Developing the supraparticle technology for round window-mediated drug administration into the cochlea.

Area of Science:

• Biomedical Engineering
• Drug Delivery Systems
• Otolaryngology

Background:

• The round window membrane (RWM) is a critical barrier for localized drug delivery to the cochlea, essential for treating hearing loss.
• Neurotrophin 3 (NT3) shows therapeutic potential for hearing loss, but requires sustained delivery across the RWM.
• Silica supraparticles (SPs) offer potential for long-term drug delivery but require optimization for RWM implantation.

Purpose of the Study:

• To evaluate strategies for enhancing the longevity and biodistribution of NT3 delivered via SPs across the RWM in animal models.
• To investigate the efficacy of coated SPs, a fibrin sealant formulation, and RWM permeabilization for improved cochlear drug delivery.

Main Methods:

• Radioactive iodine-125 labeled NT3 (¹²⁵I NT3) was loaded into SPs and coated SPs ((Chi/Alg)SPs) to assess drug release kinetics in vitro.
• SPs and (Chi/Alg)SPs were implanted onto the RWM in guinea pigs and cats, with some formulations combined with fibrin sealant.
• Cochlear drug retention and distribution were quantified using gamma counting and histological analysis of cochlear tissues.

Main Results:

• Coated (Chi/Alg)SPs demonstrated a more linear NT3 release profile and significantly slower in vitro release over 7 days compared to uncoated SPs.
• In vivo, SPs and (Chi/Alg)SPs showed improved NT3 retention and distribution within the cochlea of guinea pigs and cats up to 8 weeks post-implantation.
• Hyaluronic acid treatment did not significantly enhance acute drug entry across the RWM.

Conclusions:

• Silica supraparticles, particularly the coated (Chi/Alg)SPs, facilitate NT3 transfer across the RWM, achieving sustained drug presence in the cochlea.
• In vivo results indicate better drug retention than predicted by in vitro release, highlighting the complexity of the RWM barrier.
• Further understanding of the RWM's physical properties is crucial for developing effective therapies for hearing loss.