Sunday, May 5, 2024
5/5/2024
Abstract I am a neurotologist and assistant professor in the department of Otolaryngology-Head and Neck Surgery at the Johns Hopkins University School of Medicine. I am applying for a K08 mentored surgeon-scientist career development award (CDA) to obtain further training related to chemical engineering-based approaches to improving drug delivery in the ear for treatment of hearing loss. Specifically, I am interested in developing magnetic nanoparticles as a novel drug delivery platform in the treatment of hearing loss. My long-term career goals are to lead the translational development of novel drug delivery technologies that can enable the safe and effective delivery of emerging pharmaceutics into the inner ear. Despite rapid emergence of promising therapeutics such as protein-based neuronal growth factors and gene therapies for various forms of sensorineural hearing loss, their clinical translation is limited by the lack of a delivery vehicle that can be administered in a minimally-invasive and redoseable fashion in the clinic. Magnetic nanoparticles have unique chemical and physical properties that may be well suited as a cochlear delivery vehicle for macromolecular pharmaceutics. Their polymeric coating has payload capacity for proteins and DNA, while their superparamagnetic iron oxide nanocores can move in a magnetic field gradient, allowing for magnetically-assisted delivery across the round window membrane and into perilymph. However, rational design of magnetic nanoparticles for cochlear drug delivery requires an understanding of how nanoparticle properties relate to transport and pharmacokinetic behavior in the cochlea. This CDA proposes leveraging my previous experience in translational engineering research of the inner ear to elucidate how chemical and physical properties of custom-synthesized magnetic nanoparticles affect their consequent transport properties as cochlear drug delivery vehicles in vitro and in vivo. Specific training goals include: 1) training in nanoparticle science and drug delivery, 2) training in the guinea pig pharmacokinetic model, and 3) training in immunohistologic and histologic assays of the temporal bone, 4) training in ethical conduct of research, and 5) development of skills, techniques, and preliminary data that will lead to submission of a successful R01 application. The research plan investigates the hypothesis that nanoparticle size is an important mediator of magnetic nanoparticle transport in the cochlea and performance as a drug delivery vehicle. Using a guinea pig model validated for the study of perilymph pharmacokinetics of applied drugs, the specific aims of the proposal are to understand the impact of nanoparticle size on 1) transport across round window membrane explants in vitro, 2) perilymph concentration profiles and biodistribution in cochlear tissues in vivo, and 3) ability to deliver brain- derived neurotrophic factor into cochlear perilymph in vivo.
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