PSMA Targeted Docetaxel Loaded Magnetic Nanoparticles for Prostate Cancer Therapy

用于前列腺癌治疗的 PSMA 靶向多西紫杉醇磁性纳米颗粒

• 批准号: 8620842
• 负责人: Murali Mohan Yallapu
• 金额: $ 16.24万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-12 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8620842
• 关键词: Adverse effects; Androgens; Antibodies; Antigen Targeting; Antigens; Applications Grants; Biological Availability; Cancer Etiology; Cancer Patient; Cell Cycle; Cell Line; Cessation of life; Characteristics; Chemicals; Clinical; Clinical effectiveness; Cyclodextrins; Dental crowns; Development; Diagnostic Imaging; Disease; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Effectiveness; Engineering; Exhibits; Generations; Glutamate Carboxypeptidase II; Goals; Growth; Health; Image; Lesion; Magnetic Resonance Imaging; Magnetic nanoparticles; Malignant Neoplasms; Malignant neoplasm of prostate; Marketing; Mediating; Metastatic Prostate Cancer; Microtubule Depolymerization; Modeling; Molecular Analysis; Monoclonal Antibodies; Morbidity - disease rate; Nanotechnology; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Patients; Peptide aptamers; Pharmaceutical Preparations; Pluronics; Polymers; Property; Prostate; Prostate Cancer therapy; Prostatic Neoplasms; Radiation therapy; Resistance; Second Primary Cancers; Solubility; Solutions; Specificity; System; Taxoids; Technology; Therapeutic; Time; Toxic effect; Training; Transition Career Development Award (K22); Treatment Effectiveness; Treatment Efficacy; Treatment outcome; United States; United States Food and Drug Administration; Xenograft procedure; androgen independent prostate cancer; antitumor agent; cancer cell; cancer imaging; cancer therapy; chemotherapeutic agent; chemotherapy; clinical application; clinical efficacy; common treatment; deprivation; docetaxel; empowered; experience; hormone refractory prostate cancer; improved; inhibitor/antagonist; innovation; killings; men; mortality; mouse model; nano; nanoformulation; nanoparticle; nanotherapeutic; novel; prostate cancer cell; prostate cancer cell line; targeted cancer therapy; targeted delivery; targeted treatment; theranostics; tumor; uptake; water solubility

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.

描述（由申请人提供）：拟议的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。Yallapu博士在聚合物、药物输送和纳米技术方面经验丰富，他正在寻求癌症纳米技术方面的进一步培训和专业知识。Yallapu博士的长期目标是开发纳米疗法，以改善靶向癌症治疗并减少副作用。前列腺癌（PrCa）是一种非常普遍的癌症，也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型（AI）或激素难治性前列腺癌（HRPC）并发生转移。多西紫杉醇（Docetaxel, Dtxl）是一种有效的抗肿瘤药物，已广泛应用于雄激素依赖型和雄激素非依赖型前列腺癌的化疗中，但由于缺乏特异性，临床毒性严重。目前迫切需要改进前列腺癌的治疗方案，提高化疗药物的有效性。为了提高多西他赛的治疗效果，我们提出了一种新型的“三冠”磁性纳米颗粒（MNP）给药系统，该系统可以改善Dtxl的递送，同时增强磁共振成像（MRI）性能。治疗性纳米技术的进步导致了这种用于癌症治疗的新型材料的开发，特别是在治疗和诊断/成像方面。该资助提案的中心假设是，癌细胞/肿瘤中负载Dtxl的MNPs的增强摄取将提高治疗PrCa的有效性。此外，肿瘤对前列腺特异性膜抗原（PSMA）靶向Dtxl负载MNPs的优越摄取将对PrCa成像有效。具体目的包括：目的1：研究负载Dtxl的MNPs在前列腺癌（PrCa）中的抗癌作用。目的是确定负载Dtxl的“三冠”多功能MNPs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、内化和抗癌特性；目的2：评估PSMA靶向Dtxl负载MNP制剂在中国的治疗效果。这一目标涉及负载Dtxl的“三冠”多功能MNPs与抗psma抗体（mab）的功能化。本研究的目的是确定前列腺肿瘤中Dtxl的肿瘤摄取、传递以及这种新型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追踪转移性前列腺病变，同时提供改进的晚期前列腺癌治疗。该项目为PSMA靶向技术用于前列腺癌治疗（即观察和治疗）的临床开发提供了概念验证。