癌症已成为全球人类健康的最大威胁。小分子化疗药临床应用广泛，但由于缺乏肿瘤靶向性，普遍存在全身系统毒性强和耐药频发等问题。因此，如何将足量的化疗药物定向运送至肿瘤部位成为化学治疗的最大挑战。抗体偶联药物(ADC)利用抗体的肿瘤特异性将高毒性小分子靶向递送至肿瘤部位，能克服小分子化疗药物的上述缺陷，是近年来肿瘤药物研发热点。然而抗体的大分子特点使ADC在肿瘤部位的渗透率低，严重限制了ADC的肿瘤治疗效果。近年来，使用具有肿瘤靶向能力的多肽取代抗体发展的多肽偶联药物(PDC)是另一种新型肿瘤药物的靶向递送途径。其中，具有细胞渗透能力的肿瘤靶向肽在癌症治疗中显示出了巨大的潜力。而且多肽结构简单，可以通过化学合成或原核表达手段获得。因此，相对于ADC，PDC具有更高的载量、更强的组织渗透能力、更灵活的多功能化改造以及更低廉的制备成本。随着对胞内转运途径和药物释放机制的深入研究，PDC有望早日投入临床应用。本工作详细介绍了PDC的最新研究进展，重点阐述了不同靶向肽、细胞毒性分子和连接子对PDC抗肿瘤效果的影响，分析了现有研究的优势与不足，总结发展趋势，并为PDC的优化设计提供思路。
Cancer has become the biggest threat to human health in the world. Small-molecule chemotherapeutic drugs are widely used in clinical practice in cancer treatment, but systemic toxicity and drug resistance are common due to the lack of tumor targeting. One of the main challenges for the chemotherapeutic drug is how to directly transport sufficient drugs to tumor but not normal tissues. To solve this problem, antibody-drug conjugate (ADC) was proposed and has been the hot spot in tumor drug research for decades. Guided by the specific monoclonal antibodies, ADC can selectively deliver highly cytotoxic drugs to tumor sites therefore overcome the above shortcomings of small molecules. However, the molecule weight of antibodies is generally large that makes ADC low permeability in the tumor and seriously limits its therapeutic effect. In recent years, peptide-drug conjugate (PDC), using peptides with tumor targeting ability to replace antibodies, is emerging as another novel targeted delivery route of tumor drugs. A great number of tumor targeting penetration peptides have been investigated in PDC design and shown great potential in cancer treatment. Peptides could be easily prepared through chemical synthesis or expressed by prokaryotic systems. Therefore, compared with ADC, PDC has the advantages of higher drug loading, enhanced penetration capacity in solid tumors, easier multifunctional modification through chemical or genetic techniques, and lower production cost. With the deep study of intracellular transport pathway and drug release mechanism, PDC will be expected to be put into clinical application as soon as possible. In this review, the latest advances of PDC are summarized. Types and characteristics of different targeting peptides, cytotoxic molecules and linkers in PDC and their applications in cancer treatment are discussed. The advantages and disadvantages of current researches on PDC are reviewed, and future development prospected.
