Pharmacology of Targeted Therapy to Brain Tumors

脑肿瘤靶向治疗的药理学

• 批准号: 7016305
• 负责人: FRANCIS C. SZOKA
• 金额: $ 36.58万
• 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/7016305
• 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）：这项研究的目标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中的基因定向酶前药治疗（GDEPT）方案。我们将要解决的问题是：表达酵母胞嘧啶脱氨酶的优化的非病毒GDEPT方案会提供更好的治疗方法，而不是针对脑瘤的靶向脂质体化疗方案？ 指导该计划的假设是，多个靶向的组合将导致稳健的肿瘤特异性胞嘧啶脱氨酶基因表达和改善的肿瘤治疗。这些计划中采用的四个靶向水平是：对流增强的扩散（CED），脑肿瘤，生物辅助脂质体基因制剂，CD44受体靶向以及靶向酶的肿瘤基质靶向酶。然后，肿瘤 - 定位的胞嘧啶脱氨酶将将系统施用的前药氟细胞（FC）转换为活性剂氟尿嘧啶（FU）。这种特殊的方法组合将增强携带者对肿瘤的进入，改善载体通过肿瘤的渗透，增加载体附着在肿瘤细胞上，并改善治疗基因的质粒和旁观者活性的细胞内递送。 该程序中有四个主要活动：（1）新型组件的合成和组件与质粒DNA的合成和组装成较小的直径为小直径，稳定的脂质体指定了纳米脂质粒子（NLP）（2）控制细胞中NLP表现的因素（pH敏感性，pH敏感性，转化性，转化的动物，遗传性，疾病），并表征NLP的性能，并在pH中（ph）（2）表达式）在进入大脑后。 （3）构建细胞外基质靶向胞嘧啶脱氨酶以改善旁观者的作用。 （4）优化GDEPT的治疗效应与在CD44靶向脂质体中递送的氟酸的影响与NLP相似的物理化学特征。荧光细胞胞嘧啶和荧光酸都通过FU发挥其治疗作用。 FU和代谢物的浓度将在肿瘤和血浆中测量。我们将确定哪种方法在肿瘤中提供了更大的药物浓度X时间谱，而不是非靶细胞。 合成化学，分子生物学，药物和药理学的组合将使我们能够确定当两种方案通过CED给出两种方案时，非病毒GDEPT是否优于靶向前药，用于治疗脑肿瘤。这些结果将为人脑肿瘤的靶向疗法提供基本原理。