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

• 批准号: 8339884
• 负责人: NICHOLAS A PEPPAS
• 金额: $ 18.08万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-30 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8339884
• 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

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.

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。