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bioRxiv · 10.1101/2024.09.05.611478

Targeted Polymersomes Enable Enhanced Delivery to Peripheral Nerves Post-Injury

Trumbull, K.·Fetten, S.·Montgomery, D.·Marahrens, V.·Myers, O.·Arnold, N.·Twiss, J. L.·Larsen, J.
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Abstract

The gold standard therapy for peripheral nerve injuries involves surgical repair, which is invasive and leads to major variations in therapeutic outcomes. Because of this, smaller injuries often go untreated. However, alternative, non-invasive routes of administration are currently unviable due to the presence of the blood-nerve barrier (BNB), which prevents passage of small molecules from the blood into the endoneurium and the nerve. This paper demonstrates that ligands on the surface of nanoparticles, called polymersomes, can enable delivery to the nerve through non-invasive intramuscular injections. Polymersomes made from polyethylene glycol (PEG)-b-polylactic acid (PLA) were conjugated with either apolipoprotein E (ApoE) or rabies virus glycoprotein-based peptide, RVG29 (RVG) and loaded with near infrared dye, AlexaFluor647. ApoE was used to target receptors upregulated in post-injury inflammation, while RVG targets neural specific receptors. Untagged, ApoE-tagged, and RVG-tagged polymersomes were injected at 100 mM either intranerve (IN) or intramuscular (IM) into Sprague Dawley rats post sciatic nerve injury. The addition of the ApoE and RVG tags enabled increased AlexaFluor647 fluorescence in the injury site at 1 hour post IN injection compared to the untagged polymersome control. However, only the RVG-tagged polymersomes increased AlexaFluor647 fluorescence after intramuscular injection. Ex vivo analysis of sciatic nerves demonstrated that ApoE-tagged polymersomes enabled the greatest retention of AlexaFluor647 regardless of the injection route. This led us to conclude that using ApoE to target inflammation enabled the greatest retention of polymersome-delivered payloads while RVG to target neural cells more specifically enabled the penetration of polymersome-delivered payloads. Observations were confirmed by calculating area under the curve pharmacokinetic parameters and the use of a two-compartment pharmacokinetic model.

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Trumbull, K., Fetten, S., Montgomery, D., Marahrens, V., Myers, O., Arnold, N., Twiss, J. L., Larsen, J.. 2024-09-10. Targeted Polymersomes Enable Enhanced Delivery to Peripheral Nerves Post-Injury. https://doi.org/10.1101/2024.09.05.611478

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