Platelet Biomimicry for Treating Vascular Disorders
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CitationSarode, Apoorva. 2019. Platelet Biomimicry for Treating Vascular Disorders. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractTargeted drug delivery to the endothelium poses a significant challenge in treatment of vascular disorders like stroke, atherosclerosis, cancer, etc. While several nanoparticle-based drug delivery systems have been developed to address this problem, their utility is limited by poor circulation lifetime and unfavorable transport properties, leading to low targeting efficiency. In contrast, natural platelets have evolved to possess an innate ability to localize near the vascular wall and bind to diseased sites of the endothelium via specific ligand-receptor interactions. Owing to these distinct features, platelets have garnered immense attention as a model candidate for biomimicry in the field of vascular targeted delivery.
Taking cue from these blood cells, this thesis focuses on engineering polymeric platforms to develop vascular targeted carriers that mimic the bio-chemical and physico-mechanical features of natural platelets. Here, we report the development of polymer-peptide conjugates and layer-by-layer (LbL) particles as synthetic platelet analogs for treatment of hemorrhagic and thrombotic conditions, respectively. The polymer-peptide conjugates have been shown to effectively halt bleeding in mouse tail laceration model. This hemostatic formulation provides advantages of facile, tunable synthesis and long-term stability, motivating its future development for point-of-care administration in trauma situations. We also report another synthetic platelet design that mimics the discoidal geometry of platelets while integrating the clot targeting ability of their natural counterparts. These LbL microcapsules have been designed for site-specific delivery of the biopharmaceutical drug, tissue plasminogen activator to blood clots for fibrinolysis. However, this platform can be further extended for the treatment of various other vascular and oncological disorders.
In addition to development of new drug carriers, it is also important to understand the fundamental mechanisms by which they interact with their target organs. Particle geometry has been established as an important parameter governing their biological fate. Expanding on this knowledge, we investigated the role of shape and size of vascular targeted carriers in their transport through bloodstream, by testing wide array of functionalized polymeric particles in microfluidic devices. Implications from this study can be used to tune the design of particulate drug carriers to suit the desired therapeutic or diagnostic application.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:42013109
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