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Principal Investigator: Daniel Q Sun
Organization: UNIVERSITY OF CINCINNATI
Fiscal Year: 2024
Award: $200,880
Funding agency: National Institute on Deafness and Other Communication Disorders
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.
Terms: <Affect><Animal Model><Animal Models and Related Studies><Assay><BDNF><Behavior><Bioassay><Biodistribution><Biological><Biological Assay><Body Tissues><Brain-Derived Neurotrophic Factor><Cancer Treatment><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cavia><Chemical Engineering><Clinic><Clinical><Clinical Treatment><Cochlea><Cochlear Organ><Custom><DNA><DNA Therapy><Data><Deoxyribonucleic Acid><Development><Devices><Diffusion><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drugs><Ear><Engineering><Equilibrium><Ethics><Face><Fe oxide><Gene Transfer Clinical><General Anesthesia><Genetic Intervention><Goals><Growth Agents><Growth Factor><Growth Substances><Guinea Pigs><Guinea Pigs Mammals><Head and Neck Surgery><Hearing><Hearing Loss><Histologic><Histologically><Histology><Human><Hypoacuses><Hypoacusis><Image><Implant><In Vitro><Injections><Inner Ear Disorder><Internal Ear><K-Awards><K-Series Research Career Programs><Labyrinth><Lead><Liquid substance><Macrogols><Magnetic nanoparticles><Magnetism><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Mediating><Mediator><Medication><Membrane><Mentors><Modeling><Modern Man><Needles><Nucleic Acids><Operative Procedures><Operative Surgical Procedures><Otolaryngology><Particle Size><Patients><Pb element><Penetration><Performance><Perilymph><Pharmaceutical Preparations><Pharmaceutics><Pharmacokinetics><Pharmacy (field)><Polyethylene Glycols><Polyethylene Oxide><Polyethyleneoxide><Polymers><Polyoxyethylenes><Predisposition><Property><Proteins><Proteins Growth Factors><Research><Research Career Program><Residual><Residual state><Risk><Scala Tympani><Scala Tympanus><Science><Scientist><Sensorineural Deafness><Sensorineural Hearing Loss><Sensory Hearing Loss><Severities><Study models><Surgeon><Surgical><Surgical Interventions><Surgical Procedure><Susceptibility><Techniques><Technology><Temporal Bone><Temporal bone structure><Therapeutic><Tissues><Training><Universities><Viral Vector><anti-cancer therapy><balance><balance function><biocompatibility><biologic><biomaterial compatibility><cancer therapy><cancer-directed therapy><career><chemical property><clinical translation><clinically translatable><cochlear development><cochlear window><colcothar><customs><delivery vector><delivery vehicle><developmental><diffused><diffuses><diffusing><diffusions><drug/agent><dysfunctional hearing><ethical><experience><faces><facial><fenestra cochleae><ferric oxide><fluid><gene repair therapy><gene therapy><gene-based therapy><genetic therapy><genomic therapy><guinea pig model><hearing challenged><hearing defect><hearing deficient><hearing deficit><hearing difficulty><hearing dysfunction><hearing impairment><hearing loss therapy><hearing loss treatment><heavy metal Pb><heavy metal lead><imaging><improved><in vivo><inner ear><inner ear diseases><interest><iron oxide><liquid><macromolecule><magnetic><magnetic field><medical college><medical schools><membrane structure><middle ear><minimally invasive><model of animal><molecular size><nano particle><nano-sized particle><nanoparticle><nanosized particle><neuronal growth><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><otorhinolaryngology><particle><pharmaceutic><pharmacokinetic model><physical property><polymer><polymeric><pre-clinical><preclinical><professor><rational design><red iron oxide><round window><school of medicine><sensorineural hearing impairment><skill acquisition><skill development><small molecule><superparamagnetic><superparamagnetism><surgery><treatment for hearing loss><trial regimen><trial treatment><validation studies>