Nanomanufacturing of Hybrid Nanocarriers and Understanding their Physicochemical Properties for Targeted Drug Delivery

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Therapeutic nanocarriers have transformed the landscape of multiple diseases by enabling site-specific drug delivery. The localization of nanocarriers in biological cells is controlled by their physical and biochemical properties. The goal of this award is to design and manufacture hybrid liposomal nanocarriers, simultaneously tuning their mechanical and molecular properties to achieve high cellular uptake. This project demonstrates this goal in a brain model since nanocarrier transport through the blood brain barrier remains a critical challenge. Further, this work examines spatiotemporally controlled drug release from these nanocarriers using light to enable safe and targeted therapeutics. The research establishes mechanisms that show drug transport is controlled by novel physicochemical properties allowing the tailoring of a new class of nanocarriers targeted to study biological interactions. This class of nanocarriers advances drug delivery in difficult to treat disorders of the brain. The principles learnt can also be extended to achieve therapeutic response in other diseases, thus meeting national healthcare needs. This project seamlessly integrates research with education to transition this work through ‘lab-bench-to-classroom’ activities and by dissemination of ‘Fun with Color Capsules’ kits to K-12 students targeting underprivileged youths. By leveraging established and effective outreach programs, this work enables training of undergraduate and graduate students for the future workforce.The physicochemical behavior of therapeutic liposomal nanocarriers drives their interaction with biological interfaces and controls endocytosis in cells. Yet which properties should be tuned to enable efficient nanocarrier transport through biological barriers remains paradoxical. Therefore, approaches that leverage unexplored properties of nanocarriers are imperative to enable a paradigm shift in spatiotemporally controlled drug delivery. The goal of this project is to design and manufacture unconventional nanocarriers via bottom-up, directed self-assembly approaches. The research involves fabricating hybrid liposomal nanocarriers (LNCs) that synergize the properties of soft (liposome) core and hard (gold) shell nanoparticles in a single manufacturing platform enabling tunability of the elastic modulus and surface ligands. The research hypothesis is that these properties are mutually dependent, and when simultaneously tuned, achieve cell- and phenotype-specific targeting and therapeutic function demonstrated in an in vitro blood brain barrier (BBB) model. Further, LNCs are functionalized with antibody fragments that specifically target cells in the BBB. Another aim is to track LNCs in both cells and neurospheroids and pursue combinatorial optimization of the ligand density with elastic modulus to determine the stiffness-ligand regime that impacts cell-specific targeting. Finally, the project aims to demonstrate that these properties of LNCs enable effective photothermally actuated drug transport across the BBB.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.