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TAT-Peptide conjugated nanoparticles for CNS Delivery

用于中枢神经系统输送的 TAT-肽缀合纳米颗粒

基本信息

批准号：
6828259
负责人：
VINOD D LABHASETWAR
金额：
$ 22.88万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-12-01 至 2006-11-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The major limitation of the currently used anti-HIV drugs such as protease inhibitors is their poor passage through the blood-brain barrier to the center nervous system, which acts as a hidden cellular reservoir for HIV-I. The poor permeability of these agents is considered to be due to the efflux action of the membrane associated MDR1 multidrug transporter, p-glycoprotein (P-gp). Furthermore, the high drug protein binding of protease inhibitors limits the free drug available in the serum for uptake by the brain. In this study, we propose to investigate TAT-peptide conjugated nanoparticles as a delivery mechanism to enhance the CNS delivery of anti-HIV drugs. Nanoparticles in our study are extremely small biodegradable colloidal particles (20 to 40 nm in diameter) with a therapeutic agent encapsulated (entrapped) in the polymer matrix. The hypothesis of the proposed research is that a TAT-peptide conjugated to nanoparticles would increase their permeability across the BBB and hence the transport of the encapsulated drug to the CNS. Nanoparticles once localized in the CNS would release the encapsulated therapeutic agent slowly due to their biodegradation. Thus, it is anticipated that the nanoparticle-mediated drug delivery would enhance the CNS bioavailability of the drug as well as its retention, which would enhance the therapeutic efficacy of the drug. The specific aims are to test the hypotheses that the -i) TATconjugated nanoparticles bypass the efflux action of the membrane bound P-gp and ii) TATconjugated nanoparticles result in greater CNS delivery and sustained drug retention than that with drug in solution. The successful outcome of the proposed approach could provide a novel modality to deliver several classes of therapeutic agents including anticancer agents, proteins, peptides, and genes to the CNS.

描述（由申请人提供）：目前使用的抗HIV药物（如蛋白酶抑制剂）的主要局限性是其通过血脑屏障到达中枢神经系统的能力较差，中枢神经系统是HIV-I的隐藏细胞储存库。认为这些药物的渗透性差是由于膜相关MDR 1多药转运蛋白P-糖蛋白（P-gp）的外排作用。此外，蛋白酶抑制剂的高药物蛋白结合限制了血清中可用于脑摄取的游离药物。在这项研究中，我们建议调查TAT-肽共轭纳米粒子作为一种传递机制，以提高抗艾滋病毒药物的中枢神经系统的交付。我们研究中的纳米颗粒是极小的可生物降解的胶体颗粒（直径20至40 nm），其中治疗剂包封（捕获）在聚合物基质中。所提出的研究的假设是，与纳米颗粒缀合的TAT-肽将增加它们穿过BBB的渗透性，从而增加封装的药物向CNS的转运。纳米颗粒一旦定位在中枢神经系统中，就会由于其生物降解而缓慢释放包裹的治疗剂。因此，预期纳米颗粒介导的药物递送将增强药物的CNS生物利用度以及其保留，这将增强药物的治疗功效。具体目的是检验以下假设：i）TAT缀合的纳米颗粒绕过膜结合的P-gp的外排作用和ii）TAT缀合的纳米颗粒导致比溶液中的药物更大的CNS递送和持续的药物保留。所提出的方法的成功结果可以提供一种新的方式来提供几类治疗剂，包括抗癌剂，蛋白质，肽和基因的中枢神经系统。