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Brain-targeted nanomedicine via buccal administration

通过口腔给药的脑靶向纳米药物

基本信息

批准号：
7844989
负责人：
Hu Yang
金额：
$ 13.89万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7844989
关键词：
Absence of pain sensation Address Adverse effects Alzheimer&apos s Disease Area Base of the Brain Blood Blood - brain barrier anatomy Blood Circulation Brain Bypass Central Nervous System Agents Central Nervous System Diseases Chemicals Clinical Treatment Clinical Trials Data Dendrimers Developing Countries Disease Dosage Forms Drug Delivery Systems Drug Formulations Drug Prescriptions Gastrointestinal tract structure Gelatin Generations HIV Infections Health Health Services Huntington Disease Hydrogels In Vitro Kinetics Life Ligands Literature Liver Lung Malignant neoplasm of brain Mediating Medical Medicine Membrane Modeling Modification Neuraxis Opioid Peptide Opioid Receptor Organ Permeability Pharmaceutical Preparations Polymers Risk Route Services Shapes Spleen Stroke System Technology Testing Therapeutic Toxic effect Translational Research Translations Treatment Cost Treatment Efficacy base biomaterial compatibility clinically relevant compliance behavior controlled release dosage improved in vivo innovation intravenous administration intravenous injection nanomedicine nanoparticle nanoparticulate nanoscale neuroprotection novel public health relevance spinal cord and brain injury therapeutic effectiveness transcytosis uptake

项目摘要

DESCRIPTION (provided by applicant): Central nervous system (CNS) diseases and disorders represent the largest and fastest growing area of unmet medical need. Over 1.5 billion people worldwide, including over 100 million people in the US, suffer from CNS diseases or disorders. This project is aimed at finding a new way to get therapeutic drugs to CNS more effectively, more safely, and more conveniently. It is hypothesized that dendrimer nanoparticles carrying brain- specific ligand and a high payload of CNS drugs will cross the BBB in significant amounts via transcytosis. It is further hypothesized that brain-targeted dendrimer nanoparticles can cross the buccal membrane to get into the systemic circulation. To test the above hypotheses, the following three specific aims are proposed: Aim 1: Synthesize and characterize a novel brain-targeted dendrimer-based nanoparticulate drug delivery system; Aim 2: Assess the brain-targeting ability and permeability of brain-targeted dendrimer nanoparticles across the BBB in vitro; Aim 3: Formulate a mucoadhesive PEG/gelatin IPN hydrogel for buccal administration of brain-targeted dendrimer nanoparticles, and determine the controlled release kinetics and permeability across the buccal membrane. To address Aim 1, a layer-by-layer synthesis will be carried out to create a brain- targeted dendrimer drug delivery system. The biocompatibility, toxicity, and immunocompatibility of dendrimers will be modulated through proper chemical modification at the periphery, and their composition, shape, and size will be tuned to optimize therapeutic efficacy and delivery efficiency. To address Aim 2, a dynamic in vitro (DIV)-BBB model will be employed to test the synthesized brain-targeted dendrimer nanoparticles in terms of targeting ability, permeability efficiency across the BBB, and transcytosis. To address Aim 3, a dosage form based on PEG/gelatin IPN hydrogel will be formulated to deliver brain-targeted dendrimer nanoparticles. Drug release kinetics and permeability across the buccal membrane will be evaluated. To demonstrate the potential clinical relevance, a well-characterized opioid peptide, DPDPE (NH2-Tyr1-D- Pen2-Gly3-Phe4-D-Pen5-OH) will be used as a model drug. Its definitive CNS-mediated analgesia, well- defined opioid receptors, and in vitro and in vivo data readily available in the literature will allow us to compare and confirm the efficacy of the established brain-targeted dendrimer drug delivery system e with a relatively high level of confidence. The unique integration of developing a new brain-targeted drug delivery system based on dendrimers and exploring buccal administration for its delivery will result in an innovative non-invasive treatment to deliver drugs to the brain across the BBB selectively and collectively, thus improving therapeutic effectiveness and reducing side effects. The ease of buccal drug administration will reduce treatment cost and societal burden, increase patient compliance as well as improve the quality of the overall treatment. PUBLIC HEALTH RELEVANCE: This project will develop a novel brain-targeted nanomedicine based on dendrimers to deliver drugs to the brain across the blood-brain barrier (BBB) selectively and collectively, thus improving therapeutic effectiveness and reducing side effects. This project will also explore buccal administration for systemic delivery of the proposed nanomedicine to reduce treatment cost and societal burden, increase patient compliance as well as improve the quality of the overall treatment.

描述（由申请人提供）：中枢神经系统 (CNS) 疾病和病症是未满足的医疗需求最大且增长最快的领域。全球有超过 15 亿人，包括超过 1 亿美国人，患有中枢神经系统疾病或紊乱。该项目旨在寻找一种新的方法，使治疗药物更有效、更安全、更方便地到达中枢神经系统。据推测，携带脑特异性配体和高负载中枢神经系统药物的树枝状聚合物纳米颗粒将通过转胞吞作用大量穿过血脑屏障。进一步假设脑靶向树枝状聚合物纳米颗粒可以穿过颊膜进入体循环。为了检验上述假设，提出了以下三个具体目标：目标 1：合成并表征一种新型脑靶向树枝状大分子纳米颗粒药物递送系统；目标2：体外评估脑靶向树枝状聚合物纳米粒子跨血脑屏障的脑靶向能力和渗透性；目标 3：配制粘膜粘附 PEG/明胶 IPN 水凝胶，用于口腔靶向脑靶向树枝状聚合物纳米颗粒的给药，并确定跨颊膜的控释动力学和渗透性。为了实现目标 1，将进行逐层合成，以创建脑靶向树枝状大分子药物递送系统。树枝状聚合物的生物相容性、毒性和免疫相容性将通过外围适当的化学修饰来调节，并且它们的组成、形状和尺寸将被调整以优化治疗功效和递送效率。为了实现目标 2，将采用动态体外 (DIV)-BBB 模型来测试合成的脑靶向树枝状聚合物纳米颗粒的靶向能力、跨 BBB 的渗透效率和转胞吞作用。为了实现目标 3，将配制一种基于 PEG/明胶 IPN 水凝胶的剂型，以递送脑靶向树枝状聚合物纳米颗粒。将评估药物释放动力学和跨颊膜的渗透性。为了证明潜在的临床相关性，将使用一种充分表征的阿片肽 DPDPE (NH2-Tyr1-D-Pen2-Gly3-Phe4-D-Pen5-OH) 作为模型药物。其明确的中枢神经系统介导的镇痛作用、明确的阿片受体以及文献中容易获得的体外和体内数据将使我们能够以相对较高的置信度比较和确认已建立的脑靶向树枝状聚合物药物递送系统的功效。开发基于树枝状大分子的新型脑靶向药物输送系统和探索口腔给药的独特整合将产生一种创新的非侵入性治疗方法，将药物选择性地和集体地穿过血脑屏障输送到大脑，从而提高治疗效果并减少副作用。口腔给药的便利性将降低治疗成本和社会负担，提高患者的依从性并提高整体治疗的质量。公共健康相关性：该项目将开发一种基于树枝状聚合物的新型脑靶向纳米药物，选择性地、集中地将药物穿过血脑屏障（BBB）输送到大脑，从而提高治疗效果并减少副作用。该项目还将探索口腔给药，以系统输送所提出的纳米药物，以降低治疗成本和社会负担，提高患者的依从性并提高整体治疗的质量。