PSMA Targeted Docetaxel Loaded Magnetic Nanoparticles for Prostate Cancer Therapy

描述（由申请人提供）：拟议的NCI职业过渡发展奖将促进Murali Yallapu博士作为一名独立的癌症纳米技术专家的成长。Yallapu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的进一步培训和专业知识。Yallapu博士的长期目标是开发纳米治疗药物，改善靶向癌症治疗并减少副作用。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最常见的治疗方案包括手术、化疗和放疗。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）并患有转移。多西他赛（Dtxl）是一种有效的抗肿瘤药物，已广泛用于雄激素依赖性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。迫切需要开发用于管理前列腺癌的改进的治疗选择和提高化疗剂的有效性。为了改善多西他赛的治疗效果，我们提出了一种新的“三冠”磁性纳米颗粒（MNP）药物递送系统，其提供了改善的Dtxl递送，沿着增强的磁共振成像（MRI）性质。治疗诊断纳米技术的进步已经导致开发用于癌症治疗的这种新型材料，特别强调治疗和诊断/成像。该资助提案的中心假设是，癌细胞/肿瘤中Dtxl负载的MNP的增强摄取将提高PrCa治疗的有效性。此外，前列腺特异性膜抗原（PSMA）靶向的负载Dtxl的MNP的上级肿瘤摄取对于PrCa成像将是有效的。具体目标包括：目的1：研究负载Dtxl的MNP在前列腺癌（PrCa）中的抗癌功效。该目的的目的是确定负载Dtxl的“三冠”多功能MNP在雄激素依赖性（AD）、雄激素非依赖性（AI）PrCa和非癌细胞系模型中的物理化学特性、内化和抗癌性质;目的2：评估PSMA靶向的负载Dtxl的MNP制剂在PrCa中的治疗诊断功效。该目的涉及用抗PSM抗体（MAb）官能化负载Dtxl的“三冠”多功能MNP。该目的的目的是确定肿瘤摄取、前列腺肿瘤中Dtxl的递送以及这种新型PSMA靶向制剂在PrCa细胞系和异种移植小鼠模型中的增强的治疗和磁共振成像（MRI）对比度特征。该项目旨在使临床医生能够跟踪转移性前列腺病变，同时提供先进的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（即，前列腺癌的治疗方法有哪些

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.