CONVECTION ENHANCED DRUG DELIVERY TO BRAIN TUMORS

这个应用程序的长期目标是深入探索 一种新的长期给药和增加给药的方法 到恶性脑瘤。对流强化的间隙输送 (CEID)通过将血脑屏障(BBB)注入 间隙，之后药物分布分两个阶段进行： 对流(压力驱动)相和扩散(浓度)相 驱动)阶段。控制输液速度和/或药物浓度 可控制局部组织浓度。我们首先提议 通过测定6种模型的药代动力学确定CEID的限值 RG-2大鼠体内大小从60到2.8×106道尔顿的化合物 神经胶质瘤。对于每个化合物，我们将确定中场休息的时间 达到平衡的对流和扩散分量和体积 均衡分配的理论。我们将测量药代动力学 对局部药物浓度影响最大的参数，包括 跨毛细血管的外流常数以及内流和外流常数 在正常脑和RG-2神经胶质瘤细胞中。药物分布稳定 CEID后的状态将与静脉分娩进行比较。最后，量化 放射自显影将被用来构建药物的三维地图 在肿瘤及周围脑内的浓度，并构建模型 用于通过CEID预测脑肿瘤的药物传递参数。 第二，我们将提供针对血管内皮生长因子的反义寡核苷酸 并用碱性成纤维细胞生长因子抑制ASV诱导的犬脑胶质瘤血管生成。 与人类胶质瘤一样，ASV诱导的胶质瘤具有不同的组织学和 渗透性。我们将使用CT测量肿瘤的渗透性，并测试 药代动力学模型预测局部组织药物的准确性 浓度。我们将把ODN的浓度个性化为 血管内皮生长因子反义寡核苷酸治疗ASV-胶质瘤 碱性成纤维细胞生长因子结果将通过肿瘤大小和肿瘤大小的系列CT研究来衡量 渗透性，以及对血管内皮生长因子和碱性成纤维细胞生长因子表达的身体研究 第VIII因子染色显示微血管。ODN的神经毒性将是 对正常犬进行CEID注射评估。一旦模型成为 经过验证，证实没有神经毒性，我们确认 慢性注入反义寡核苷酸抑制肿瘤生长， 我们将开始对恶性胶质瘤患者进行I期研究。 受试者将接受个性化剂量的ODN。书房设计将 是基于个性化ODN浓度的剂量递增 关于CT渗透性研究，以及神经毒性和 肿瘤大小。我们希望将CEID发展为一种新的药物输送方式 到恶性胶质瘤，以供将来用于第二阶段试验。

This application's long term objectives are to explore, in depth, a novel method for chronically administering and increasing drug delivery to malignant brain tumors. convection-enhanced interstitial delivery (CEID) bypasses the blood-brain barrier (BBB) by infusion into the interstitial space, after which drug distribution occurs in two phases: a convection (pressure driven) phase and a diffusion (concentration driven) phase. Manipulating the infusion rate and/or drug concentration provides control over local tissue concentration. We first propose to define the limits of CEID by measuring the pharmacokinetics of 6 model compounds varying in size from 60 to 2.8 x 106 Daltons in RG-2 rat gliomas. For each compound, we will determine the halftime for the convection and diffusion components to reach equilibrium and the volume of distribution at equilibrium. We will measure pharmacokinetic parameters that most affect local drug concentration, including the efflux constant across capillaries and the influx and efflux constants across normal brain and RG-2 glioma cells. Drug distribution at steady state after CEID will be compared to IV delivery. Finally, quantitative autoradiography will be used to construct 3 dimensional maps of drug concentration in tumor and surrounding brain and to construct a model for predicting drug delivery parameters to brain tumors by CEID. Second, we will delivery antisense oligonucleotides (ODN) against VEGF and bFGF to ASV-induced gliomas in dogs to suppress tumor angiogenesis. Like human gliomas, ASV-induced gliomas have variable histology and permeability. We will measure tumor permeability using CT and test the accuracy of the pharmacokinetic model to predict local tissue drug concentrations. We will individualize the concentration of ODN to be administered and treat ASV-gliomas with antisense ODN against VEGF and bFGF. Outcome will be measured with serial CT studies of tumor size and permeability, and postmortem studies of VEGF and bFGF expression and microvascularity with Factor VIII staining. ODN Neurotoxicity will be evaluated with CEID infusions into normal dogs. Once the model is validated, the absence of neurotoxicity established, and we confirm suppression of tumor growth by chronic CEID infusion of antisense ODNs, we will begin Phase I studies in patients with malignant gliomas. Subjects will receive individualized doses of ODNs. Study design will be that of dose escalation with individualized ODN concentrations based on CT permeability studies, with outcome measures for neurotoxicity and tumor size. We expect to develop CEID as a new method of drug delivery to malignant gliomas for future use in Phase II trials.