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）：此修订的R21探索性研究赠款的申请是对PA-11-149的响应，题为“生物学和医学中的纳米科学和纳米技术”。该项目介绍了国家癌症研究所感兴趣的领域，以寻求评估基于纳米技术的方法，以使人们能够理解，预防，检测和消除转移。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，这些纳米颗粒与IL-8特异性siRNA（BDT IL-8-SIRNA纳米纳经）相吻合，以在死亡导致死亡的CAP细胞中有效且延长的敲低IL-8基因表达，从而有效且延长敲低的IL-8基因表达。该项目的一个组成部分将使我们能够生产出足够数量的治疗性纳米插曲，用于在体内动物CAP模型中使用。 BDT IL-8-SIRNA纳米插曲建立在烯丙基官能化的L-乳肽单体上，得出官能化的聚乳酸（PLA）骨架，并且具有高度生物相容性，使其成为纳米疗法的理想药物。尽管我们先前对PC-3盖细胞系进行了初步研究，但我们将在此提案中使用LNCAP细胞系，因为它表达了前列腺特异性 膜抗原（PSMA）允许其通过定制的纳米插曲进行选择性靶向，这些纳米词富含单克隆抗体（MAB）。最初，我们将进行体外实验，以确定用BDT IL-8-SIRNA纳米插曲处理LNCAP细胞的影响。 Nanoplex控件将掺入炒siRNA。随后的体内实验将使用我们已建立的无胸腺裸鼠模型的人盖模型，该模型使用LNCAP细胞的直接接种到前列腺中，从而形成原发性肿瘤和随后的转移酶。动物将用直接在前列腺中施用的i.V给药的BDT IL-8-SIRNA纳米封纸处理。此外，将对在体内进行全身性靶向递送的BDT IL-8-SIRNA纳米纳宾。前瞻性遵循治疗的动物，我们希望与对照组相比会看到肿瘤和转移的消退。将分析血清和肿瘤组织在治疗动物中敲低IL-8表达以及血管生成和抗凋亡因子的表达。这些探索性研究旨在为CAP患者的BDT IL-8-SIRNA纳米插曲的最终临床试验建立概念证明。