Intratumoral, multiplexed and polymer-assisted dosing of drugs as a new method for assessment of efficacy of new oncology drug candidates or drug combinations.

Abstract

Motivated by the global toll of cancer-related health issues and death, this work identifies some of the key issues facing the pharmaceutical development industry and presents a technological solution to these challenges. This new technology provides the unique capability to interrogate responses to multiple anti-cancer drugs in a fully intact tumor microenvironment without exposing subjects to potential systemic drug toxicities. The experiments presented here describe a novel protocol for formulation of biocompatible polymer micro-implants loaded with drug, and a protocol for successful multiplexed injection of multiple micro-implants inside a living tumor. Standard observational and analytical methods are used to assess key micro-implant performance parameters, within the limits of the time and budget allocated for this work. General method feasibility and procedure tolerability are assessed through a series of mouse experiments. The detection of drug-specific tissue responses to drug delivering micro-implants is validated through in vivo experiment with murine STING ligand DMXAA. The IHC assessment of tissue from in vivo experiment shows generally regionalized distribution of drug around the micro-implants, with sustained drug release for up to 5 days after injection. Consistent with other research, the STING ligand also induces perturbations of the local immune microenvironment following the prolonged intratumoral exposure of DMXAA. The successful experimentation in this thesis provides a solid foundation for future expansion of the platform to enable assessment of dozens anti-cancer drugs and drug combinations within each patient and thus speed up the search for effective therapies.