Extended Local Release of Neuromodulators from a Novel Nanoparticle System for Chronic Migraine and Facial Aesthetics
Year: 2021
Type: article
Abstract: PURPOSE: Neuromodulators of the botulinum toxin family (eg, Botox) have been used effectively to treat a wide range of conditions, including chronic migraine, spasticity, hyperhidrosis, and facial rhytids. Despite their broad utility and commercial success, these agents suffer from two significant shortcomings: limited duration of effect, necessitating frequent redosing, and diffusion from target sites leading to unwanted muscle paralysis. To overcome these challenges, we have developed a novel nanoparticle-based botulinum toxin system that prolongs therapeutic effects while preventing off-target activity. METHODS: Botulinum toxin A (BoNTA) and BoNTA toxoid (chemically inactivated form of the toxin) were each encapsulated within polymeric nanoparticles. BoNTA or toxoid was mixed with a carrier molecule and assembled into polyelectrolyte complex nanoparticles using a biodegradable amphiphilic block copolymer using a flash nanocomplexation/nanoprecipitation process.1 Nanoparticles were characterized by dynamic light scattering for size distribution and zeta potential, and transmission electron microscopy for morphology. In vitro release of BoNTA or toxoid was determined using ELISA and bioactivity of released BoNTA was analyzed using a substrate hydrolysis assay. The in vivo paralytic effect of BoNTA nanoparticles was assessed using a quantitative rodent forepaw model using stimulated grip strength testing.2 RESULTS: The BoNTA and its toxoid both demonstrated high encapsulation efficiency of 83%–88% of the input protein into NPs; and the average loading level (mass of total protein/mass of NPs) was 13.4–14.2%. Both NPs showed a similar, sustained linear release profile with 30%–35% of protein released within 30 days, ~75% in 98 days, and a projected release duration of about 4 months. Critically, BoNTA released from NPs demonstrated high levels (>80%) of bioactivity retention, confirming that the encapsulation process and release did not impair the bioactivity of BoNTA. Reference protein-loaded NPs showed superior localization when injected in rodent models when compared with unencapsulated proteins. Finally, the NPs stored at ambient temperature (20°C–25°C) for 70 days exhibited a similar release kinetics, demonstrating a good shelf stability. CONCLUSIONS: We demonstrated a novel NP-based neuromodulator system that enables local, linear, long-acting neuromodulator release with strong preservation of bioactivity. Given the high level of potency of BoNTA and the linear release above the EC50 for almost 4 months, we anticipate powerful extended neuromodulatory effect in vivo with this formulation. It is hoped that clinical translation of this system will yield superior therapeutic outcomes with less frequent dosing and an improved margin of safety. REFERENCES: 1. Hu H. et al. Flash technology-based self-assembly in nanoformulation: Fabrication to biomedical applications. Materials Today doi:10.1016/j.mattod.2020.08.019 (2020). 2. Hanwright PJ, et al. Stimulated grip strength measurement: Validation of a novel method for functional assessment. Muscle Nerve 2019;60(4):437–442. doi: 10.1002/mus.26646 (2019).
Authors: Thomas Harris, Chenhu Qiu, Salih Colakoglu, Sami Tuffaha, Hai-Quan Mao, Sashank K. Reddy
Institution: Johns Hopkins University
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,195
OpenAlex ID: W4310485692