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.
Although advances have been made in drug delivery approaches for treating diseases, there are still several shortcomings need to be addressed. In this proposal we plan to develop a novel drug delivery approach utilizing mechano sensitive peptide aggregates particles. The aggregates would be developed to achieve targeted delivery of therapeutics at the disease site, increase cellular uptake and transmission, and hence the therapeutic efficacy.
