46. Nanomaterial-based Neuromodulators for Extended Duration of Therapeutic Effect

Abstract

Purpose: Neuromodulators of the botulinum toxin family are highly effective therapeutics for aesthetic and medical indications. However, wider use of these agents is hampered by their limited duration of effect which necessitates in frequent redosing. In addition, diffusion away from the target site resulting in off-target activity with unwanted muscle paralysis. The aim of this study was to (1) develop a novel nanoparticle-based delivery system for neuromodulators that enables sustained release at target tissue sites and (2) assess the efficacy of locally delivered neuromodulation in prolonging muscle paralysis. Methods: Botulinum toxin A (BoNTA), BoNTA toxoid (chemically inactivated form of the toxin) Neuromodulators were each encapsulated within polymeric nanoparticles (NPs). BoNTA or its toxoid were mixed with carrier molecules and fabricated into polymeric nanoparticles. Release kinetics were of the nanomaterial-based neuromodulator formulation were evaluated in vitro using enzyme-linked immunosorbent assays. The bioactivity of released neuromodulator was assessed using a substrate hydrolysis assay. The therapeutic potential was assessed in vivo using a quantitative forelimb grip strength model in rats. The nanomaterial-based neuromodulator formulations were injected into the muscles of the anterior compartment in the forearm and the paralytic effect was quantified by assessing functional recovery using stimulated grip strength testing. Functional recovery was assessed weekly and compared to baseline grip strength as percentage recovery from baseline until this was complete at which point animals were sacrificed for histologic analyses. Results: Reference protein-loaded NPs showed superior localization when injected in rodent models when compared to unencapsulated proteins. Rodents injected with unencapsulated BoNTA (1X BoNTA) fully regained grip strength fastest with 80% recovery in only 8 weeks. Doubling the dose of unencapsulated BoNTA (2X BoNTA) delayed 80% recovery to 18 weeks. Strikingly, the nanoparticle encapsulated BoNTA (1X BoNTA/NP) at the original 1X dose outperformed even this group with 65% recovery at 18 weeks. Conclusion: Our novel nanomaterial-based neuromodulator formulation provides linear, long-acting release while the encapsulation process did not diminish the bioactivity of BoNTA. This prolongation of effect is achieved without increasing BoNTA dosing. Such a sustained release formulation and local delivery modality promises superior therapeutic outcomes with less frequent re-dosing.