“Bottom-up” Construction of Multi-Polyprodrug-Arm Hyperbranched Amphiphiles for Cancer Therapy

Abstract

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.

Hyperbranched Polymers with Controllable Topologies for Drug Delivery

“…Attractively, the hPAs can not only be used for drug delivery but also be applied as MR (magnetic resonance) imaging contrast agents for cancer imaging because of the introduction of the Gd complex. In addition, RAFT polymerization has also been adopted to prepare multi‐polyprodrug‐arm hyperbranched amphiphiles (Figure b) . The drug‐loading content can be conveniently tuned by adjusting the feed ratio of the prodrug to macroRAFT agent.…”

“…In addition, RAFT polymerization has also been adopted to preparem ulti-polyprodrug-arm hyperbranched amphiphiles (Figure 9b). [48] The drug-loading content can be conveniently tuned by adjusting the feed ratio of the prodrug to macroRAFT agent. Duan et al [49] have recently reported the direct preparation of ah yperbranched polyprodrug by using drug molecules as polymericm onomers with drug-loading contentso f2 2a nd 24 %.…”

“…b) Multi-polyprodrug-arm hyperbranched amphiphiles; HCPTMA = acid-labile 10-hydroxycamptothecinprodrugmonomer,MPC = 2methacryloyloxyethyl phosphorylcholine. Reproduced from Ref [48]. with permission from the Wiley.…”

Oncolytic virus delivery: from nano-pharmacodynamics to enhanced oncolytic effect

“…Similarly, optimal water solubility has been achieved by introducing a pH-sensitive cleavable linker and target moiety to a multi-arm copolymer and ultimately complexing it with viral particles. 74 , 75 …”

Self‐Assembled Polyprodrug Amphiphile for Subcutaneous Xenograft Tumor Inhibition with Prolonged Acting Time In Vivo

“…Free drugs are designed to be polymerizable for constructing the polymer skeleton as repeating prodrug units through stimuli‐responsive linkages between drug molecules and polymer backbone, therefore, considerable portion of drugs (even up to >50 wt%) in the whole complex could be feasible. Moreover, the drug loading amount can be facilely modulated by tuning the feed ratio of chain transfer agent/prodrug monomer during polymerization …”