(166a) Radiation-Controlled Drug Release Formulation with Improved Therapeutic Index for Treatment of Head and Neck Cancer

Head and neck squamous cell carcinomas (HNSCC) are the 6th most common cancer in the United States predominantly affecting people over 65 years of age. Currently used modalities for treating HNSCCs include surgical resection, chemotherapy (CT) and radiotherapy (RT). Surgery is often not an option for the relatively older patient population due to exclusion criteria and post-operative decrease in the quality of life. For locally advanced HNSCC, combination CT-RT has been proven to be more effective than CT or RT alone and represents the current standard of care, but severe side-effects impacting a patient’s quality of life persist. CT is associated with systemic toxicity causing grade 3 and grade 4 side effects post administration of chemotherapeutic drugs and poor localization causing secondary organ damage. Radiotherapy kills normal cells along with cancer cells along radiation beam tracks used for treatment and potentially lead to secondary cancers years post therapy. Intratumorally delivered chemotherapeutic drugs can potentially overcome some of these challenges by providing localized concomitant CT-RT. A calcium tungstate (CaWO4)-based nanoparticle formulation (NPF) has been developed in our laboratory to facilitate controlled intratumoral CT-RT. Previous work has demonstrated the in vitro and in vivo efficacy of the formulation and demonstrated increased survival in mouse xenograft models as compared to primary radiation.

The formulation consists of a CaWO4 core encapsulated with poly(ethylene glycol-block-lactic acid) co-polymer which is co-loaded with hydrophobic anti-cancer drugs that can be directly injected in solid HNSCC tumors. In the present work, we show that the rate of drug release can be controlled by varying the incident radiation doses which proceeds via a hydrolytic polymer degradation mechanism. The NPF has shown higher therapeutic index than clinically used modalities and is validated by histopathological analysis confirming lesser secondary organ damage. The in vivo efficacy of two different stereoisomers of Paclitaxel, a clinically used anti-cancer drug, vary with our NPF due to the different adsorption and release kinetics which sheds important information on how these interactions could be important towards designing nanomedicine formulations. A multi-compartment model has been developed based on pharmacokinetic release parameters obtained from in vivo experiments which predict the NPF can maintain the intratumoral drug concentration above the therapeutic limit for a significant time post single injection and can help predict clinical performances of the formulation.

These data collected for the NPF used as an alternative to systemic combination CT-RT is promising and can potentially be translated to the oncology clinic to improve treatment efficacy and provide a safer alternative to systemic CT and RT for head and neck cancers.