IL-8 targeted Nanotherapy for Prostate Cancer.

描述（由申请人提供）：这份修订后的R21探索性研究资助申请是对题为“生物学和医学中的纳米科学和纳米技术”的PA-11-149的回应。该项目解决了美国国家癌症研究所感兴趣的一个领域，寻求基于纳米技术的方法的评估，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纳米复合物）的复合物，以有效和持久地降低CaP细胞中IL-8基因的表达，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的体内动物模型。BDT IL-8-siRNA纳米复合物建立在烯丙基功能化的l-丙交酯单体上，产生功能化的聚乳酸（PLA）骨架，具有高度的生物相容性，使其成为纳米治疗的理想药物。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

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. PUBLIC HEALTH RELEVANCE: The goal of this project is to develop a unique and safe, biodegradable nanotherapy for local and metastatic prostate cancer by suppressing the gene for interleukin-8 which is required for their growth and metastasis.