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Principal Investigator: Murali Mohan Yallapu
Organization: UNIVERSITY OF TEXAS RIO GRANDE VALLEY
Fiscal Year: 2024
Award: $363,250
Funding agency: National Institute of General Medical Sciences
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.
Terms: <1-Phosphatidylinositol 3-Kinase><Address><Affect><Antigen Targeting><Apoptotic><Assay><Award><Bioassay><Bioavailability><Biodistribution><Biological><Biological Assay><Biological Availability><Biomedical Research><Blood><Blood Reticuloendothelial System><Body Tissues><Breast Cancer><Cancers><Cell Body><Cell Survival><Cell Viability><Cells><Characteristics><Chemoresistance><Chemosensitization><Chemosensitization/Potentiation><Clinic><Clinical><Clinical Oncology><Complex><Data><Development><Down-Regulation><Drug resistance><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelium><FDA approved><FOLH><FOLH1><FOLH1 gene><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fluorescence><Folate Hydrolase 1><Formulation><GCP2><Gel><Generalized Growth><Genes><Glutamate Carboxypeptidase II><Growth><Heterograft><Heterologous Transplantation><Human><Immunoblotting><Immunology><In Vitro><Investigation><Link><Literature><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Magnetic nanoparticles><Magnetism><Malignant Breast Neoplasm><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methods><Micro RNA><MicroRNAs><Microbiology><Mission><Modern Man><Molecular><N-Acetylated Alpha-Linked Acidic Dipeptidase 1><NAALAD1><NAALADase I><NIH><NMR Imaging><NMR Tomography><Nanoplatform><Nanotechnological platform><National Institutes of Health><Neoplasm Metastasis><Normal Tissue><Normal tissue morphology><Nuclear Magnetic Resonance Imaging><Oncogenesis><Oncogenic><Outcome><PDX model><PI-3 Kinase><PI3-Kinase><PI3CG><PI3KGamma><PI3k><PIK3><PIK3CG><PIK3CG gene><PSM><PSMA><Particle Size><Pathway interactions><Patient derived xenograft><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Physiologic Availability><Potentiation><Productivity><Prostate><Prostate CA><Prostate Cancer><Prostate Gland><Prostate malignancy><Prostate-Specific Membrane Antigen><Prostatic Cancer><Prostatic Gland><PtdIns 3-Kinase><Publications><Recurrence><Recurrent><Regulation><Replacement Therapy><Research><Research Activity><Research Support><Resistance><Risk><Role><Safety><Science><Scientific Publication><Secondary Neoplasm><Secondary Tumor><Shapes><Signal Pathway><Site><Stream><Surface><System><Taxotere><Texas><Therapeutic><Time><Tissue Growth><Tissues><Toxic effect><Toxicities><Training><Treatment Efficacy><Tumor Suppressor Proteins><Tumor Tissue><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><United States National Institutes of Health><Universities><Virus><Western Blotting><Western Immunoblotting><Work><Xenograft><Xenograft procedure><Xenotransplantation><Zeugmatography><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen resistance in prostate cancer><androgen resistant prostate cancer><anti-cancer research><associate faculty><associate professor><beta Tubulin><biocompatibility><biologic><biomaterial compatibility><cancer cell><cancer metastasis><cancer research><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><contrast enhanced><cost effective><cost efficient><determine efficacy><developmental><docetaxel><docetaxol><drug resistant><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><epigenetically><epithelial to mesenchymal transition><evaluate efficacy><examine efficacy><flow cytophotometry><graduate student><hormone refractory prostate cancer><improved><in vivo><intervention efficacy><magnetic><malignancy><malignant breast tumor><medical college><medical schools><men><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA delivery><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA delivery><microRNA therapy><microRNA-based therapeutic><microRNA-based therapy><mid-career faculty><midcareer faculty><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanoparticle therapy><nanosized particle><nanotechnology platform><neoplasm/cancer><neovasculature><novel><ontogeny><particle><pathway><patient derived xenograft model><pre-clinical study><preclinical study><programs><prostate cancer cell><prostate cancer cell line><prostate cancer progression><prostate cancer resistant to androgen><prostate tumor cell><protein blotting><resistance mechanism><resistance to Drug><resistant><resistant mechanism><resistant to Drug><restoration><school of medicine><self assembly><social role><systemic toxicity><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><theranostics><therapeutic efficacy><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><therapeutic nanoparticles><therapeutic outcome><therapy efficacy><therapy outcome><tumor><tumor cell metastasis><tumor suppressor><tumorigenesis><undergrad><undergraduate><undergraduate student><uptake><xeno-transplant><xeno-transplantation><zeta potential><β-Tubulin>