IL-8 targeted Nanotherapy for Prostate Cancer.

IL-8 靶向纳米疗法治疗前列腺癌。

• 批准号: 8507652
• 负责人: STANLEY A SCHWARTZ
• 金额: $ 16.2万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-09 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8507652
• 关键词: Ablation; Accounting; Address; Adverse effects; Animal Model; Animals; Antineoplastic Agents; Apoptotic; Area; Award; Benign; Biocompatible; Biology; Cancer Diagnostics; Cancer Etiology; Cancer Patient; Cell Line; Cells; Cessation of life; Clinical Trials; Complex; Complication; Coupled; Data; Detection; Development; Disease; Distant; Distant Metastasis; Dose; Drug Formulations; Equilibrium; Evaluation; Gene Expression; Genes; Glutamate Carboxypeptidase II; Goals; Grant; Growth; Hormones; Human; Hypertrophy; IL8 gene; In Situ; In Vitro; Interleukin-8; LNCaP; Local Therapy; Malignant Neoplasms; Malignant neoplasm of prostate; Medicine; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Methods; Modeling; Monoclonal Antibodies; Mus; Nanotechnology; National Cancer Institute; Neoplasm Metastasis; Normal Cell; Organ; Osteoblasts; Osteoclasts; Patients; Pharmaceutical Preparations; Prevention; Primary Neoplasm; Process; Prostate; Prostate Adenocarcinoma; Quality of life; Radiation therapy; Recurrence; Research Design; Research Project Grants; Role; Serum; Small Interfering RNA; Therapeutic; Therapeutic Agents; Therapeutic Effect; Tissues; Toxic effect; Tumor Tissue; Vertebral column; base; bone; cancer cell; cancer therapy; chemotherapy; effective therapy; human glutamate carboxypeptidase II; improved; in vivo; innovation; interest; killings; monomer; mortality; nanoparticle; nanoscience; nanotherapeutic; nanotherapy; outcome forecast; poly(lactic acid); prophylactic; release factor; research study; response; targeted delivery; translational study; tumor

DESCRIPTION (provided by applicant): This revised application for an R21 exploratory research grant is in response to PA-11-149 entitled "Nanoscience and Nanotechnology in Biology and Medicine". This project addresses an area of interest of the National Cancer Institute seeking evaluation of nanotechnology-based methods to enable the understanding, prevention, detection, and elimination of metastases. In this exploratory research project we shall validate our recently developed, unique, biodegradable targeted nanoparticle complexed with IL-8 specific siRNA (BDT IL- 8-siRNA nanoplex) for the efficient and prolonged knockdown IL-8 gene expression in CaP cells resulting in their death. A component of this project will allow us to produce sufficient quantities of therapeutic nanoplexes for use in an in vivo animal model of CaP. BDT IL-8-siRNA nanoplexes are built on allyl-functionalized L-lactide monomers, yielding a functionalized polylactic acid (PLA) backbone and are highly biocompatible, making them ideal agents for nanotherapy. In spite of our prior preliminary studies with the PC-3 CaP cell line, we shall use the LNCaP cell line in this proposal because it expresses prostate specific membrane antigen (PSMA) allowing for its selective targeting by customized nanoplexes incorporating monoclonal antibodies (MAb) to PSMA. Initially we shall perform in vitro experiments to determine the effect of treating LNCaP cells with BDT IL-8-siRNA nanoplexes. Nanoplex controls will incorporate a scrambled siRNA. Subsequent in vivo experiments will use our established athymic, nude murine model of human CaP employing orthopic inoculation of LNCaP cells into the prostate allowing formation of a primary tumor and subsequent metastases. Animals will be treated with BDT IL-8-siRNA nanoplexes administered i.v directly into the prostate. Further, BDT IL-8-siRNA nanoplexes coupled to MAb to PSMA will be administered for systemic targeted delivery in vivo. Treated animals will be followed prospectively and we expect to see regression of tumors and metastases compared to controls. Serum and tumor tissue will be analyzed for knockdown of IL-8 expression in treated animals as well as the expression of angiogenic and anti-apoptotic factors. These exploratory studies are designed to establish proof of concept for eventual clinical trials of BDT IL-8-siRNA nanoplexes in patients with CaP.

描述（由申请人提供）：此修订后的 R21 探索性研究补助金申请是对题为“生物和医学中的纳米科学和纳米技术”的 PA-11-149 的回应。该项目涉及国家癌症研究所感兴趣的一个领域，即寻求对基于纳米技术的方法进行评估，以实现对转移的理解、预防、检测和消除。在这个探索性研究项目中，我们将验证我们最近开发的、独特的、可生物降解的靶向纳米颗粒与 IL-8 特异性 siRNA (BDT IL-8-siRNA nanoplex) 的复合物，以有效且长时间地敲低 CaP 细胞中的 IL-8 基因表达，从而导致其死亡。该项目的一个组成部分将使我们能够生产足够数量的治疗性纳米复合物，用于 CaP 体内动物模型。 BDT IL-8-siRNA 纳米复合物基于烯丙基功能化的 L-丙交酯单体构建，产生功能化的聚乳酸 (PLA) 主链，并且具有高度生物相容性，使其成为纳米疗法的理想药物。尽管我们之前对 PC-3 CaP 细胞系进行了初步研究，但我们将在本提案中使用 LNCaP 细胞系，因为它表达前列腺特异性 膜抗原 (PSMA) 允许通过结合 PSMA 单克隆抗体 (MAb) 的定制纳米复合物选择性靶向。首先，我们将进行体外实验以确定用 BDT IL-8-siRNA 纳米复合物处理 LNCaP 细胞的效果。 Nanoplex 对照将包含扰乱的 siRNA。随后的体内实验将使用我们建立的人 CaP 的无胸腺裸鼠模型，将 LNCaP 细胞原位接种到前列腺中，从而形成原发肿瘤和随后的转移。将用 BDT IL-8-siRNA 纳米复合物直接静脉内施用到前列腺中来治疗动物。此外，与 PSMA 的 MAb 偶联的 BDT IL-8-siRNA 纳米复合物将被施用用于体内全身靶向递送。我们将对接受治疗的动物进行前瞻性随访，与对照组相比，我们预计会看到肿瘤和转移灶的消退。将分析血清和肿瘤组织中治疗动物中 IL-8 表达的敲低以及血管生成因子和抗凋亡因子的表达。这些探索性研究旨在为 BDT IL-8-siRNA 纳米复合物在 CaP 患者中的最终临床试验建立概念验证。