Efficacy of approved small molecule anticancer medicines and immunomodulators, as well as of the drug candidates currently in clinical development is often restricted by several important limitations. Because of their low water solubility and short circulation life-times, many chemotherapeutics are injected intravenously in repeated fashion, often in conjunction with an encapsulating agent to improve their solubility. The systemic administration and importantly narrow therapeutic window, are associated with severe side-effects. An alternative to systemic dosing is the use of drug-loaded delivery vehicles that can be directly injected at the tumor site allowing local drug release. We have developed a thermoresponsive delivery system that enables a single dose administration and maximizes concentration of drug molecules at tumor site for prolonged periods, at the same time minimizing unwanted exposure to healthy tissues, thereby reducing serious side-effects.<br/>We describe a thermorespnosive three block copolymer that can serve as a versatile platform for local delivery of anticancer medicines. The copolymer is an amphiphile that self-assembles into micelles enabling solvation of hydrophobic drugs into water and at room temperature provides straightforward administration using a syringe for direct injection at the tumor site. We achieve efficient loading of three widely used chemotherapeutics: Paclitaxel, Gemcitabine, and SN-38. The drug-loaded micelles demonstrate rapid gelation when heated to 37 °C and in vitro experiments confirmed formation of a local reservoir for sustained release of medicines. We show that upon intratumor injection of combination drug-loaded hydrogel resulted in eradication of A549, human lung cancer cells, in mice. We further used the copolymer for immunochemotherapy, delivering Paclitaxel and Resiquimod, an important immunomodulator, intratumorally achieving significant inhibition in proliferation of aggressive colon cancer cells, CT-26. To best of our knowledge this is the first report of a platform that can be used for delivery of immunomodulator and along with a chemotherapeutic for combination therapy.

Thermoresponsive copolymers for immunotherapy applications

255th National Meeting (2018)

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