Design, synthesis and bioactivity investigation of peptide-camptothecin conjugates as anticancer agents with a potential to overcome drug resistance.

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.