Immunoliposome-Mediated Gene Therapy for Prostate Cancer

描述（由申请人提供）：晚期前列腺癌倾向于 对标准化疗剂和放射相对难治 治疗，并且这种抗性与功能性p53的缺乏相关。我们 先前的数据表明癌细胞可以对辐射敏感， 使用肿瘤靶向脂质体递送通过p53替代的化疗 系统在STTR第一阶段的建议中，我们构建了一个重组的复制链， - 来源于针对所述抗体的单克隆抗体的单链抗体片段（scFv）， 转铁蛋白受体，已知在细胞表面升高， 包括前列腺在内的多种肿瘤。表达了单链抗体， 纯化，并在培养物中评估递送和转染效率。 使用裸鼠模型，免疫脂质体靶向原发性肝癌的能力被证实。 并显示转移性肿瘤。在取得了超越 在第一阶段提出，在第二阶段的应用中，我们将测试疗效 的scFv靶向脂质体递送p53以敏化几种前列腺 癌细胞系在体外和体内的放射/化学疗法。我们还将 进行必要的临床前动物研究，以执行 人体临床试验该项目的长期目标是发展和 前列腺癌的一种更有效的治疗方法， 免疫脂质体介导的p53基因治疗加放化疗。

DESCRIPTION (provided by applicant): Advanced prostate cancer tends to be relatively refractory to standard chemotherapeutic agents and radiation treatment, and this resistance correlates with a lack of functional p53. Our previous data indicate that cancer cells can be sensitized to radiation and chemotherapy via p53 replacement using a tumor-targeting liposomal delivery system. In the STTR Phase I proposal, we constructed a recombinant singlechain fragment (scFv) derived from a monoclonal antibody against the transferrin receptor that is known to be elevated on the surface of cells from a variety of tumor types including prostate. The scFv was expressed and purified, and the delivery and transfection efficiency assessed in culture. Using a nude mouse model, the ability of the immunoliposomes to target primary and metastatic tumors was demonstrated. After achieving above and beyond what was proposed in Phase I, in this Phase II application we will test the efficacy of the scFv-targeted liposome delivered p53 to sensitize several prostate cancer cell lines to radio-/chemo-therapy in vitro and in vivo. We will also perform the requisite pre-clinical animal studies leading to performance of human clinical trials. The longer-term aim of this project is development and marketing of a more effective treatment for prostate cancer using immunoliposome-mediated p53 gene therapy plus radiation/chemotherapy.