Polymer nanoparticle delivery of dichloroacetate and DACH-Pt to enhance antitumor efficacy and lower systemic toxicity

Biomaterials Science
Qiang YangZehua Wang

Abstract

Platinum agents can cause DNA damage and thus induce apoptosis of cancer cells, which has made them the backbone of cancer chemotherapy regimens. However, most cancers will develop drug resistance over the course of treatment. Meanwhile, most tumors meet energy needs largely by aerobic glycolysis (glycolysis in the presence of oxygen, called the Warburg effect), which is related to their resistance to apoptosis. Therefore, we have used a biodegradable polymer carrier to conjugate with DACH-Pt and dichloroacetate, a PDK inhibitor that can reverse the Warburg effect and derepress the resistance to apoptosis, thus sensitizing cancer cells to platinum. The as-prepared polymer-drug conjugates can be assembled into nanoparticles for effective delivery and better synergism. In vitro and in vivo studies revealed that the combination of polymer-DCA and polymer-DACH-Pt are much better than the free drugs administered simultaneously, in terms of both safety and antitumor efficacy.

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