Pharmacokinetics and biodistribution of supraparticle-delivered neurotrophin 3 in the guinea pig cochlea

Niliksha Gunewardene; Patrick Lam; Yutian Ma; Frank Caruso; Sherryl Wagstaff; Rachael T Richardson; Andrew K Wise

doi:10.1016/j.jconrel.2021.12.037

Pharmacokinetics and biodistribution of supraparticle-delivered neurotrophin 3 in the guinea pig cochlea

J Control Release. 2022 Feb:342:295-307. doi: 10.1016/j.jconrel.2021.12.037. Epub 2022 Jan 6.

Authors

Niliksha Gunewardene¹, Patrick Lam², Yutian Ma³, Frank Caruso⁴, Sherryl Wagstaff², Rachael T Richardson⁵, Andrew K Wise⁶

Affiliations

¹ Bionics Institute, Melbourne, Australia; Medical Bionics Department, University of Melbourne, Australia. Electronic address: ngunewardene@bionicsinstitute.org.
² Bionics Institute, Melbourne, Australia.
³ Bionics Institute, Melbourne, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
⁴ ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria 3010, Australia.
⁵ Bionics Institute, Melbourne, Australia; Medical Bionics Department, University of Melbourne, Australia; Department of Surgery (Otolaryngology), University of Melbourne, Australia.
⁶ Bionics Institute, Melbourne, Australia; Medical Bionics Department, University of Melbourne, Australia; Department of Surgery (Otolaryngology), University of Melbourne, Australia. Electronic address: awise@bionicsinstitute.org.

PMID: 34999140
DOI: 10.1016/j.jconrel.2021.12.037

Abstract

Hearing loss is the most prevalent sensory disorder affecting nearly half a billion people worldwide. Aside from devices to assist hearing, such as hearing aids and cochlear implants, a drug treatment for hearing loss has yet to be developed. The neurotrophin family of growth factors has long been established as a potential therapy, however delivery of these factors into the inner ear at therapeutic levels over a sustained period of time has remained a challenge restricting clinical translation. We previously demonstrated that direct delivery of exogenous neurotrophin-3 (NT3) in the guinea pig cochleae via a bolus injection was rapidly cleared from the inner ear, with almost complete elimination 3 days post-treatment. Here, we explored the potential of suprapaticles (SPs) for NT3 delivery to the inner ear to achieve sustained delivery over time. SPs are porous spheroid structures comprised of smaller colloidal silica nanoparticles that provide a platform for long-term controlled release of therapeutics. This study aimed to assess the pharmacokinetics and biodistribution of SP-delivered NT3. We used a radioactive tracer (iodine 125: ¹²⁵I) to label the NT3 to determine the loading, retention and distribution of NT3 delivered via SPs. Gamma measurements taken from ¹²⁵I NT3 loaded SPs revealed high drug loading (an average of 5.3 μg of NT3 loaded per SP weighing 50 μg) and elution capacities in vitro (67% cumulative release over one month). Whole cochlear gamma measurements from SP-implanted cochleae harvested at various time points revealed detection of ¹²⁵I NT3 in the guinea pig cochlea after one month, with 3.6 and 10% of the loaded drug remaining in the intracochlear and round window-implanted cochleae respectively. Autoradiography analysis of cochlear micro-sections revealed widespread ¹²⁵I NT3 distribution after intracochlear SP delivery, but more restricted distribution with the round window delivery approach. Collectively, drug delivery into the inner ear using SPs support sustained, long-term availability and release of neurotrophins in the inner ear.

Keywords: Drug delivery; Hearing loss; Neurotrophin-3; Pharmacokinetics; Supraparticles.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cochlea
Deafness* / drug therapy
Ear, Inner*
Guinea Pigs
Humans
Neurotrophin 3
Tissue Distribution

Substances

Neurotrophin 3