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

职业：开发带电生物材料，用于将靶向药物输送到带负电的复杂组织环境

• 批准号: 2141841
• 负责人: Ambika Bajpayee
• 金额: $ 63.14万
• 依托单位: Northeastern University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2141841&HistoricalAwards=false
• 关键词: CAREER; Developing; electrically; charged; biomaterials

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.

该奖项全部或部分根据2021年美国救援计划法案（公法117-2）资助。非技术摘要：人体内有一些组织由于其高负电荷密度和缺乏血管而不接受全身或局部药物递送方法。拟议的工作将研究如何通过使用电荷相互作用来改善药物在这些接受性较低的组织中的递送。将使用软骨和关节液作为带负电荷的组织环境的模型，评价改变带正电荷的生物材料的不同物理和化学性质对其运输的影响。该研究将揭示健康和患病状态下带电生物材料和复杂的带负电荷的肌肉骨骼组织环境中的关键结构-性质关系，这些关系可以推广并调整为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性质的其他组织（半月板，椎间盘，骨折骨痂，眼睛，粘液），疾病和各种药物和成像剂的输送-最终促进其临床转化。补充这一研究计划是一个综合性的教育计划，旨在培养学生接近研究，对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，本科女性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，以促进美国不同社区之间的关系，帮助培养更多理解和广泛有效的科学领导者。技术摘要：该提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转运，并利用这些知识合理设计阳离子载体，用于基于其负固定电荷密度（FCD）向组织递送靶向药物。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，全身和局部药物递送都无法进入这些组织。然而，这种高负FCD可以通过修饰治疗剂以添加最佳带电的阳离子结构域而转化为机会，使得静电相互作用可以增强它们的转运而不是阻碍它们。这种长程、弱可逆的基于电荷的组织内结合可以通过短程结合效应（H-键、疏水性）协同稳定，使得这些载体即使在FCD减少的变性组织中也可以具有长的停留时间。使用软骨作为高负FCD的模型靶组织，由于其高密度的糖胺聚糖（GAG），该提议将在目的1中研究阳离子载体的理化性质对其转运的影响。将设计具有相同短长度但由精氨酸（表现出H-键和电荷相互作用）或赖氨酸（主要是电荷）组成的不同净电荷的阳离子肽载体（CPC），以确定最快组织内扩散率、全深度渗透、最高平衡摄取以及与健康和关节炎软骨中的靶软骨细胞长期结合的最佳构型。除了由于药物快速离开关节外，关节内药物停留时间短，软骨靶向还受到与滑液竞争性结合的影响，滑液包含带负电荷的透明质酸和疏水球蛋白。在目标2中，将疏水或亲水尾部添加到优化的CPC设计中，以研究在滑液存在下对不同FCD的软骨内基于电荷的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上，以证明在滑液存在下关节炎软骨的靶向改善。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Effects of polycationic drug carriers on the electromechanical and swelling properties of cartilage

聚阳离子药物载体对软骨机电和溶胀性能的影响

• DOI: 10.1016/j.bpj.2022.06.024
• 发表时间: 2022
• 期刊: Biophysical Journal
• 影响因子: 3.4
• 作者: Warren, Matthew R.;Vedadghavami, Armin;Bhagavatula, Sanjana;Bajpayee, Ambika G.
• 通讯作者: Bajpayee, Ambika G.

Milk exosomes anchored with hydrophilic and zwitterionic motifs enhance mucus permeability for applications in oral gene delivery

锚定有亲水性和两性离子基序的乳外泌体可增强粘液通透性，用于口腔基因递送应用

• DOI: 10.1039/d3bm01089a
• 发表时间: 2024
• 期刊: Biomaterials Science
• 影响因子: 6.6
• 作者: Zhang, Chenzhen;Zhang, Hengli;Millán Cotto, Héctor A.;Boyer, Timothy L.;Warren, Matthew R.;Wang, Chia-Ming;Luchan, Joshua;Dhal, Pradeep K.;Carrier, Rebecca L.;Bajpayee, Ambika G.
• 通讯作者: Bajpayee, Ambika G.