Dual controlled delivery of squalenoyl-gemcitabine and paclitaxel using thermo-responsive polymeric micelles for pancreatic cancer

In this study we report the synthesis of a themroresponsive block copolymer by reversible addition fragmentation transfer polymerization comprising poly(2-ethylhexyl methacrylate)- b -poly[di(ethylene glycol)methyl ether methacrylate- co -oligo(ethylene glycol)methyl ether methacrylate] as hydrophobic and thermoresponsive blocks respectively. The polymer self-assembles into sub-50 micelles and can carry simultaneously two drug molecules, namely squalene-gemcitabine and paclitaxel. Both drugs can be released from the micellar compartment in a thermally controlled manner owing to the controllable disruption of the micellar corona above the lower critical solution temperature of the polymer. We demonstrate that the formulation augments synergistically the cytotoxicity of the two drugs in vitro against a model pancreatic cancer cell line. More importantly, it is shown that the polymer exerts a direct interaction with the cell membrane which further augments the cytotoxicity of the drug cargo in a thermally controlled manner. A thermoresponsive block copolymer has been developed with the capability to co-carry two drug molecules and to augment their cytotoxic properties via direct cell membrane interaction with cancer cells.