The proposed NCI Career Transition Development Award will facilitate Dr. Murali Yallapu's growth as an independent cancer nanotechnologist. Dr. Yallapu is experienced in polymer, drug delivery, and nanotechnology who is seeking further training and expertise in cancer nanotechnology. Dr. Yallapu's long term goal is to develop nanotherapeutics which improve targeted cancer therapy and reduce side effects. Prostate cancer (PrCa) is a highly prevalent cancer and the second leading cause of cancer related deaths in men in the United States. Most common treatment options for PrCa include surgery, chemotherapy, and radiation therapy. While the majority of PrCa patients initially respond to androgen deprivation, most patients develop androgen independent (AI) or hormone refractory prostate cancer (HRPC) and suffer from metastasis. Docetaxel (Dtxl) is a potent antitumor agent and has been widely used in chemotherapy against androgen dependant and androgen independent prostate cancers but it has severe clinical toxicity due to lack of specificity. There s an urgent need for developing improved therapeutic options for the management of prostate cancer and for improving the effectiveness of chemotherapeutic agents. In an effort to improve docetaxel's therapeutic efficacy we propose a novel triple crown magnetic nanoparticle (MNP) drug delivery system which provides improved delivery of Dtxl along with enhancing the magnetic resonance imaging (MRI) properties. Advances in theranostic nanotechnology has led to developing such novel materials for cancer therapeutics with particular emphasis in therapy and diagnostics/imaging. The central hypothesis of this grant proposal is that enhanced uptake of Dtxl loaded MNPs in cancer cells/tumors will improve the effectiveness of treatment for PrCa. Additionally, superior tumor uptake of prostate-specific membrane antigen (PSMA) targeted Dtxl loaded MNPs will be effective for PrCa imaging.
Specific aims i nclude:
AIM 1 : To investigate the anti-cancer efficacy of Dtxl loaded MNPs in prostate cancer (PrCa). The purpose of this aim is to determine the physico-chemical characteristics, internalization, and anti-cancer properties of Dtxl loaded triple crown multi-functional MNPs in androgen dependent (AD), androgen independent (AI) PrCa and non-cancerous cell line models;
AIM 2 : To evaluate the theranostic efficacy of a PSMA targeted Dtxl loaded MNP formulation in PrCa.
This aim i nvolves functionalization of Dtxl loaded triple crown multi- functional MNPs with anti-PSMA antibodies (MAbs). The purpose of this aim is to determine the tumor uptake, delivery of Dtxl in prostate tumors and enhanced therapeutic and magnetic resonance imaging (MRI) contrast features of this novel PSMA targeted formulation in PrCa cell lines and xenograft mouse models. This project aims to empower clinicians to track metastatic prostate lesions while offering improved treatment of advanced PrCa. This project provides a proof-of-concept for clinical development of PSMA targeted technology for use in (i.e., see and treat) prostate cancer treatment.
Nano-theranostics, an elegant approach which combines therapeutic and diagnostic/imaging properties, has tremendous potential to advance therapy and imaging of PrCa. Docetaxel is a potent chemotherapeutic agent for prostate cancer which exhibits severe clinical toxicity. The goal of this project is to increase the efficacy of Docetaxe (Dtxl) therapy through targeted delivery and tumor imaging. We plan to prepare novel ?-cyclodextrin (CD) and Pluronic polymer (F127) coated 'triple crown' magnetic nanoparticles loaded with docetaxel to kill prostate cancer cells. Dtxl will be effectively targeted to PrCa tumors through the conjugation of anti-PSMA MAb to the MNPs. Results of this project will advance imaging and treatment of PrCa to reduce the morbidity and mortality caused by this disease.
| Chowdhury, Pallabita; Nagesh, Prashanth K B; Khan, Sheema et al. (2018) Development of polyvinylpyrrolidone/paclitaxel self-assemblies for breast cancer. Acta Pharm Sin B 8:602-614 |
| Varaprasad, Kokkarachedu; Nunez, Dariela; Yallapu, Murali Mohan et al. (2018) Nano-hydroxyapatite polymeric hydrogels for dye removal. RSC Adv 8:18118-18127 |
| Nagesh, Prashanth K B; Hatami, Elham; Chowdhury, Pallabita et al. (2018) Tannic Acid Induces Endoplasmic Reticulum Stress-Mediated Apoptosis in Prostate Cancer. Cancers (Basel) 10: |
| Khan, Sheema; Zafar, Nadeem; Khan, Shabia S et al. (2018) Clinical significance of MUC13 in pancreatic ductal adenocarcinoma. HPB (Oxford) 20:563-572 |
| Nagesh, Prashanth K B; Chowdhury, Pallabita; Hatami, Elham et al. (2018) miRNA-205 Nanoformulation Sensitizes Prostate Cancer Cells to Chemotherapy. Cancers (Basel) 10: |
| Karuri, Asok Ranjan; Kashyap, Vivek Kumar; Yallapu, Murali Mohan et al. (2017) Disparity in rates of HPV infection and cervical cancer in underserved US populations. Front Biosci (Schol Ed) 9:254-269 |
| Chowdhury, Pallabita; Roberts, Allison M; Khan, Sheema et al. (2017) Magnetic nanoformulations for prostate cancer. Drug Discov Today 22:1233-1241 |
| Gong, Yuqing; Chowdhury, Pallabita; Midde, Narasimha M et al. (2017) Novel elvitegravir nanoformulation approach to suppress the viral load in HIV-infected macrophages. Biochem Biophys Rep 12:214-219 |
| Setua, Saini; Khan, Sheema; Yallapu, Murali M et al. (2017) Restitution of Tumor Suppressor MicroRNA-145 Using Magnetic Nanoformulation for Pancreatic Cancer Therapy. J Gastrointest Surg 21:94-105 |
| Khan, S; Sikander, M; Ebeling, M C et al. (2017) MUC13 interaction with receptor tyrosine kinase HER2 drives pancreatic ductal adenocarcinoma progression. Oncogene 36:491-500 |
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