Thermally Responsive Magnetic-Hydrogel Nanocomposites for Advanced Drug Delivery

描述（由申请人提供）：这是一份根据PA-10-010申请R21探索性/发展性生物工程研究资助（EBRG）的修订提案，作为研究人员发起的开发纳米复合给药系统的申请。所提出的药物递送系统由可降解的、热响应的水凝胶纳米球组成，水凝胶纳米球包裹着单畴顺磁性氧化铁纳米颗粒，一旦磁触发，就会通过膨胀释放药物。磁性纳米粒子的交流感应加热将热量传导到周围的“纳米凝胶”中，这迫使它膨胀并吸收生理溶剂。然后，肿胀的凝胶通过在周期性肿胀和塌陷期间产生的扩散和对流释放合并的药物制剂，用于局部治疗递送。载体将根据尺寸、形状、电荷、可变形性、亲水性和可降解性设计出最佳的体内靶向效用。此外，纳米凝胶载体将进行表面修饰，使免疫“隐身”，以延长循环时间，并与抗体一起促进主动靶向。该复合药物输送系统可用于局部浓缩治疗药物，由外部触发机制启动释放，并在需要时增强医学成像对比度。在该系统的开发中，将解决有关纳米凝胶药物递送的几个基本挑战。具体来说，温度漂移和体积膨胀反应的影响将被检查，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，将制造一种新的测试装置，允许膨胀动力学实验作为载体尺寸的函数。这将允许预测时间的平衡和溶质运输时间与非常小的颗粒载体。特异性抗体已被选择，以提高摄取的目标细胞过度表达所需的受体。最后，纳米载体将在体外测试，以建立细胞相容性，摄取性能和触发所需的磁场强度。

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.