Mechano sensitive peptide aggregates for targeted therapy

项目摘要 机械敏感性药物贮库，包括机械敏感性聚合物聚集体，已经显示出在生物医学领域的潜力。 治疗疾病，因为它们能够在疾病部位递送药物，从而最小化全身副作用 方面的影响.机械刺激可以是外在的（超声波、磁波等）或内在的，如 由于肿瘤生长、血管狭窄、动脉粥样硬化等而产生的剪切应力，因此具有优点 与其他刺激触发相比。然而，在发展中需要解决几个缺点， 机械敏感的药物仓库，以实现其全部潜力。与聚合物聚集体相比， 蛋白质/肽聚集体由于其固有的治疗性质而具有额外的优点， 生物降解性和朊病毒样行为。此外，机械敏感性朊病毒模拟肽的用途 聚集体作为药物递送仓库尚未被探索。朊病毒是蛋白质聚集体， 对身体有益或有传染性。有益的朊病毒已被证明在生理上发挥关键作用， 功能包括：促进坏死，支持记忆，存储和支架。考虑到朊病毒的传播 从一个细胞到另一个细胞，并以快速的方式感染它们，如果一个有益的朊病毒样机制， 对正常细胞有害的药物用于治疗递送，它可以产生有利的结果。灵感来自 上述建议的假设是机械可调的肽/蛋白质聚集颗粒， 固有的朊病毒模拟物治疗性质可用作靶向药物库， 吸收、扩散和有效的细胞间传递，从而通过以下方式增加治疗功效： 几倍。这一假设进一步受到先前发表的关于致病肽的研究结果的启发 在体外表现出朊病毒样行为的聚集体（朊病毒、abeta、p53和tau肽），以及先前关于 用于治疗癌症和血管闭塞的机械敏感性聚合物聚集体 功效作为概念的证明，在该提议中，RIP 1/RIP 3激酶淀粉样蛋白复合物，其已被证明是 通过形成淀粉样蛋白样复合物促进坏死并表现出朊病毒样性质 药物储存系统该提案的主要目标是：开发和表征机械敏感的 RIP 1/RIP 3肽聚集体;研究作用机制;并在体外测试治疗效果 和体内。此外，该项目将为代表性不足的少数民族，本科生和 研究生，并加强PI的研究计划。R15提案的具体目标是： 开发新的机械敏感肽聚集体颗粒，并测试其机械敏感性，（ii）。 研究颗粒在体外模型中的潜力，以及（iii）。体内试验治疗效果。 总的来说，拟议的项目将对治疗各种疾病产生影响， 外源性机械刺激可用于朊病毒模拟聚集体的靶向递送。

Project Summary Mechano sensitive drug depots, including mechano sensitive polymeric aggregates have shown potential in treating diseases due to their ability to deliver drugs at the disease site thereby minimizing systemic side effects. Mechanical stimuli could be either extrinsic (ultrasound, magnetic waves etc.,) or intrinsic such as shear stresses due to tumor growth, vascular narrowing, atherosclerosis etc, and hence has advantages compared to other stimuli triggers. However several shortcomings need to be addressed in the development of mechano sensitive drug depots to realize their full potential. Compared to polymeric aggregates, protein/peptide aggregates could have the added advantage due to their inherent therapeutic properties, biodegradability, and prion like behavior. Further, the use of mechano sensitive prion mimetic peptide aggregates as drug delivery depots have not been explored yet. Prions are protein aggregates that can be either beneficial or infectious to the body. Beneficial prions have shown to play key roles in physiological functions including: promoting necrosis, support memory, storage and scaffolding. Given that the prions spread from cells to cell and infect them in a rapid manner, if a beneficial prion like mechanism that won’t be detrimental to normal cells is used for therapeutic delivery it could produce favorable outcome. Inspired by the above, the hypothesis of the proposal is that mechanically tunable peptide/protein aggregate particles with intrinsic prion mimetic therapeutic properties could be utilized as targeted drug depots to facilitate the cellular uptake, diffusion, and effective intercellular transmission, thereby to increase the therapeutic efficacy by several fold. This hypothesis is further motivated by previously published findings on disease causing peptide aggregates (prion, abeta, p53, and tau peptides) exhibiting prion like behavior in vitro, and previous studies on mechano sensitive polymeric aggregates to treat cancer and vascular occlusion with increased therapeutic efficacy. As a proof of concept, in this proposal RIP1/RIP3 kinases amyloid complex, which have been shown to promote necrosis by forming amyloid like complexes and exhibit prion like properties will be used as a model drug depot system. The main objective of this proposal is: to develop and characterize mechano sensitive RIP1/RIP3 peptide aggregates; investigate the mechanism of action; and to test the therapeutic effects in vitro and in vivo. Further, the project will provide opportunities for underrepresented minorities, undergraduate, and graduate students, and enhance the PI’s research program. The specific aims of the R15 proposal are: (i). Develop novel mechano sensitive peptide aggregates particles, and test their mechano sensitivity, (ii). Investigate the potential of the particles in in vitro models, and (iii). Test the therapeutic efficacy in vivo. Collectively, the proposed project will have impact in treating broad range of diseases where both intrinsic and extrinsic mechanical stimuli could be utilized for targeted delivery of the prion mimetic aggregates.