Prostate cancer (CaP) is the most commonly diagnosed non-cutaneous cancer in American males and is the second leading cause of cancer-related deaths of men in North America after lung cancer (1). In 2019, approximately 174,650 men were diagnosed with CaP and nearly 31,620 men will die from the disease. While the overall cancer incidence among men in the U.S. Veterans Affairs Health Care System mirrored the general population, it is important to understand that the U.S has an aging veteran population, and the risk of developing CaP increases with age. Furthermore, veterans who were exposed to herbicides, such as Agent Orange, are at increased risk of CaP. The first line of therapy for CaP is surgery or radiation, and the survival rate for patients diagnosed with early stage CaP is excellent (~95%). However, the prognosis for men diagnosed with advanced CaP is poor' with a five-year survival less than 30%. The major therapy for advanced CaP is androgen deprivation therapy (ADT). When the disease progresses after ADT, a stage referred to as castration resistant prostate cancer (CRPC) ensues. Efforts to develop new drugs for the treatment of CRPC have been hampered either by rapid hepatic metabolism of histone deacetylase inhibitors (HDACi) or dose limiting cytotoxicity (docetaxel and doxorubicin). To overcome this, innovative pharmaceutical solutions are needed to effectively deliver the drugs specifically to the tumor site while minimizing systemic administration of frequent and high doses of toxic chemotherapy. The enhanced, targeted, intracellular co-delivery of drug and gene therapy with novel nanocarriers composed of biocompatible and biodegradable poly(lactic-co-glycolic) acid (PLGA) is a goal of this proposal. PLGA is safe and highly effective in the targeted delivery of hydrophobic drugs such as docetaxel (Doc) to specific tumors, demonstrating enhanced therapeutic activity at lower doses than when administered alone. Active targeting, as opposed to passive targeting adds value to tumor specific-treatment. This targeting strategy is based on the molecular recognition of tumor biomarkers which are over-expressed on cancer cells, via specific vector molecules conjugated to the surface of the drug carrier. These vector molecules dictate the carrier's biodistribution and its affinity for the desired site of action. Our long-term goal is the development of a targeted hierarchical nanoparticle (HNP for the co-delivery of chemo- and gene therapies for CaP, which can overcome the limitation in systemic delivery of currently available drugs. As proof-of-principle, we will use Doc, a promoter and stabilizer of microtubule assembly, that shows excellent efficacy in vitro but which is rapidly metabolized in the liver plus a gene-silencing agent together in our HNP. Our rationale that Doc can be targeted specifically to prostate tumors in pre-clinical animal models will provide the impetus to encapsulate other therapeutics (such as cabazitaxel and paclitaxel) that have dose-limiting toxicities to improve response to drug therapies while reducing toxic side effects. Our specific aims are: Aim 1: To optimize the synthesis of a PSMA- targeted PTCS-HNP for delivery of IL-8 siRNA and Doc to CaP cells and assess the IC50 of different PTCS- HNPs; Aim 2: Determine the pharmacokinetics (PK) and pharmacodynamics (PD) of PTCS-HNP in CaP cell lines; Aim 3: To assess the effects of PTCS-HNPs on primary tumor growth and metastatic dissemination of CaP cells grown as xenografts in an orthotopic, preclinical model of human CaP. Upon conclusion of this project, we will produce a highly effective, targeted drug and gene therapy NP delivery system for the treatment of advanced CaP. The proposed research is innovative because of the exclusive chemical synthesis of our unique, multifunctional HNP, the two-hit nature of the chemo- and gene therapy and its targeted specificity for CaP. The tunable nature of our HNP will allow its application for the delivery of a host of different therapies to a wide range of tumors. Lastly, the incorporation of imaging agents into our HNP will yield a truly theranostic approach for the treatment of different cancers especially advanced CaP.

The proposed research is relevant to the public health because CRPC and advanced CaP, are increasingly becoming refractory and difficult to treat, represents a major national cost measured by both patient suffering and economic burden; and despite significant advances in care, clinical data suggest that refractory rates are at 30%. Upon conclusion, we will understand the role for co-delivery of chemotherapeutic agent and gene silencing agent in treatment outcomes for refractory and advanced CaP, and this discovery will stimulate the opening of a new avenue in nanoparticle based targeted therapeutics for prostate cancer.