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

• 批准号: 6746473
• 负责人: VINOD D LABHASETWAR
• 金额: $ 22.05万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6746473
• 关键词: P glycoprotein; antiAIDS agent; biodegradable product; blood brain barrier; central nervous system; centrally acting drug; chemical conjugate; clinical research; colloids; drug delivery systems; human tissue; laboratory mouse; membrane permeability; nanomedicine; peptides; polymers; slow release drug; terminal nick end labeling; tissue /cell culture

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(申请人提供)：目前使用的抗HIV药物，如蛋白酶抑制剂的主要限制是它们不能通过血脑屏障进入中枢神经系统，而中枢神经系统是HIV-I的隐藏细胞储存库。这些药物的通透性差被认为是由于膜相关的MDR1多药转运体P-糖蛋白(P-gp)的外排作用。此外，蛋白酶抑制剂与药物蛋白的高度结合限制了血清中可供大脑摄取的游离药物。在这项研究中，我们建议研究TAT-多肽偶联纳米粒作为一种递送机制来增强抗HIV药物的中枢神经系统递送。我们研究中的纳米颗粒是极小的可生物降解的胶体颗粒(直径为20到40 nm)，治疗剂被包裹(包裹)在聚合物基质中。这项研究的假设是，与纳米颗粒结合的TAT-肽会增加它们对血脑屏障的通透性，从而将包裹的药物输送到中枢神经系统。纳米粒子一旦定位在中枢神经系统中，由于其生物降解性，将缓慢释放包裹的治疗剂。因此，预计纳米粒介导的药物传递将提高药物的中枢神经系统的生物利用度以及药物的滞留，这将提高药物的治疗效果。具体目的是验证以下假设：1)TAT结合纳米粒绕过了膜结合的P-gp的外排作用；2)TAT结合纳米粒比溶液中的药物具有更好的中枢神经递送和药物滞留。该方法的成功结果可能提供一种新的方式将几类治疗药物包括抗癌药物、蛋白质、多肽和基因输送到中枢神经系统。