PSMA Targeted Docetaxel Loaded Magnetic Nanoparticles for Prostate Cancer Therapy

描述(由申请人提供)：建议的NCI职业转型发展奖将促进Murali Yallapu博士作为一名独立的癌症纳米技术专家的成长。雅拉普博士在聚合物、药物输送和纳米技术方面经验丰富，正在寻求癌症纳米技术方面的进一步培训和专业知识。雅拉普博士的长期目标是开发纳米疗法，改善癌症的靶向治疗，减少副作用。前列腺癌(PrCa)是一种高度流行的癌症，是美国男性癌症相关死亡的第二大原因。PrCA最常见的治疗选择包括手术、化疗和放射治疗。虽然大多数PrCa患者最初对雄激素剥夺有反应，但大多数患者发展为雄激素非依赖性(AI)或激素难治性前列腺癌(HRPC)，并遭受转移。多西紫杉醇(DtXl)是一种有效的抗肿瘤药物，已广泛用于雄激素依赖和雄激素非依赖性前列腺癌的化疗，但由于缺乏特异性而具有严重的临床毒性。S在会上指出，迫切需要改进前列腺癌的治疗方案，并提高化疗药物的疗效。为了提高多西紫杉醇的疗效，我们提出了一种新型的“三冠状”磁性纳米粒(MNP)给药系统，该系统提供了更好的DtX1给药能力，同时增强了磁共振成像(MRI)性能。医用纳米技术的进步导致了这种癌症治疗的新材料的开发，特别强调治疗和诊断/成像。这项赠款提案的中心假设是，增强DtX1负载MNPs在癌细胞/肿瘤中的摄取将改善PrCa的治疗效果。此外，肿瘤摄取靶向DtX1的前列腺特异性膜抗原(PSMA)的MNPs对于PrCa成像将是有效的。目的1：探讨DtX1-MNPs对前列腺癌(PrCa)的抗癌作用。本研究的目的是在雄激素依赖(AD)、雄激素非依赖性(AI)PrCa和非肿瘤细胞系模型中，确定DtX1负载的三冠状多功能MNP的理化特性、内化和抗癌特性；目的：评价PSMA靶向DtX1的MNP制剂对PrCa的治疗效果。这一目标包括用抗PSMA抗体(MAbs)将DtX1负载的“三冠状”多功能MNPs功能化。其目的是确定DtXl在前列腺癌中的肿瘤摄取和释放，以及这种新型PSMA靶向制剂在PrCa细胞系和异种小鼠模型中的增强治疗和磁共振成像(MRI)对比特征。该项目旨在使临床医生能够跟踪转移性前列腺病变，同时提供改进的晚期PrCA治疗。该项目为PSMA靶向技术的临床开发提供了概念验证，用于前列腺癌的治疗(即，查看和治疗)。

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.