Immunoliposome-Mediated Gene Therapy for Prostate Cancer

描述(申请人提供)：晚期前列腺癌倾向于 对标准化疗药物和放射治疗相对耐受 治疗，这种耐药性与缺乏功能性的P53有关。我们的 先前的数据表明，癌细胞可以对辐射和 肿瘤靶向脂质体的P53置换化疗 系统。在STTRI期提案中，我们构建了一个重组单链 单链抗体片段(ScFv)，来源于抗 已知的转铁蛋白受体在细胞表面升高，从 包括前列腺癌在内的多种肿瘤类型。表达了单链抗体，并 纯化，并在培养中评估输送和转染率。 利用裸鼠模型，免疫脂质体靶向原代细胞的能力 有转移性肿瘤。在取得超乎寻常的成就之后 是在第一阶段提出的，在第二阶段的应用中，我们将测试疗效 单链抗体靶向脂质体传递P53致敏多个前列腺 体外和体内放化疗对肿瘤细胞株的影响。我们还将 进行必要的临床前动物研究，以实现 人体临床试验。该项目的较长期目标是发展和 营销一种更有效的前列腺癌治疗方法 免疫脂质体介导的P53基因治疗加放疗/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.