TAT-Peptide conjugated nanoparticles for CNS Delivery

描述（由申请人提供）：目前使用的抗hiv药物（如蛋白酶抑制剂）的主要限制是它们难以通过血脑屏障到达中枢神经系统，中枢神经系统是HIV-I的隐藏细胞储存库。这些药物的渗透性差被认为是由于膜相关的MDR1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的游离药物被大脑吸收。在这项研究中，我们建议研究tat肽共轭纳米颗粒作为一种递送机制，以增强抗hiv药物的中枢神经系统递送。在我们的研究中，纳米颗粒是非常小的可生物降解的胶体颗粒（直径20至40纳米），其治疗剂被包裹（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肽会增加其穿过血脑屏障的通透性，从而增加被封装药物到中枢神经系统的运输。纳米粒子一旦定位于中枢神经系统，由于其生物降解，将缓慢释放被封装的治疗剂。因此，预计纳米颗粒介导的药物递送将提高药物在中枢神经系统的生物利用度和保留率，从而提高药物的治疗效果。具体目的是验证以下假设：1)tat缀合纳米颗粒绕过膜结合P-gp的外排作用；2)与溶液中的药物相比，tat缀合纳米颗粒导致更大的中枢神经系统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传递几种治疗药物，包括抗癌药物、蛋白质、肽和基因到中枢神经系统。

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.