Sensorineural Hearing loss (SNHL) is one of the most common sensory deficits in humans, affecting millions of people worldwide, and is primarily attributed to inner ear dysfunction. Although a lot of progress has been made recently in understanding the etiology and molecular mechanisms of this disease, there are almost no non-invasive therapeutic approaches targeting to the pathological sites of the inner ear that are responsible for the majority of SNHL. A targeted multifunctional nanoparticle (MFNP) system (called nanohydrogel) proposed in this study is, to our knowledge, the first system to serve as a platform for the non-invasive delivery of biomaterials into specific inner ear structures for the treatment of the inner ear diseases. The MFNPs are usually smaller than 200 nm in diameter, and can be equipped with several functions, such as the ability to target specific cells, evade the immune system, and deliver the payload across different barriers. Unfortunately, current nanoparticle delivery systems are unable to efficiently deliver biomaterials to the to specific inner ear structures. These issues can be solved through the use of a biocompatible and biodegradable chitosan-glycerophosphate (CGP) hydrogel, which the principle investigator (PI) has shown to be capable of attaching to the round window membrane (RWM) and efficiently releasing therapeutic agents across the intact membrane in a controlled and sustained manner, and can be regulated using a glycolytic enzyme called chitosanase. Additionally, using innovative click-chemistry, MFNPs can incorporate targeting ligands to allow for better selectivity or targeting of these particles to cells of interest. In this proposal, the PI hypotheizes that the use of a regulated CGP-hydrogel-MNFP system (nanohydrogel) would result in a controlled, targeted, and highly effective delivery platform, bringing therapeutic biomaterial agents to specific cellular structures within the inner ear for the treatment of inner ear diseases This unique system has the potential to select ligands or therapeutic biomaterials depending on the need for different therapeutic approaches. The hypothesis is evaluated using a mouse model with different nanohydrogel formulations on the RWM to slowly and steadily release the MFNP into the inner ear. The ability to target specific inner ear cells will be evaluated by measuring the distribution of MFNPs in inner ear structures. To test the effectiveness and safety of this delivery system, the nanohydrogel system will be used to deliver MFNPs to the inner ear for the prevention of noise-induced SNHL in a mouse model. If the use of this novel nanohydrogel system proves to be an effective method of drug delivery for prevention of SNHL, it would signify a major step forward in the non-invasive treatment of inner ear diseases, which are currently untreatable. Moreover, this modular nanohydrogel system would allow for the development of better targeted therapies, extending it to a large variety of targeting moieties and treatment options, for this important functional region that has been marked by limited anatomic access. If this innovative system proves effective and safe, it will represent a major breakthrough in the treatment of the inner ear diseases, where a non-invasive delivery system carrying biomaterials or molecular agents is desperately needed.

Public Health Relevance

The PI believes that chitosan glycerophosphate inner ear delivery system is more effective and safer than the current method and it will represent a major breakthrough in otologic drug delivery, not only for specific case of steroid- responsive inner ear diseases, but also for diseases where a sustained delivery of other drugs or molecular agents is desperately needed.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC014464-04
Application #
9435101
Study Section
Bioengineering of Neuroscience, Vision and Low Vision Technologies Study Section (BNVT)
Program Officer
Cyr, Janet
Project Start
2015-03-01
Project End
2020-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kayyali, Mohammad N; Wright, Alexander C; Ramsey, Andrew J et al. (2017) Challenges and opportunities in developing targeted molecular imaging to determine inner ear defects of sensorineural hearing loss. Nanomedicine 14:397-404
Li, Lilun; Chao, Tiffany; Brant, Jason et al. (2017) Advances in nano-based inner ear delivery systems for the treatment of sensorineural hearing loss. Adv Drug Deliv Rev 108:2-12
Kayyali, M N; Brake, L; Ramsey, A J et al. (2017) A Novel Nano-approach for Targeted Inner Ear Imaging. J Nanomed Nanotechnol 8: