CAREER: Developing electrically charged biomaterials for targeted drug delivery to negatively charged complex tissue environments

该奖项全部或部分由《2021年美国救援计划法案》（公法117-2）资助。非技术摘要：由于人体组织的高负电荷密度和缺乏血管，它们不能接受全身或局部给药方法。提出的工作将研究如何通过使用电荷相互作用来改善这些接受性较差的组织中的药物递送。改变带正电的生物材料的不同物理和化学性质对其运输的影响将使用软骨和关节液作为带负电的组织环境模型进行评估。该研究将揭示在健康和患病状态下带电生物材料和复杂负电荷肌肉骨骼组织环境中的关键结构-性质关系，可以推广和调整到针对其他带电组织系统。从长远来看，该程序具有广泛的适用性，因为它可以扩展到具有类似特性的其他组织（半月板，椎间盘，骨折骨痂，眼睛，粘液），疾病以及各种药物和显像剂的输送-最终促进其临床转化。与这个研究项目相辅相成的是一个综合教育计划，旨在培养学生从可翻译性和创造现实影响的角度来进行研究。该教育计划将建立一个合作转化生物材料会议，与当地工业界合作，为本科生和研究生提供专业发展机会。将开发新的模块和演示视频，重点关注生物材料设计和基于电荷的药物输送，目标是高中、本科妇女和代表性不足的少数民族。最后，将建立一个独特的美国内部科学交流计划，以促进美国境内不同社区之间的关系，帮助创造更多的理解和广泛有效的科学领袖。技术摘要：本课题旨在研究多价阳离子大分子的物理化学性质如何影响其在带负电荷的组织及其细胞微环境中的电扩散传输，并利用这些知识合理设计基于其负电荷固定密度（FCD）的靶向药物递送到组织的阳离子载体。人体含有几种带负电荷的组织，由于其无血管、致密的细胞外基质，这些组织无法进入全身和局部药物输送。然而，这种高负的FCD可以通过修改治疗方法来转化为机会，以添加最佳带电的阳离子结构域，这样静电相互作用可以增强而不是阻碍它们的传输。这种远距离的、弱可逆的、基于电荷的组织内结合可以通过短程结合效应（氢键、疏水性）协同稳定，这样，即使在FCD减少的变性组织中，这些载体也可以有很长的停留时间。利用软骨作为高负性FCD的模型靶组织，由于其具有高密度的糖胺聚糖（GAGs），本提议将在aim 1中研究阳离子载体的物理化学性质对其运输的影响。阳离子多肽载体（CPCs）具有相同的短长度但不同的净电荷，包括精氨酸（表现出h键和电荷相互作用）或赖氨酸（主要电荷），将被设计用于确定最佳配置，以实现最快的组织内扩散，全深度渗透，最高的平衡摄取，以及与健康和关节炎软骨中的目标软骨细胞的长期结合。除了药物在关节内的停留时间较短（由于淋巴细胞的快速退出）外，软骨靶向性进一步受到与滑膜液的竞争性结合的影响，滑膜液由带负电荷的透明质酸和疏水球蛋白组成。在目标2中，疏水或亲水性尾巴将被添加到优化的CPC设计中，以研究滑膜液存在下不同FCD对软骨内电荷结合的协同或竞争效应。在目标3中，这些优化的阳离子基序将以不同的密度锚定在外泌体的阴离子表面，以证明在滑膜液存在时改善关节炎软骨的靶向性。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).Non-Technical Abstract: There are tissues within the human body that are not receptive to systemic or local drug delivery methods due to their high negative charge density and lack of blood vessels. The proposed work will investigate how to improve drug delivery in these less receptive tissues by using charge interactions. The impact of modifying different physical and chemical properties of positively charged biomaterials on their transport will be evaluated using cartilage and joint fluid, as a model of negatively charged tissue environment. The study will reveal key structure-property relationships in electrically charged biomaterials and complex negatively charged musculoskeletal tissue environments in both healthy and diseased states that can be generalized and tuned to target other charged tissue systems. Long-term, the program has wide applicability as it can be extended to other tissues with similar properties (meniscus, intervertebral disc, fracture callus, eye, mucus), diseases and for delivery of various drugs and imaging agents – ultimately facilitating their clinical translation. Complementing this research program is an integrative education plan designed to train students to approach research with a view towards translatability and creating real-world impact. The education program will establish a collaborative translational biomaterials conference to engage local industry to provide undergraduate and graduate students with professional developmental opportunities. New modules and demonstration videos focused on biomaterials design and electric charge-based drug delivery will be developed that target high school, undergraduate women and underrepresented minorities. Finally, a unique intra-American scientific exchange program will be established to foster relationship between diverse communities within the US to help create more understanding and broadly effective scientific leaders. Technical Abstract: This proposal investigates how physicochemical properties of polyvalent cationic macromolecules affect their electro-diffusive transport within negatively charged tissues and their cellular microenvironments and uses this knowledge to rationally design cationic carriers for targeted drug delivery to tissues based on their negative fixed charge density (FCD). Human body contains several negatively charged tissues that are inaccessible to both systemic and local drug delivery due to their avascular, dense extracellular matrix. This high negative FCD, however, can be converted to an opportunity by modifying therapeutics to add optimally charged cationic domains such that electrostatic interactions can enhance their transport rather than hindering them. This long-range, weak-reversible charge-based intra-tissue binding can be synergistically stabilized by short-range binding effects (H-bond, hydrophobicity) such that these carriers can have long residence times even in degenerated tissues with diminished FCD. Using cartilage as a model target tissue of high negative FCD owing to its high density of glycosaminoglycans (GAGs), this proposal will investigate the effects of physicochemical properties of cationic carriers on their transport in aim 1. Cationic peptide carriers (CPCs) with the same short length but varying net charge comprising of arginine (exhibits H-bonds and charge interactions) or lysine (primarily charge) will be designed to determine an optimal configuration for fastest intra-tissue diffusivity, full-depth penetration, highest equilibrium uptake, and long-term binding to target chondrocytes residing in both healthy and arthritic cartilage. In addition to short intra-joint residence time of drugs due to rapid exit from lymphatics, cartilage targeting is further compromised by competitive binding with synovial fluid, that comprises of both negatively charged hyaluronic acid and hydrophobic globulins. In aim 2, hydrophobic or hydrophilic tails will be added to the optimized CPC designs to investigate the synergistic or competitive effects on charge-based binding within cartilage of varying FCD in presence of synovial fluid. In aim 3, these optimized cationic motifs will be anchored on exosome’s anionic surface in varying densities to demonstrate improved targeting of arthritic cartilage in presence of synovial fluid.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.