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.