Enhancement of tumor radiation response by ultrasound-driven nanobubble stimulation

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Project Summary Radiation is a mainstay of cancer treatment, yet challenges remain. The long term goal of the proposed research is to transform traditional cancer radiation therapy protocols by including a pre-treatment step involving perturbing the vascular and cellular function of tumors with ultrasound-activated radiosensitizing nanobubbles (NBs). The new paradigm in cancer treatment protocol builds upon a decade of prior work that used commercial microbubbles (MBs) to elicit a radiosensitizing effect. The MB radiosensitization effects are primarily intravascular, with significant endothelial damage incurred. In contrast, in the strategy proposed here, we hypothesize that the NBs will also extravasate into the tumor parenchyma, which will result in significant increases in direct damage to the cancer cells, in addition to the vascular damage. Thus the effect will be both intra- and extra-vascular. The tumors treated in this way will respond better to radiation, lowering the effective radiation dose and decreasing residual surviving tumor. The technique further allows targeting of tumor specific volumes allowing healthy tissues to be spared. We have demonstrated in preliminary studies in vivo that ultrasound-activated NB perturbation of tumors results in a significantly greater enhancement in tumor kill compared to MBs when followed by traditional radiation therapy. This approach could markedly improve existing therapies and reduce the associated side-effects. This is clinically important for prostate cancer treatment where collateral damage and off-target effects are common and lead to years of complications in many patients. Therefore, we propose a set of four specific aims to test, develop, optimize, demonstrate and quantify the efficacy of this novel technique in prostate cancer. Aim 1 will focus on the development of stable, uniformly-sized radiosensitizing NBs. The acoustic and bio-activity of the bubbles will be measured, and baseline biodistribution in tumor bearing mice will be carried out. In Aim 2, the NBs will be tested in combination with radiation in a mouse model of prostate cancer so that treatment parameters can be optimized. In Aim 3, carried out concurrently with Aim 2, we will develop a photoacoustic imaging approach for monitoring early treatment response. This tool will be used to predict therapeutic efficacy and completeness of tumor treatment as soon as 2 hours after the therapy. Finally, in Aim 4, we will test the combination approach in a large (rabbit) orthotopic model of human prostate cancer. We have assembled a multidisciplinary MPI team of investigators with a demonstrated track record of collaborative work in this field. The team includes Dr. Czarnota MD/Ph.D., a physician-scientist and discoverer of the original MB sensitizing approach now in clinical trials, Dr. Michael Kolios Ph.D. is a medical physicist with broad experience in photoacoustic imaging for therapy response and ultrasound physics and Dr. Agata Exner, Ph.D., a biomedical engineer with extensive expertise in formulation and implementation of nanobubbles for imaging and therapy. Members of the team are actively collaborating, have shared publications, grants and projects, and record of technology translation to the clinic. The team will ensure timely completion of the proposed research and rapid translation of the approach to clinical use.