Thermally Responsive Magnetic-Hydrogel Nanocomposites for Advanced Drug Delivery

描述(由申请人提供)：这是PA-10-010下的R21探索/发展生物工程研究补助金(EBRG)的修订提案，作为研究人员发起的开发纳米复合药物输送系统的申请。所提出的药物输送系统包括一个可降解的、热响应的水凝胶纳米球，它包裹着一个单域顺磁性氧化铁纳米粒子，一旦被磁触发就可以通过溶胀释放药物。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中，迫使其膨胀并吸收生理溶剂。然后，膨胀的凝胶通过在周期性肿胀和崩溃过程中产生的扩散和对流释放包含的药物，用于局部治疗。载体将根据大小、形状、电荷、变形性、亲水性和降解性设计用于最佳的体内靶向用途。此外，纳米凝胶载体将进行表面修饰，以进行免疫“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，释放由外部触发机制启动，并在需要时具有增强的医学成像对比度。在这一系统的开发中，将解决有关纳米凝胶药物输送的几个根本挑战。具体来说，将考察温度漂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，还将制造一种新的测试设备，允许进行作为载体大小函数的膨胀动力学实验。这将使人们能够用非常小的颗粒载体预测达到平衡的时间和溶质的传输时间。已经选择了特定的抗体来增强过表达所需受体的靶细胞的摄取。最后，将在体外测试纳米载体，以确定细胞兼容性、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.