Efficient Synthesis of Polymer Prodrug by Thiol-Acrylate Michael Addition Reaction and Fabrication of pH-Responsive Prodrug Nanoparticles

In this study, an efficient method is proposed for the synthesis of polymer prodrug with acid-liable linkage via thiol acrylate Michael addition reaction of the camptothecin with tethering acrylate group and polymer scaffold containing multiple thiol groups. The polymer scaffold P(HEO(2)MA)-b-P(HEMA-DHLA) is prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization of the methacrylate of lipoic acid (HEMA-LA) using poly(2-(2-hydroethoxy) ethyl methacrylate) (PHEO(2)MA) as macro-RAFT agent followed by reduction of the disulfides in lipoic acid (LA) groups to give polymer scaffold with dihydrolipoic acid (DHLA) pendent groups. Acrylate-tethering camptothecin (ACPT) is connected to P(HEO(2)MA)-b-P(HEMA-DHLA) via Michael addition reaction between thiol and acrylate with a high coupling efficiency (95%). Amphiphilic polymer prodrug P(HEO(2)MA)-b-P(HEMA-DHLA-CPT) spontaneously self-assembles into nanoparticles in an aqueous solution and exhibits a CPT loading content as high as 40.1%. The prodrug nanoparticles with the acid-liable beta-thiopropionate linkages can release CPT under acidic conditions, and the prodrug nanoparticles show similar cytotoxicity to HeLa cells as free CPT. Overall, the prodrug nanoparticles with high drug loading contents and acid-liable linkages are promising for pH-responsive anticancer therapy.