The design and synthesis of dextran-doxorubicin prodrug-based pH-sensitive drug delivery system for improving chemotherapy efficacy

Tumor cells show acidic conditions compared with normal cells, which further inspires scientist to build nanocarrier responsive to tumor microenvironment (TME) for enhancing tumor therapeutic efficacy. Here, we report a pH-sensitive and biocompatible polyprodrug based on dextran-doxorubicin (DOX) prodrug (DOXDT) for enhanced chemotherapy. High-density DOX component was covalently decorated on the nanocarrier and the drug molecules could be effectively released in the acidic tumor tissue/cells, improving chemotherapy efficacy. Specifically, a dextran-based copolymer was preliminarily prepared by one-step atom transfer radical polymerization (ATRP); then DOX was conjugated on the copolymer component via pH-responsive hydrazone bond. The structure of DOXDT can be well-controlled. The resulting DOXDT was able to further self-assemble into nanoscale micelles with a hydration diameter of about 32.4 nm, which presented excellent micellar stability. Compared to lipid-based drug delivery system, the DOXDT prodrug showed higher drug load capacity up to 23.6%. In addition, excellent stability and smaller size of the nanocarrier contributed to better tissue permeability and tumor suppressive effects in vivo. Hence, this amphipathic DOXDT prodrug is promising in the development of translational DOX formulations, which would be widely applied in cancer therapy.