Pharmacology of Targeted Therapy to Brain Tumors

脑肿瘤靶向治疗的药理学

• 批准号: 6861041
• 负责人: FRANCIS C. SZOKA
• 金额: $ 36.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6861041
• 关键词: CD44 molecule; aminohydrolases; antineoplastics; biotechnology; brain neoplasms; cell line; chemical synthesis; disease /disorder model; flucytosine; fluorouracil; fungal proteins; gene delivery system; gene expression; gene therapy; human genetic material tag; laboratory rat; liposomes; molecular biology; nanomedicine; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; nonhuman therapy evaluation; particle; pharmacokinetics; prodrugs; technology /technique development; transfection; xenotransplantation

DESCRIPTION (provided by applicant): The objectives of this research are to devise improved non-viral gene carriers and to apply them in a Gene-Directed Enzyme Prodrug Therapy (GDEPT) protocol in a rat brain human tumor model. The question we will address is: will an optimized non-viral GDEPT protocol expressing yeast cytosine deaminase provide better therapy then a targeted liposome chemotherapy protocol in brain tumors? The hypothesis guiding this plan is that a combination of multiple levels of targeting will result in robust tumor-specific cytosine deaminase gene expression and improved tumor therapy. The four levels of targeting employed in these plans are: convective enhanced diffusion (CED) into the brain tumor, bioresponsive liposome gene formulations, CD44 receptor targeting, and a tumor matrix targeted enzyme. Tumor-localized cytosine deaminase will then convert the systemically administered prodrug, fluorocytosine (FC), to fluorouracil (FU), the active agent. This particular combination of approaches will enhance access of the carrier to the tumor, improve percolation of the carrier through the tumor, increase carrier attachment to tumor cells and improve intracellular delivery of the plasmid and bystander activity of the therapeutic gene. There are four major activities in the program: (1) synthesis of novel components and assembly of the components with plasmid DNA into a small diameter, stable liposome designated a nanolipoparticle (NLP)(2) characterization of the factors that control the performance of the NLP in cells (pH sensitivity, cell association, gene transfer activity, toxicity) and in animals (distribution, pharmacokinetics, toxicity and gene expression) after CED into the brain. (3) Construction of an extracellular matrix targeted cytosine deaminase to improve the bystander effect. (4) Comparison of the therapeutic effect of the optimized GDEPT to the effect of fluoroorotic acid delivered in a CD44 targeted liposome of similar physicochemical characteristics as the NLP. Fluorocytosine and fluoroorotic acid both exert their therapeutic effect through FU. The concentration of FU and metabolites will be measured in the tumor and plasma. We will determine which approach provides a greater drug concentration x time profile in the tumor as opposed to non-target cells. The combination of synthetic chemistry, molecular biology, pharmaceutics, and pharmacology will permit us to determine if a non-viral GDEPT is superior to a targeted prodrug for the treatment of brain tumors when both protocols are given by CED. These results will provide a rationale for targeted therapies for human brain tumors.

描述（由申请人提供）：本研究的目的是设计改进的非病毒基因载体，并将其应用于大鼠脑人类肿瘤模型的基因定向酶前药疗法（GDEPT）方案中。我们要解决的问题是：表达酵母胞嘧啶脱氨酶的优化非病毒 GDEPT 方案是否会比靶向脂质体化疗方案在脑肿瘤中提供更好的治疗？ 指导该计划的假设是，多个靶向水平的组合将导致强大的肿瘤特异性胞嘧啶脱氨酶基因表达并改善肿瘤治疗。这些计划中采用的四个靶向水平是：进入脑肿瘤的对流增强扩散（CED）、生物响应性脂质体基因制剂、CD44受体靶向和肿瘤基质靶向酶。然后，肿瘤定位的胞嘧啶脱氨酶会将全身施用的前药氟胞嘧啶（FC）转化为活性剂氟尿嘧啶（FU）。这种特殊的方法组合将增强载体对肿瘤的接近，改善载体通过肿瘤的渗透，增加载体对肿瘤细胞的附着，并改善质粒的细胞内递送和治疗基因的旁观者活性。 该计划有四项主要活动：(1) 合成新成​​分，并将这些成分与质粒 DNA 组装成小直径、稳定的脂质体，称为纳米脂质颗粒 (NLP)(2) 表征控制纳米脂质体性能的因素。 CED 进入大脑后，细胞中的 NLP（pH 敏感性、细胞关联、基因转移活性、毒性）和动物中的 NLP（分布、药代动力学、毒性和基因表达）。 (3)构建细胞外基质靶向胞嘧啶脱氨酶，提高旁观者效应。 (4)优化的GDEPT的治疗效果与在与NLP具有相似理化特性的CD44靶向脂质体中递送的氟乳清酸的效果的比较。氟胞嘧啶和氟乳清酸均通过FU发挥治疗作用。将测量肿瘤和血浆中 FU 和代谢物的浓度。我们将确定哪种方法在肿瘤中提供比非靶细胞更大的药物浓度x时间曲线。 合成化学、分子生物学、药剂学和药理学的结合将使我们能够确定，当 CED 提供两种方案时，非病毒 GDEPT 是否优于靶向前药来治疗脑肿瘤。这些结果将为人类脑肿瘤的靶向治疗提供依据。