Localized Drug Delivery: A Therapeutic Approach for Retroperitoneal Sarcoma

Abstract

This thesis entitled “Localized Drug Delivery: A Therapeutic Approach for Retroperitoneal Sarcoma” delves into the clinical unmet need of providing therapy for tumors that have high locoregional recurrence yet are difficult to treat with typical therapies in the oncologic armamentarium, such as chemotherapy, radiation therapy, or immunotherapy. Although there are several tumors with this biology, retroperitoneal sarcoma provides a particularly good use case as it is aggressive with high morbidity and mortality without significant advances in treatment modalities for several decades. Local drug delivery is poised to address this clinical problem given several theoretical advantages: local drug may address residual or microscopic tumor burden in areas of high risk without incurring significant systemic toxicity. For example, localized drug delivery may benefit retroperitoneal sarcoma in cases where a large tumor abuts critical structures such as the spine or diaphragm, which are not easily resected. However, although prior work has been done in this field demonstrating feasibility of the fabrication of these localized drug delivery depots and efficacy in small animal models, many questions remain, which this thesis seeks to address. On a mechanistic level, if the drug being delivered systemically has minimal effect, why should this drug be efficacious when delivered locally? If efficacious, by which mechanism is the drug functioning and how is it different from systemic administration? Moreover, is this local drug delivery mechanism feasible and safe to apply in a large animal model, more akin to the clinical realm as compared to a small animal model? These questions were the foundation for the hypotheses posed and experimentation that ensues.