Multifunctional Nanoemulsions for Modulation of BBB Transport

描述(由申请人提供)：血脑屏障(BBB)是系统输送治疗中枢神经系统(CNS)疾病的药物的一个巨大挑战。此外，对艾滋病毒/艾滋病等传染病缺乏有效的治疗，使病毒能够利用中枢神经系统作为避难所。由于血脑屏障是药物转运的物理障碍(例如，紧密的细胞连接)和生物障碍(例如，膜外排转运体)，因此，有效地系统性地将药物输送到中枢神经系统是必要的多模式策略。在这份R21提案中，主要目标是开发和评估多功能水包油纳米乳液，该乳液专门用富含omega-3多不饱和脂肪酸(PUFA)的食用油制成，以增强血脑屏障的通透性，并加入姜黄素(Cur)以下调膜外排出转运体。使用沙奎那韦(SQV)，一种典型的HIV蛋白酶抑制剂，也是一种P-糖蛋白底物，我们将检测系统在大脑中的给药效率。我们的初步研究表明，含有SQV的亚麻籽油纳米乳可以促进口腔吸收和血脑屏障通透性。此外，掺入Gd3+的纳米乳液的磁共振成像(MRI)研究也显示出对比度增强。该应用的具体目的是：(1)制备、表征和优化用于MRI和SQV的含CuR的亚麻籽和鱼油纳米乳液，以提高药物的释药效率；(2)体外评价CUR下调外排转运体的作用，增强磁共振成像(MRI)对比度，以及增强血脑屏障共培养模型的SQV通透性；(3)体内评价Cur/SQV纳米乳液制剂的给药效率，以及对Balb/c小鼠进行MRI研究。所提出的多功能纳米乳液系统，使用富含omega-3脂肪酸的油来增强通透性，使用CUR来下调外排转运体，将为非侵入性全身给药提供一个新的平台，具有较低的CNS生物利用度。多功能纳米乳液策略可以从艾滋病毒/艾滋病治疗扩展到其他传染病、癌症和神经退行性疾病。 公共卫生相关性：超过98%被发现用于治疗脑部疾病的小分子疗法在全身给药时不能越过血脑屏障(BBB)。此外，在艾滋病毒/艾滋病和其他感染中，大脑也是病毒在长期抗病毒治疗的情况下存活的有效避难所。由于血脑屏障是药物运输的物理和生物障碍，我们的战略是开发一种能够同时解决这两个问题的运载工具。我们将专门用富含omega-3多不饱和脂肪酸的油配制水包油纳米乳剂，以增加血脑屏障的渗透率，并使用姜黄素来减少药物外排。将以抗HIV蛋白水解酶抑制剂沙奎那韦为模型药物进行研究，以评估改善大脑中的递送效率。此外，我们还将配制用于磁共振成像研究的含Gd离子的纳米乳剂。

DESCRIPTION (provided by applicant): The blood-brain barrier (BBB) presents a formidable challenge in systemic delivery of therapeutic agents intended for central nervous system (CNS) diseases. In addition, lack of effective therapeutic delivery in infectious diseases, like HIV/AIDS, allows the virus to use the CNS as a sanctuary site. Since the BBB is both a physical (e.g., tight cellular junctions) and biological (e.g., membrane efflux transporters) obstacle to drug transport, a multi-modal strategy that addresses both of these issues is necessary for effective systemic delivery into the CNS. In this R21 proposal, the main objective is to develop and evaluate multifunctional oil-in-water nanoemulsions, made specifically with omega-3 polyunsaturated fatty acids (PUFA)-rich edible oils to enhance BBB permeability, and incorporate curcumin (CUR) for down-regulation of membrane efflux transporters. Using saquinavir (SQV), a model HIV protease inhibitor, which is also a P-glycoprotein substrate, we will examine systemic delivery efficiency in the brain. Our preliminary studies show that SQV- containing flax-seed oil nanoemulsions can promote oral absorption and BBB permeability. In addition, magnetic resonance imaging (MRI) studies with gadolinium ion (Gd3+)-incorporated nanoemulsions also show contrast enhancement. The specific aims of the application are to: (1) prepare, characterize, and optimize CUR-containing flax- seed and fish oil nanoemulsions with Gd3+ ions for MRI and SQV for enhanced drug delivery efficiency, (2) in vitro evaluations of efflux transporter down-regulation with CUR, MRI contrast enhancement, and SQV permeability enhancement in BBB co-culture model, and (3) in vivo evaluations of drug delivery efficacy upon systemic administration of CUR/SQV nanoemulsion formulations and MRI studies in Balb/c mice. The proposed multifunctional nanoemulsion systems, made with the use of omega-3 fatty acids-rich oils for enhancing permeability and CUR for down-regulation of efflux transporters, will provide a novel platform for non-invasive systemic administration of hydrophobic therapeutic agents with low CNS bioavailability. The multifunctional nanoemulsion strategy can be extended beyond HIV/AIDS therapy to other infectious diseases, cancer, and neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: More than 98% of small molecules therapeutics discovered for the treatment of brain diseases cannot cross the blood-brain barrier (BBB) upon systemic administration. Additionally, in HIV/AIDS and other infections, the brain also acts as an effective sanctuary site for the virus to survive despite chronic anti-viral therapy. Since the BBB is both a physical and biological obstacle to drug transport, our strategy is to develop a delivery vehicle that can address both of these issues. We will formulate oil-in-water nanoemulsions specifically with oils rich in omega-3 polyunsaturated fatty acids to increase BBB penetration and use curcumin to reduce drug efflux. Studies to evaluate improvement in delivery efficiency in the brain will be carried out with saquinavir, an anti-HIV protease inhibitor as a model drug. Additionally, we will formulate the nanoemulsion with gadolinium ions for magnetic resonance imaging studies.