Engineering Dual-Targeted Nanoplatforms to Effectively Treat NSCLC.

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ABSTRACT Nanomedicine provides new opportunities to solve medical problems that were previously perceived as unsolvable by clinicians. One such problem is drug resistance in Non-Small Cell Lung Cancer (NSCLC). Attempts to overcome the resistance using small molecule inhibitors have failed to restore the drug sensitivity. Alternative compensation survival pathways emerge to allow the regrowth of the tumor. To abate the tumor growth, we need to suppress more than one survival pathway with minimal or no side effects. Nanoparticles possess the ability to selectively and simultaneously arrest multiple survival pathways to control the growth of the tumor. However, nanoparticles to co-knockdown multiple cross-linked survival pathways have not been explored yet. We recently identified two targets AXL and FN14 and demonstrated that the cross-talk between these markers is responsible for resistance in EGFR mutant NSCLC. Subsequently, we designed nanoparticles to simultaneously co-knockdown both AXL and FN14 in the tumor, disrupted the cross-talk, and successfully overcame drug resistance in murine models. The logical next step is to validate the findings in clinically relevant animal models and patient samples. It is equally important to optimize the size of nanoparticles further to maximize deep tumor delivery with favorable in vivo characteristics. Therefore, in this proposal, we will synthesize different sizes of NP, understand their ability to penetrate deep inside the tumor to fully restore drug sensitivity for a long-lasting therapeutic response. We will use patient tissues, patient-derived organoids, drug- resistant cell lines, orthotopic animal models, and patient-derived xenografts to establish the efficacy of the nanoplatform. The data will validate our new nanoparticle platform, as a promising strategy to combat drug resistance in NSCLC and catalyze clinical trials in the future.