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pH Responsive Doxorubicin Delivery by Fluorous Polymers for Cancer Treatment.

Polymeric nanoparticles have emerged as valuable drug delivery vehicles as they improve solubility of hydrophobic drugs, enhance circulation lifetime, and can improve the biodistribution profile of small-molecule therapeutics. These nanoparticles can take on a host of polymer architectures including polymersomes, hyperbranched nanoparticles, and dendrimers. We have recently reported that simple low molecular weight fluorous copolymers can self-assemble into nanoparticles and show exceptional passive targeting into multiple tumor models. Given the favorable biodistribution of these particles, we sought to develop systems that enable selective delivery in acidic environments, such as the tumor microenvironment or the lysosomal compartment. In this report, we describe the synthesis and in vitro biological studies of a pH-responsive doxorubicin (DOX) fluorous polymer conjugate. A propargyl DOX hydrazone was synthesized and covalently attached to a water-dispersible fluorous polymer composed of trifluoroethyl methacrylate (TFEMA) and oligo(ethylene glycol) methyl ether methacrylate (OEGMEMA) using the ligand-accelerated copper-catalyzed azide-alkyne cycloaddition. Driven by the high fluorine content of the copolymer carrier, the DOX-copolymer formed stable micelles under aqueous conditions with a hydrodynamic diameter of 250 nm. The DOX-copolymer showed internalization into multiple in vitro models for breast and ovarian cancer. Cytotoxicity assays demonstrated efficacy in both breast and ovarian cancer with overall efficacy being highly dependent on the cell line chosen. Taken together, these results present a platform for the pH-triggered delivery of DOX from a fluorous micelle carrier effective against multiple cancer models in vitro.