miR-205 Nanoparticle system circumvents docetaxel resistance in prostate cancer

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The current SC01 application is aimed to develop a program that increase the research competitiveness of Dr. Yallapu at the University of Texas Rio Grande Valley (UTRGV). The UTRGV has historical mission and track record of training and graduating students from backgrounds underrepresented in biomedical research. The UTRGV awards science degrees to undergraduate and/or graduate students and have received less than 6 million dollars per year of NIH R01 support in each of the last 2 fiscal years. Dr. Yallapu proposed to achieve a microRNA Nanoparticle formulation which can circumvent docetaxel resistance in prostate cancer. Loss of tumor suppressor miRNAs in cancer cells promotes cancer tumorigenesis and progression. However, the efficient delivery of miRNAs to target tumor tissues is a major challenge in the transition of miRNA therapy to the clinic. The current approaches to deliver miRNAs not only introduce the risk, associated with virus-based carriers but also systemic toxicity and low therapeutic outcome. To address these challenges and barriers use of nanoparticle mediated delivery is implemented which can offer protection to miRNA in the blood stream and accumulation at the tumor site which can enhance efficiency of therapy. Thus, the objective of this study is to employ dual layer magnetic nanoparticle system that is constructed to release miRNA at tumor site. This nanoparticle formulation can be applied for improved systemic bioavailability, low toxicity, and tumor targeting of therapeutics. The nanoparticle therapies are highly suitable to target and treat resistant tumors (castration resistant prostate cancer, CRPC) that affects thousands of men each year. Recent studies demonstrate miR-205 loss is correlated with prostate cancer (PrCa) progression, metastasis, and drug resistance. Restoration of miR-205 induces pro-apoptotic, anti-proliferative, and epigenetic modulator roles. Literature and our preliminary data suggest re-expression of miR-205 in PrCa cells/tumors result in sensitizing cells to chemotherapy, reverses drug resistance, EMT regulation, and suppression of PrCa growth. Therefore, the central hypothesis of this proposal is that dual layered magnetic nanoparticles can enhance the loading capacity of miRNA per particle and delivery to PrCa cells. This study aims to 1) delineate development of miR-205 nanoparticle formulation, performing its physico-chemical and biological fate, mechanistic investigations of in vitro uptake, intercellular accumulation of the miRNA, and 2) study in vivo tracking and biodistribution miR-205 (MRI) that are in nanoparticles, and 3) examination target gene modulation, and 4) determine improved chemosensitization potential for docetaxel in drug resistant PrCa cells and relevant orthotopic mouse models. The clinical outcome led us to develop a unique microRNA nanoplatform, which can be efficient in inhibiting oncogenic pathways that are linked to drug resistance. Additionally, this award enables Dr. Yallapu to improve and obtain high quality/quantity of preliminary data and publications to be able to succeed in acquiring non-SCORE research support.