Prostate Cancer Therapy with Annexin II Nanoparticles

描述(申请人提供)：膜联蛋白II的表达在 前列腺癌从前列腺上皮内瘤变(PIN)阶段进展到癌症。Annexin II在细胞表面和细胞核中发挥作用：在细胞表面，Annexin II组织一个蛋白分解中心，旨在调节血管生成、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生和发展的关键分子事件，以便开发改进的检测方法和治疗这种疾病的疗法。本申请概述的研究目的是确定Annexin II基因的替换是否会抑制前列腺癌的生长和血管生成。我们的中心假设是，纳米颗粒介导的Annexin II基因的持续表达会导致Annexin II在细胞核中的长期积聚，从而抑制细胞增殖和持续的细胞表面Annexin II表达，从而抑制血管生成，共同抑制前列腺癌的生长。我们提出了以下具体目标： 目的1：研究纳米颗粒介导的Annexin II载体对前列腺癌生长相关表型的影响。基于初步数据，这一目标的工作假设是，持续的纳米颗粒介导的Annexin II核积聚导致前列腺癌细胞增殖受到抑制。目的：研究纳米颗粒介导的Annexin II载体对小鼠前列腺肿瘤生长和血管生成的影响。这一目标的工作假设是，将抗血管生成的Annexin II持续输送到小鼠前列腺肿瘤中，可以减少肿瘤的数量和体积，并延长动物的生存时间。 这些研究是创新的，因为我们提出了一种基于Annexin 11的前列腺癌治疗的新方法。在这个项目完成时，我们期望我们已经确定纳米颗粒介导的持续Annexin II基因传递将导致前列腺生长迟缓和减轻肿瘤负担。

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.