Improving anticancer activity and selectivity of camptothecin through conjugation with releasable substance P

Substance P, an 11-residue neuropeptide, can be rapidly internalized through specific interaction with the neurokinin-1 receptor. Therefore, we designed and synthesized the substance P targeted camptothecin (CPT) conjugates via a releasable disulfide carbonate linker. All the conjugates exhibited comparable or stronger cytotoxicity to cancer cells that highly over-express neurokinin-1 receptor than free CPT. More importantly, the selectivity of conjugates was significantly improved compared with CPT. Our results indicated that these conjugates can be promising candidates for new chemotherapeutic drugs. In addition, increasing CPT loading or attachment of CPT to the C-terminal hexapeptide of substance P are useful strategies to enhance the therapeutic efficacy of substance P targeted conjugates.

Graphical abstractThe substance P targeted CPT conjugates with a disulfide carbonate releasable linker exhibited significant cytotoxicity and selectivity to tumor cells that highly over-express neurokinin-1 receptor (NK1R).Figure optionsDownload full-size imageDownload as PowerPoint slide