Stopping The Clock: Agrin Nanoparticle Therapy Reduces Neuromuscular Junction Degradation After Peripheral Nerve Injury
Erica B. Lee, MS, Chenhu Qiu, BS, Thomas G.W. Harris, MBChB, Nicholas von Guionneau, MBBS, Zohra Alsami, BS, Matthew Generoso, BS, Yicheng Zhang, BS, Zhicheng Yao, MS, Ahmet Hoke, MD PhD, Hai-Quan Mao, PhD, Sami Tuffaha, MD.
Johns Hopkins School of Medicine, Baltimore, MD, USA.
PURPOSE: Agrin, a proteoglycan involved in neuromuscular junction (NMJ) formation, may be essential in preserving NMJs following peripheral nerve injury. This study aimed to (1) encapsulate agrin into biodegradable nanoparticles (NPs) that enable sustained release at target tissues; and (2) assess the efficacy of locally-delivered Agrin-NPs in preserving NMJs in denervated muscle.
METHODS: (1) Agrin was complexed with dextran sulfate to create polyelectrolyte complex cores and encapsulated in biodegradable amphiphilic block co-polymers. In vitro NP release kinetics and mitogenic activity were evaluated. (2) Using a rat tibial nerve transection-without-repair model, animals were injected with low, medium, or high doses of agrin-NPs incorporated into a nanofiber-hyaluronic acid hydrogel composite (NHC) gel, empty-NPs within NHC, free agrin, or saline.
RESULTS: (1) Uniform NPs were achieved with an encapsulation efficiency of 85.6%. Agrin-NPs exhibited near-zero-order release over 70 days and comparable bioactivity to native agrin. (2) Agrin-NP animals retained significantly greater NMJ pretzel-like morphology after 6 weeks of denervation compared to free agrin and empty-NP groups with optimal benefit achieved by the medium dose (35.0% vs 23.1% free agrin, 35.0% vs 7.1% empty-NP; p<0.0001). Agrin muscle ELISA levels were significantly higher than free agrin-treated animals (p<0.01).
CONCLUSION: Encapsulation of bioactive agrin with sustained release was achieved. Agrin-NP treatment in vivo limits NMJ degradation during denervation and thereby has potential as a therapeutic target to improve motor functional recovery.
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