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

该奖项的全部或部分资金来自《2021年美国救援计划法案》(公法117-2)。非技术摘要：人体内的一些组织由于其高负电荷密度和缺乏血管，不能接受全身或局部的药物输送方法。这项拟议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输送。改变带正电生物材料的不同物理和化学性质对其传输的影响将使用软骨和关节液作为负电组织环境的模型来评估。这项研究将揭示健康和疾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-性能关系，这些关系可以推广和调整以针对其他带电组织系统。从长远来看，该计划具有广泛的适用性，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、骨折痂、眼部、粘液)、疾病以及各种药物和显像剂的输送-最终促进其临床翻译。与这项研究计划相辅相成的是一项综合教育计划，旨在培训学生进行研究，以期达到可译性和创造现实世界的影响。该教育计划将建立一个合作的翻译生物材料会议，让当地行业参与，为本科生和研究生提供职业发展机会。将开发新的模块和演示视频，重点是生物材料设计和基于电荷的药物输送，目标是高中、本科生女性和代表性不足的少数族裔。最后，将建立一个独特的美洲内部科学交流计划，以促进美国不同社区之间的关系，以帮助培养更多理解和广泛有效的科学领袖。技术摘要：该方案研究了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，并利用这一知识根据其负定电荷密度(FCD)合理地设计用于靶向给药的阳离子载体。人体含有几个带负电荷的组织，由于其无血管、致密的细胞外基质，全身和局部给药都无法获得这些组织。然而，这种高负值的FCD可以通过修改治疗药物来添加最佳带电的阳离子结构域，从而使静电相互作用可以加强而不是阻碍它们的传输，从而将其转化为机会。这种长距离、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减少的退化组织中，这些载体也可以有很长的停留时间。利用软骨作为高负值FCD的模型靶组织，由于其高密度的糖胺多聚糖(GAG)，这项建议将调查阳离子载体的物理化学性质对其在AIM 1中的转运的影响。具有相同长度但不同净电荷的阳离子多肽载体(CPC)将被设计为确定最快的组织内扩散、全深度渗透、最高平衡摄取和与驻留在健康和关节炎软骨中的目标软骨细胞的长期结合的最佳构型。除了由于药物快速从淋巴管中排出而在关节内停留时间短之外，软骨靶向还受到与滑液的竞争结合的影响，滑液包括带负电荷的透明质酸和疏水球蛋白。在目标2中，疏水或亲水的尾巴将被添加到优化的CPC设计中，以研究在滑液存在的情况下，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体的阴离子表面，以证明在存在滑膜液体的情况下改善了对关节炎软骨的靶向。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.