Multifunctional Nanoemulsions for Modulation of BBB Transport

用于调节血脑屏障运输的多功能纳米乳液

基本信息

批准号：
8026013
负责人：
Mansoor M Amiji
金额：
$ 23.4万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-15 至 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8026013
关键词：
AIDS/HIV problem Acids Active Biological Transport Address Adopted Antiviral Agents Area Asians Astrocytes Biological Biological Availability Blood Blood - brain barrier anatomy Brain Brain Diseases Cell Culture Techniques Cells Central Nervous System Diseases Charge Chronic Clinical Coculture Techniques Communicable Diseases Curcumin Development Disease Down-Regulation Drug Delivery Systems Drug Efflux Drug Formulations Drug Kinetics Drug Transport Electrical Resistance Electron Microscopy Encapsulated Endothelial Cells Enhancers Epithelial Evaluation Female Fish Oils Flax Flow Cytometry Gadolinium Gadopentetate Dimeglumine Goals HIV HIV Protease Inhibitors Image In Vitro Infection Ions Linseed Oil Literature Magnetic Resonance Imaging Magnetism Malignant Neoplasms Membrane Modality Modeling Modification Molecular Weight Morphology Mus Neuraxis Neurodegenerative Disorders Nuclear Magnetic Resonance Nucleic Acids Oils Omega-3 Fatty Acids Oral Organ P-Glycoprotein P-Glycoproteins Paclitaxel Penetration Peptides Permeability Pharmaceutical Preparations Phase Phosphatidylethanolamine Preparation Protease Inhibitor Proteins Role Saquinavir Site Spices Surface System Tail Therapeutic Therapeutic Agents Tight Junctions Time Translations Unsaturated Fatty Acids Veins Viral Virus Water absorption base chelation diethylenetriamine gadolinium oxide in vivo in vivo Model monolayer nanoemulsion novel phosphatidylethanolamine public health relevance small molecule

项目摘要

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.

描述（由申请人提供）：血脑屏障（BBB）对用于中枢神经系统（CNS）疾病的治疗剂的全身递送提出了巨大的挑战。此外，艾滋病毒/艾滋病等传染病缺乏有效的治疗方法，导致病毒利用中枢神经系统作为避难所。由于血脑屏障既是药物转运的物理障碍（例如，紧密的细胞连接）又是生物障碍（例如，膜流出转运蛋白），因此解决这两个问题的多模式策略对于有效地全身递送到中枢神经系统是必要的。在该 R21 提案中，主要目标是开发和评估多功能水包油纳米乳液，该乳液专门由富含 omega-3 多不饱和脂肪酸 (PUFA) 的食用油制成，可增强 BBB 渗透性，并掺入姜黄素 (CUR) -膜流出转运蛋白的调节。使用沙奎那韦 (SQV)（一种 HIV 蛋白酶抑制剂模型，也是一种 P-糖蛋白底物），我们将检查大脑中的全身递送效率。我们的初步研究表明，含有SQV的亚麻籽油纳米乳液可以促进口服吸收和血脑屏障渗透性。此外，掺入钆离子 (Gd3+) 的纳米乳剂的磁共振成像 (MRI) 研究也显示出对比度增强。该应用的具体目标是：(1) 制备、表征和优化含有 Gd3+ 离子的 CUR 亚麻籽和鱼油纳米乳剂，用于 MRI 和 SQV，以提高药物输送效率，(2) 外排转运蛋白的体外评估BBB 共培养模型中 CUR、MRI 对比度增强和 SQV 通透性增强的下调，以及 (3) 全身施用 CUR/SQV 后药物递送功效的体内评估Balb/c 小鼠的纳米乳剂配方和 MRI 研究。所提出的多功能纳米乳剂系统，使用富含 omega-3 脂肪酸的油来增强渗透性，并使用 CUR 来下调外排转运蛋白，将为低 CNS 疏水性治疗剂的非侵入性全身给药提供一个新的平台生物利用度。多功能纳米乳剂策略可以扩展到艾滋病毒/艾滋病治疗之外的其他传染病、癌症和神经退行性疾病。公共健康相关性：超过 98% 的用于治疗脑部疾病的小分子疗法在全身给药后无法穿过血脑屏障 (BBB)。此外，在艾滋病毒/艾滋病和其他感染中，尽管接受长期抗病毒治疗，大脑还是病毒存活的有效避难所。由于 BBB 是药物转运的物理和生物障碍，我们的策略是开发一种可以解决这两个问题的递送工具。我们将专门用富含 omega-3 多不饱和脂肪酸的油来配制水包油纳米乳剂，以增加 BBB 渗透，并使用姜黄素来减少药物外流。将以沙奎那韦（一种抗艾滋病毒蛋白酶抑制剂）为模型药物来评估大脑输送效率的改善情况。此外，我们将用钆离子配制纳米乳液，用于磁共振成像研究。