Polymer Chemistry

Polymeric prodrugs conjugated with reduction-sensitive dextran-camptothecin and pH-responsive dextran-doxorubicin: An effective combinatorial drug delivery platform for cancer therapy

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Multiple drugs in combinatory therapy can improve the treatment of cancer due to their efficient reduction of multidrug resistance (MDR) of tumor cells. In this paper, we first synthesized a reduction-sensitive dextran-ss-camptothecin (Dex-ss-CPT, or Dex-CPT) prodrug conjugated by a disulfide bond, and a pH-responsive dextran-hyd-doxorubicin (Dex-hyd-DOX, or Dex-DOX) prodrug linked with an acid-cleavable hydrazone group. The chemical structures of the intermediate polymers and polymeric prodrugs have been fully characterized by 1H NMR, FT-IR, UV-Vis and HPLC analyses, respectively. Both prodrugs could self-assemble into uniform particles in aqueous solution. Subsequently, in vitro synergistic drug release of the two prodrugs was studied by methyl thiazolyl tetrazolium (MTT) assay. The reduction of a disulfide linker generates a thiol intermediate that is followed by intramolecular cyclization and the cleavage of the neighboring carbonate bridge, thus releasing native CPT molecules from the Dex-ss-CPT micelles. Similarly, the pH-sensitive hydrazone bond is broken under intracellular acidic conditions and the DOX parent drug is released from the Dex-hyd-DOX micelles. Finally, in vivo pharmacokinetics and biodistribution were investigated via intravenous administration with various formulations to treat 4T1 tumor-bearing mice. Meanwhile, the antitumor activity was also studied. This work demonstrates an effective anti-cancer prodrug design platform, which is expected to be useful for the treatment of various tumors.