Peptide-drug conjugates with linker-dependent payload release coordinate dual antitumor efficacy: Intrinsic RGDS-mediated metastasis suppression synergizes with camptothecin cytotoxicity

Camptothecin and its derivatives exhibit broad-spectrum antitumor activity, but their clinical application is hampered by poor water solubility, myelosuppression, and gastrointestinal toxicity. Peptide-drug conjugates (PDCs) represent the next generation of targeted therapeutic agents. In this study, we designed two RGDS-hydroxycamptothecin conjugates, 6-RGDS and 2-RGDS, which were linked via ester and ether bonds, respectively. The antitumor proliferation and anti-metastatic effects of these conjugates were evaluated. 6-RGDS exhibited significant antitumor activity both in vitro and in vivo, whereas the ether-linked 2-RGDS showed relatively lower activity. The RGDS tetrapeptide endowed the compound with favorable anti-tumor metastatic properties and also reduced gastrointestinal toxicity. Our findings suggested that RGDS-modified hydroxycamptothecin conjugates could overcome the limitations associated with camptothecin, offering a promising approach for more effective and safer antitumor therapies. Moreover, the presence of a cleavable ester bond, as seen in 6-RGDS, appears to be essential for the efficient release of active substances, thereby enhancing therapeutic efficacy.