Prostate Cancer Therapy with Annexin II Nanoparticles

描述（由申请人提供）：膜联蛋白II表达在 前列腺癌从前列腺上皮内瘤变（PIN）阶段进展为癌症。膜联蛋白II在细胞表面和细胞核中均起作用：在细胞表面，膜联蛋白II组织蛋白水解中心，被提议调节血管生成、肿瘤侵袭和转移。细胞核中的膜联蛋白II调节细胞增殖和DNA合成。我们研究计划的长期目标是确定导致前列腺癌发展和进展的关键分子事件，以便开发治疗这种疾病的改进检测方法和疗法。本申请中概述的研究的目的是确定膜联蛋白II基因的替换是否导致前列腺癌生长和血管生成的抑制。我们的中心假设是纳米颗粒介导的膜联蛋白II基因的持续表达将导致膜联蛋白II在细胞核中的长期积累，从而抑制细胞增殖和持续的细胞表面膜联蛋白II表达，从而产生抗血管生成，共同抑制前列腺癌生长。我们提出以下具体目标： 目的1：确定纳米颗粒介导的膜联蛋白II递送对与前列腺癌生长相关的表型的体外作用。基于初步数据，该目的的工作假设是持续的纳米颗粒介导的膜联蛋白II的核积累导致前列腺癌细胞增殖的抑制。 目的2：在小鼠模型系统中确定纳米颗粒介导的膜联蛋白II递送对前列腺肿瘤生长和血管生成的影响。该目的的工作假设是，持续递送抗血管生成膜联蛋白II至小鼠中的前列腺肿瘤导致肿瘤数量和体积的减少，以及动物存活率的降低。 这些研究是创新的，因为我们提出了一种基于膜联蛋白II的前列腺癌治疗的新方法。在这个项目完成时，我们期望我们将确定纳米颗粒介导的持续的膜联蛋白II基因递送将导致前列腺生长的阻滞和肿瘤负荷的降低。

DESCRIPTION (provided by applicant): Annexin II expression is lost during progression of prostate cancer from the prostate intraepithelial neoplasia (PIN) stage to cancer. Annexin II functions both at the cell surface and in the nucleus: At the cell surface, Annexin II organizes a proteolytic center proposed to regulate angiogenesis, tumor invasion and metastasis. Annexin II in the cell nucleus regulates cell proliferation and DNA synthesis. The long-term goal of our research program is to identify the key molecular events that lead to development and progression of prostate cancer, in order that improved detection methods and therapies to treat this disease can be developed. The objective of studies outlined in this application is to determine if replacement of the Annexin II gene results in inhibition of prostate cancer growth and angiogenesis. Our central hypothesis is that the nanoparticle-mediated sustained expression of Annexin II gene would lead to prolonged accumulation of Annexin II in the nucleus resulting in inhibition of cell proliferation and sustained cell surface Annexin II expression resulting anti-angiogenesis, collectively inhibiting prostate cancer growth. We propose the following specific aims: Aim 1: To determine the in vitro effect of nanoparticle-mediated Annexin II delivery on phenotypes associated with prostate cancer growth. The working hypothesis for this aim, based upon preliminary data, is that sustained nanoparticle- mediated nuclear accumulation of Annexin II results in inhibition of prostate cancer cell proliferation. Aim 2: To determine the effect of nanoparticle-mediated Annexin II delivery on growth and angiogenesis of prostate tumors in a mouse model system. The working hypothesis for this aim is that sustained delivery of the anti-angiogenic Annexin II to prostate tumors in mice leads to reduction in tumor number and volume, and prolongs animal survival. These studies are innovative in that we are proposing a new approach of Annexin ll-based therapy for prostate cancer. At the completion of this project, it is our expectation that we will have determined that the nanoparticle-mediated sustained Annexin II gene delivery would result in retardation of prostate growth and reduced tumor burden.