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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

基本信息

批准号：
9201317
负责人：
Murali Mohan Yallapu
金额：
$ 16.1万
依托单位：
UNIVERSITY OF TENNESSEE HEALTH SCI CTR
依托单位国家：
美国
项目类别：
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/9201317
关键词：
Adverse effects Androgens Antibodies Antigen Targeting Antigens Applications Grants Biological Availability Cancer Etiology Cancer Patient Cancer cell line Cell Cycle Cell Line Cessation of life Characteristics Clinical Clinical effectiveness Cyclodextrins Dental crowns Diagnostic Imaging Disease Drug Delivery Systems Drug Kinetics Effectiveness Engineering Exhibits FOLH1 gene Formulation Generations Goals Growth Image Lesion Magnetic Resonance Imaging Magnetic nanoparticles Malignant Neoplasms Malignant neoplasm of prostate Mediating Metastatic Prostate Cancer Microtubule Depolymerization Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Nanotechnology Neoplasm Metastasis Operative Surgical Procedures Patient-Focused Outcomes Patients Peptide antibodies Peptide aptamers Pharmaceutical Preparations Pluronics Polymers Property Prostate Prostate Cancer therapy Prostatic Neoplasms Radiation therapy Resistance Solubility 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 androgen sensitive antitumor agent cancer cell cancer imaging cancer therapy chemotherapeutic agent chemotherapy clinical application clinical development clinical efficacy common treatment contrast imaging deprivation docetaxel experience hormone refractory prostate cancer imaging properties improved inhibitor/antagonist innovation killings men mortality mouse model nanoformulation nanoparticle nanotheranostics nanotherapeutic neoplastic cell novel prostate cancer cell prostate cancer cell line public health relevance targeted cancer therapy targeted delivery targeted treatment theranostics therapy outcome tumor uptake water solubility

项目摘要

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 博士成长为一名独立的癌症纳米技术专家。 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，以改善癌症靶向治疗并减少副作用。前列腺癌 (PrCa) 是一种非常流行的癌症，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，但大多数患者会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，已广泛用于治疗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。迫切需要开发改进的治疗方案来管理前列腺癌并提高化疗剂的有效性。为了提高多西紫杉醇的治疗效果，我们提出了一种新型“三冠”磁性纳米颗粒（MNP）药物递送系统，该系统可改善 Dtxl 的递送并增强磁共振成像（MRI）特性。治疗诊断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。该拨款提案的中心假设是，增强癌细胞/肿瘤中加载 Dtxl 的 MNP 的摄取将提高 PrCa 治疗的有效性。此外，肿瘤对前列腺特异性膜抗原 (PSMA) 靶向 Dtxl 负载的 MNP 的良好摄取将有效用于 PrCa 成像。具体目标包括：目标 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 在雄激素依赖型 (AD)、雄激素非依赖型 (AI) PrCa 和非癌细胞系模型中的理化特性、内化和抗癌特性；目标 2：评估 PSMA 靶向 Dtxl 负载 MNP 制剂在 PrCa 中的治疗诊断功效。该目标涉及用抗PSMA抗体(MAb)对负载Dtxl的“三冠”多功能MNP进行功能化。该目的的目的是确定前列腺肿瘤中 Dtxl 的肿瘤摄取和递送，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增强的治疗和磁共振成像 (MRI) 对比特征。该项目旨在帮助临床医生追踪转移性前列腺病变，同时改善晚期 PrCa 的治疗。该项目为用于前列腺癌治疗（即观察和治疗）的 PSMA 靶向技术的临床开发提供了概念验证。