考文献 References

[1] GOTWALS P, CAMERON S, CIPOLLETTA D, et al. Prospects for combining targeted and conventional cancer therapy with immunotherapy[J]. Nature Reviews Cancer, 2017, 17(5): 286-301.

[2] SU Z, XIAO D, XIE F, et al. Antibody–drug conjugates: Recent advances in linker chemistry[J]. Acta Pharmaceutica Sinica B, 2021, 11(12): 3889-3907.

[3] ZIAEI E, PAIVA I M D, YAO S J, et al. Peptide–Drug Conjugate Targeting Keratin 1 Inhibits Triple-Negative Breast Cancer in Mice[J]. Molecular Pharmaceutics, 2023, 20(7): 3570-3577.

[4] WANG Y, CHEETHAM A G, ANGACIAN G, et al. Peptide–drug conjugates as effective prodrug strategies for targeted delivery[J]. Advanced Drug Delivery Reviews, 2017, 110-111: 112-126.

[5] LIN X, TAN S M, LAW S K A, et al. Two types of transmembrane homomeric interactions in the integrin receptor family are evolutionarily conserved[J]. Proteins: Structure, Function, and Bioinformatics, 2006, 63(1): 16-23.

[6] CHATZISIDERI T, LEONIDIS G, KARAMPELAS T, et al. Integrin-Mediated Targeted Cancer Therapy Using c(RGDyK)-Based Conjugates of Gemcitabine[J]. Journal of Medicinal Chemistry, 2022, 65(1): 271-284.

[7] VRETTOS E I, KARAMPELAS T, SAYYAD N, et al. Development of programmable gemcitabine-GnRH pro-drugs bearing linker controllable “click” oxime bond tethers and preclinical evaluation against prostate cancer[J]. European Journal of Medicinal Chemistry, 2021, 211: 113018.

[8] VATS K, SATPATI D, SHARMA R, et al. 99m T c‐labeled NGR ‐chlorambucil conjugate,99m T c‐ HYNIC ‐ CLB ‐c( NGR ) for targeted chemotherapy and molecular imaging[J]. Journal of Labelled Compounds and Radiopharmaceuticals, 2017, 60(9): 431-438.

[9] SHOKRI B, ZARGHI A, SHAHHOSEINI S, et al. Design, synthesis and biological evaluation of peptide‐NSAID conjugates for targeted cancer therapy[J]. Archiv der Pharmazie, 2019, 352(8): 1800379.

[10] AL MUSAIMI O. Peptide Therapeutics: Unveiling the Potential against Cancer—A Journey through 1989[J]. Cancers, 2024, 16(5): 1032.

[11] SALNER A L, BLANKENSHIP B, DUNNACK H, et al. Lutetium Lu-177 Dotatate Flare Reaction[J]. Advances in Radiation Oncology, 2021, 6(1): 100623.

[12] DARWISH S, SADEGHIANI N, FONG S, et al. Synthesis and antiproliferative activities of doxorubicin thiol conjugates and doxorubicin-SS-cyclic peptide[J]. European Journal of Medicinal Chemistry, 2019, 161: 594-606.

[13] ZHAO S, YU N, HAN H, et al. Advances in acid-degradable and enzyme-cleavable linkers for drug delivery[J]. Current Opinion in Chemical Biology, 2025, 84: 102552.

[14] RÉGINA A, DEMEULE M, CHÉ C, et al. Antitumour activity of ANG1005, a conjugate between paclitaxel and the new brain delivery vector Angiopep‐2[J]. British Journal of Pharmacology, 2008, 155(2): 185-197.

[15] BARGH J D, ISIDRO-LLOBET A, PARKER J S, et al. Cleavable linkers in antibody–drug conjugates[J]. Chemical Society Reviews, 2019, 48(16): 4361-4374.

[16] ALAS M, SAGHAEIDEHKORDI A, KAUR K. Peptide–Drug Conjugates with Different Linkers for Cancer Therapy[J]. Journal of Medicinal Chemistry, 2021, 64(1): 216-232.

[17] HAN J, FU J, YANG Q, et al. Rational design and biological evaluation of gemfibrozil modified Xenopus GLP-1 derivatives as long-acting hypoglycemic agents[J]. European Journal of Medicinal Chemistry, 2020, 198: 112389.

[18] LI S, ZHAO H, MAO X, et al. Transferrin Receptor Targeted Cellular Delivery of Doxorubicin Via a Reduction-Responsive Peptide-Drug Conjugate[J]. Pharmaceutical Research, 2019, 36(12): 168.

[19] ZHAO L, WEN X, XU W, et al. Clinical Evaluation of68 Ga-FAPI-RGD for Imaging of Fibroblast Activation Protein and Integrin αv β3 in Various Cancer Types[J]. Journal of Nuclear Medicine, 2023, 64(8): 1210-1217.

[20] HANKE N, TEIFEL M, MOJ D, et al. A physiologically based pharmacokinetic (PBPK) parent-metabolite model of the chemotherapeutic zoptarelin doxorubicin—integration of in vitro results, Phase I and Phase II data and model application for drug–drug interaction potential analysis[J]. Cancer Chemotherapy and Pharmacology, 2018, 81(2): 291-304.

[21] MAHALINGAM D, PEGUERO J, CEN P, et al. A Phase II, Multicenter, Single-Arm Study of Mipsagargin (G-202) as a Second-Line Therapy Following Sorafenib for Adult Patients with Progressive Advanced Hepatocellular Carcinoma[J]. Cancers, 2019, 11(6): 833.

[22] DEMEULE M, CHARFI C, CURRIE J, et al. TH1902, a new docetaxel‐peptide conjugate for the treatment of sortilin‐positive triple‐negative breast cancer[J]. Cancer Science, 2021, 112(10): 4317-4334.

[23] KUMTHEKAR P, TANG S C, BRENNER A J, et al. ANG1005, a Brain-Penetrating Peptide–Drug Conjugate, Shows Activity in Patients with Breast Cancer with Leptomeningeal Carcinomatosis and Recurrent Brain Metastases[J]. Clinical Cancer Research, 2020, 26(12): 2789-2799.

[24] WHALEN K A, WHITE B H, QUINN J M, et al. Targeting the Somatostatin Receptor 2 with the Miniaturized Drug Conjugate, PEN-221: A Potent and Novel Therapeutic for the Treatment of Small Cell Lung Cancer[J]. Molecular Cancer Therapeutics, 2019, 18(11): 1926-1936.

[25] WERLE M, BERNKOP-SCHNÜRCH A. Strategies to improve plasma half life time of peptide and protein drugs[J]. Amino Acids, 2006, 30(4): 351-367.

[26] LAU J, BLOCH P, SCHÄFFER L, et al. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide[J]. Journal of Medicinal Chemistry, 2015, 58(18): 7370-7380.

[27] ZHENG S, CAI Y, HONG Y, et al. Legumain/pH dual-responsive lytic peptide–paclitaxel conjugate for synergistic cancer therapy[J]. Drug Delivery, 2022, 29(1): 1764-1775.

引用本文

张薛龙, 姚彧远, 徐翀, 吴君臣, 多肽偶联药物:下一代靶向治疗的方向[J]. 国际医药研究前沿, 2025; 9: (4) : 15-19.