"Bottom-up" Construction of Multi-Polyprodrug-Arm Hyperbranched Amphiphiles for Cancer Therapy.

Despite the great advantages of polymer-drug conjugates (PDC) in cancer therapy, control of the drug loading site and degree via a facile approach remains a great challenge. Herein, by combining the controllability of the "bottom-up" strategy and the stability of multiarm hyperbranched amphiphiles, we have developed novel multi-polyprodrug-arm hyperbranched amphiphiles (H40-star-(PHCPTMA-b-PMPC), hPCM) via reversible addition-fragmentation chain transfer (RAFT) polymerization for cancer therapy. The hPCM was constructed via two-step polymerization of an acid-labile prodrug monomer and a zwitterionic monomer, respectively. By using an H40 macroRAFT agent, 10-hydroxycamptothecine (HCPT) prodrug monomers were directly polymerized via the "bottom-up" strategy as a polyprodrug-arm inner-shell of hPCM with homogeneous drug distribution. The drug loading content can be facilely tuned through variation of the feed ratio of HCPTMA/H40 macroRAFT agent. Finally, the poly-zwitterionic hydrophilic outer-shell of hPCM was formed by RAFT polymerization of zwitterionic monomer to ensure preferable biocompatibility. By dissolving in dilute solution, unimolecular micelles of hPCM can be obtained, which endow desirable stability for the micelles. The effective cellular internalization, extended blood retention time, considerable accumulation in tumor tissue, and excellent anticancer activity of the hPCM micelles have been evaluated both in vitro and in vivo. This novel multi-polyprodrug-arm hyperbranched amphiphile constructed via the "bottom-up" strategy may open up new horizons for exploring next-generation PDC-based drug delivery systems.