Imaging radiation-enhanced drug delivery for safer and more effective chemoradiotherapy

Locally advanced head and neck squamous cell carcinoma and anaplastic thyroid cancer remain challenging to treat, with locoregional recurrence occurring in over 40% of patients with the standard of care treatment that includes combinations of radiation therapy, systemic chemotherapy, and surgery. Unfortunately, most systemic therapies used with chemoradiotherapy (CRT) exhibit rapid and non-specific distribution throughout the body and elicit off-target toxicities that limit their use and dosage. Although selective drug delivery to tumor versus off-target tissues plays a major role in defining the balance between effectiveness and toxicity, little data describe how fractionated radiation affects the tumor microenvironment to affect drug delivery. This project will therefore evaluate how fractionated radiation affects the collection of properties that impact the “enhanced permeability and retention” effect within the tumor microenvironment, which defines how macromolecular biologic and therapeutic materials are able to access tumor tissue. Aim 1 will combine in vivo radiologic imaging, highly multiplexed microscopy, and functional perturbations on immune response behaviors to quantify how local radiation reshapes the tumor microenvironment to influence passive drug delivery in mouse and patient-derived models of cancer. Aim 2 will test whether long- circulating chemotherapy can combine with standard CRT to synergistically and safely improve responses. Preliminary studies have shown how new chemical strategies can activate long- circulating drug-conjugates in situ following exposure to radiation, therefore leading to highly selective drug action and synergistic efficacy. We hypothesize i) that long-acting cytotoxic payloads will more selectively accumulate in tumor tissue and exhibit a superior safety and efficacy profile compared to traditional chemotherapy, and ii) that new radiation-activatable drug delivery can dramatically expand the therapeutic window of CRT to improve local disease control. This project will provide a foundation for understanding how cellular and molecular responses to fractionated radiation impact drug delivery in the tumor microenvironment, and will help establish the basis for clinical translation based on radiologic imaging and the next generation of radiation-enhanced therapeutics.