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）在全身递送用于中枢神经系统（CNS）疾病的治疗剂中提出了巨大挑战。此外，在传染病（如艾滋病毒/艾滋病）中缺乏有效的治疗性递送，使该病毒可以使用中枢神经系统作为避难所。由于BBB既是物理（例如，紧密的细胞连接），又是生物学（例如，膜外排运输蛋白）的障碍物，这是一种多模式策略，该策略解决这两个问题都是有效地进入CNS的这些问题所必需的。在此R21提案中，主要目的是开发和评估多功能的水中油纳米乳液，专门用欧米茄3多不饱和脂肪酸（PUFA） - 富含食用油来增强BBB渗透性，以增强BBB的渗透性，并掺入姜黄素（CUR）（CUR）以下调用于避孕型转换剂。使用Saquinavir（SQV），一种模型的HIV蛋白酶抑制剂（也是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，含有亚麻籽油纳米乳液的SQV可以促进口服吸收和BBB渗透性。此外，使用Gadolinium Ion（GD3+） - 掺入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）用MRI和SQV的GD3+离子进行准备，表征和优化，用于MRI和SQV，以提高药物递送效率，（2）在体外评估中，将EFFLUX TRASTOPORS与CURI对比增强的频率增强bb的体外评估（2）在BALB/C小鼠中，全身给药/SQV纳米乳液制剂和MRI研究的药物输送功效的体内评估。拟议的多功能纳米乳液系统是使用欧米茄-3脂肪酸富含油的油来增强渗透性和下调外排转运蛋白的CUR制成的，它将为非侵入性的疏水性治疗剂提供新的平台，并使用低CNS生物利用性。多功能纳米乳液策略可以扩展到其他传染病，癌症和神经退行性疾病的艾滋病毒/艾滋病疗法。公共卫生相关性：用于治疗脑部疾病的98％以上的小分子疗法不能在全身给药后越过血脑屏障（BBB）。此外，在艾滋病毒/艾滋病和其他感染中，尽管慢性抗病毒疗法，大脑也充当病毒生存的有效庇护部位。由于BBB既是药物运输的物理和生物学障碍，因此我们的策略是开发可以解决这两个问题的运输工具。我们将使用富含omega-3的多不饱和脂肪酸的油制定油纳米乳剂，以增加BBB渗透并使用姜黄素来减少药物外排。评估大脑递送效率提高的研究将使用Saquinavir（一种抗HIV蛋白酶抑制剂作为模型药物）进行。此外，我们将用Gadolinium离子制定纳米乳液进行磁共振成像研究。