Macrophage-Mediated Delivery of Acoustically Propelled Nanoparticles for Sensitizing Immunologically Cold Tumors

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ABSTRACT The overall goal of this project is to simultaneously reprogram immunologically cold tumors and destroy tumor cells through the targeted delivery of cavitation-enhancing nanoparticles by adoptive macrophage transfers. Engineered immune cells have the capacity to treat patients with relapsing or refractory cancers. However, antigen-directed therapies like CAR T-cell therapy have shown limited efficacy in some advanced cancers due to the highly immunosuppressive microenvironment of solid tumors, expression of immune checkpoints, and lack of tumor-associated antigens. Thus, there is a need for therapies that are agnostic to the expression of tumor- associated antigens and that sensitize solid tumors to established antigen-directed therapies. To meet this important need, we will develop an adoptive cellular transfer technology to deliver a class of propulsive nanoparticles to solid tumors. Delivery of nanoparticles inside of macrophages will increase their accumulation within tumors and reduce off-target toxicity. Once localized, the highly porous design of the silica nanoparticles promotes the nucleation and growth of bubbles on their surfaces to guide their rapid and efficient penetration through dense tumorous tissue in response to high-intensity focused ultrasound (HIFU). By loading immunomodulatory drugs that stimulate macrophages into the nanoparticles, we will simultaneously lyse cancer cells and repolarize a large volume of neighboring tumor-associated macrophages (TAMs) toward antitumor phenotypes, providing amplified stimulation of the tumor immune microenvironment. The unique combination of particle propulsion and enhanced transport of drugs will maximize the repolarization of TAMs and eventually other immune cells by the inclusion of different drugs. In this R21 project, our primary goals are to validate the biodistribution, propulsion, and immunomodulatory effects of the nanoparticles in murine 4T1 mammary carcinoma models, which will allow us to later study the capabilities of this technology in other aggressive tumor models. The outcome of this work will be an adoptive cell transfer technology to deliver propulsive nanoparticles for treating solid tumors that are weakly immunogenic in a way that is extendable to a variety of cancers. Feasibility for this work is supported by the expertise of the PIs: nanoscale interfacial engineering (Goodwin) and adoptive macrophage transfers to solid tumors (Shields) for a multipronged approach to stimulate TAMs and eventually other tumor-associated immune cells. We will develop this technology through the following Specific Aims: 1) Design particles for cavitation-based drug release in macrophages. 2) Understand effects of focused ultrasound on acoustically triggered nanoparticles on tumor spheroid models. And 3) Evaluate the therapeutic potential of macrophage-mediated transport of particles to tumors after ultrasound stimulation.