坎普托西林（CPT）是一种源自于幸松-t毛楸的天然植物生物碱，具有强大的抗癌活性。然而，由于其水溶性低和肿瘤选择性有限等缺点，其持续利用受到了阻碍。阳离子型抗癌肽（CAPs）一般在水中溶解性较好，并且对恶性细胞具有良好的选择性。在前期研究中，我们报道了一种名为KM8-Aib的CAP，它显示出明显的选择性抗癌效果。因此，假设将KM8-Aib与CPT结合可能是改善CPT缺陷的一种可行方法。我们合成了一系列肽-CPT结合物，并进行了生物评价。在这些化合物中，Kb-CC07对一组包括耐药细胞在内的癌细胞株表现出最高的选择性活性，其IC50值在0.11-1.01 μM范围内，比CPT好1.9-22.6倍，并且具有宽阔的治疗指数124.5（对比CPT的治疗指数是5.3）。与CPT相比，Kb-CC07的水溶性也提高了约100倍。进一步的研究揭示了Kb-CC07能够有效穿透细胞膜，将更多的CPT分子传递到癌细胞内，克服了由肿瘤表面外流药物转运体引起的耐药性。体内实验证明，与CPT相比，Kb-CC07具有优异的抗肿瘤增殖活性（5 μmol·kg-1时，对应的肿瘤生长抑制率分别为98.2%和37.5%）。此外，Kb-CC07促使CPT在肿瘤组织中的积累，而对正常器官产生有限的毒性。总之，将治疗药物与CAPs结合可能是克服抗癌药物缺陷的一种潜在策略。此外，建议进一步深入研究Kb-CC07，作为一种有前景的抗癌候选药物。© 2023版权归Elsevier B.V.所有。

Camptothecin (CPT) is a natural plant alkaloid from Camptotheca that exhibits a potent anticancer activity. However, its continued utilization is hindered by drawbacks such as low water solubility and restricted tumor selectivity. Cationic anticancer peptides (CAPs) are generally soluble in water, and exhibit favorable selectivity against malignant cells. In previous study, we have reported a CAP termed KM8-Aib present conspicuous selective anticancer effect. Thus, it is postulated conjugating KM8-Aib with CPT might be a plausible approach to improve the defects of CPT. A series of peptide-CPT conjugates were synthesized and subjected to biological evaluation. Among these compounds, Kb-CC07 displayed the highest selective activity against a set of cancer cell lines including drug-resistant cells, showing the IC50 values in the 0.11-1.01 μM range which is 1.9-22.6 times better than that of CPT, and a wide therapeutic index of 124.5 (vs 5.3 for CPT). The water solubility of Kb-CC07 was also improved by ∼100 fold compared with CPT. Further investigation unraveled that Kb-CC07 could effectively penetrate across plasma membranes and delivered more CPT molecules into cancer cells, overcoming the drug-resistance result from efflux drug transporters on tumor surface. In vivo experiments supported that Kb-CC07 has excellent in vivo antiproliferative activity against drug-resistant tumors over CPT (tumor growth inhibition of 98.2% and 37.5% for Kb-CC07 and CPT, respectively, at 5 μmol·kg-1), and prompts CPT accumulation in tumor tissue rather than normal organs, thus producing limited toxicities. To sum up, coupling therapeutic agents to CAPs would be a potential strategy to conquer the shortcomings of anticancer drugs. Additionally, Kb-CC07 is suggested to be a promising anticancer candidate deserving further investigation.Copyright © 2023. Published by Elsevier B.V.