PSMA Targeted Docetaxel Loaded Magnetic Nanoparticles for Prostate Cancer Therapy

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DESCRIPTION (provided by applicant): 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 include: 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 involves 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.