Thermally Responsive Magnetic-Hydrogel Nanocomposites for Advanced Drug Delivery

用于先进药物输送的热响应磁水凝胶纳米复合材料

基本信息

批准号：
8242598
负责人：
NICHOLAS A PEPPAS
金额：
$ 21.21万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-30 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242598
关键词：
Address Adsorption Adverse effects Affect Antibodies Behavior Binding Biomedical Engineering Blood Blood Circulation Cell Surface Receptors Cells Characteristics Charge Deposition Development Diffusion Dose Drug Carriers Drug Delivery Systems Drug Transport Encapsulated Equilibrium Ethylene Glycols Fever Frequencies Gel Gold Half-Life Heating Hydrogels Image Immune Immunoglobulin G Implant Kinetics Light Location Magnetic Resonance Imaging Magnetism Medical Imaging Metals Modeling Morphology N-isopropylacrylamide NanoGel Nanosphere Particulate Penetration Performance Pharmaceutical Preparations Pharmacotherapy Photons Physiological Polymers Positioning Attribute Property Proteins Research Research Personnel Research Project Grants Shapes Solvents Surface Swelling System Systems Development Temperature Testing Therapeutic Therapeutic Agents Time Tissues Work absorption base biomaterial compatibility chemical stability clinically relevant crosslink density design environmental change ethylene glycol hydrophilicity improved in vitro testing in vivo iron oxide magnetic field metal oxide nanocarrier nanocomposite nanomaterials nanoparticle nanoshell novel overexpression particle physical property receptor research study response solute spatiotemporal success uptake

项目摘要

DESCRIPTION (provided by applicant): This is a revised proposal for an R21 Exploratory / Developmental Bioengineering Research Grant (EBRG) under PA-10-010 as an investigator-initiated application for developing a nanocomposite drug delivery system. The proposed drug delivery system consists of a degradable, thermally-responsive hydrogel nanosphere encapsulating a single domain paramagnetic iron oxide nanoparticle to release drug by swelling once magnetically-triggered. AC inductive heating of the magnetic nanoparticle conducts heat into the surrounding 'nanogel', which forces it to swell and imbibe physiological solvent. The swollen gel then releases incorporated drug agents for localized therapeutic delivery by diffusion and convective currents created during cyclical swelling and collapsing. The carriers will be designed for optimal in vivo targeting utility based on size, shape, charge, deformability, hydrophilicity, and degradability. Additionally, nanogel carriers will be surface modified for immune 'stealthing' to prolong circulation times, and with antibodies to facilitate active targeting. This composite drug delivery system can be used to concentrate therapeutics locally with release initiated by an external triggering mechanism and with enhanced medical imaging contrast if desired. In the development of this system, several fundamental challenges regarding nanogel drug delivery will be addressed. Specifically, the impact of temperature excursions and volume swelling responses will be examined to determine their impact on carrier stability, active targeting, and on non-specific protein adsorption. Furthermore, a novel testing apparatus will be fabricated that allows for swelling kinetics experiments as a function of carrier size. This will allow predictions to be made as to time to equilibrium and solute transport times with very small particulate carriers. Specific antibodies have been selected to enhance uptake by targeted cells overexpressing the desired receptor. Finally, nanocarriers will be tested in vitro to establish cytocompatibility, uptake performance, and required magnetic field strengths for triggering. PUBLIC HEALTH RELEVANCE: Drug therapies such as anticancer chemotherapeutics utilize toxic drugs which are typically administered systemically and therefore cause substantial unwanted side effects. Using nanocarriers, it is possible to deliver highly concentrated doses of these drugs at the anatomical locations where therapeutic benefit is greatest. An advanced nanocarrier system can be molecularly-targeted to the affected tissues, verified by imaging, and triggered externally for maximum control over treatment with greatly improved success rates.

描述（由申请人提供）：这是 PA-10-010 项下的 R21 探索性/发展性生物工程研究补助金 (EBRG) 的修订提案，作为研究者发起的用于开发纳米复合药物输送系统的申请。所提出的药物递送系统由可降解的热响应水凝胶纳米球组成，该水凝胶纳米球封装了单域顺磁性氧化铁纳米颗粒，一旦磁触发就会通过膨胀来释放药物。磁性纳米颗粒的交流感应加热将热量传导到周围的“纳米凝胶”，迫使其膨胀并吸收生理溶剂。然后，膨胀的凝胶释放出掺入的药物，通过周期性膨胀和塌陷期间产生的扩散和对流来进行局部治疗递送。载体将根据尺寸、形状、电荷、可变形性、亲水性和可降解性进行设计，以实现最佳的体内靶向效用。此外，纳米凝胶载体将进行表面修饰，以实现免疫“隐形”，以延长循环时间，并使用抗体来促进主动靶向。这种复合药物输送系统可用于局部集中治疗药物，通过外部触发机制启动释放，并在需要时增强医学成像对比度。在该系统的开发过程中，将解决有关纳米凝胶药物输送的几个基本挑战。具体来说，将检查温度偏移和体积膨胀反应的影响，以确定它们对载体稳定性、主动靶向和非特异性蛋白质吸附的影响。此外，将制造一种新颖的测试装置，允许根据载体尺寸进行膨胀动力学实验。这将允许预测非常小的颗粒载体的平衡时间和溶质传输时间。已选择特定抗体来增强过度表达所需受体的靶细胞的摄取。最后，纳米载体将在体外进行测试，以确定细胞相容性、摄取性能和触发所需的磁场强度。公共卫生相关性：抗癌化疗等药物疗法使用有毒药物，这些药物通常全身给药，因此会引起严重的不良副作用。使用纳米载体，可以将高浓度剂量的这些药物输送到治疗效果最大的解剖位置。先进的纳米载体系统可以分子靶向受影响的组织，通过成像验证，并从外部触发，以最大限度地控制治疗，从而大大提高成功率。