Targeting Small Molecule Delivery to the Brain and Spinal Cord via Intranasal Administration of Rabies Virus Glycoprotein (RVG29)-Modified PLGA Nanoparticles.

Eugene P Chung,Alesia V Prakapenka,Jennifer D Cotter,Rebecca L Cook,Rachael W Sirianni,Danielle M Diperna

doi:10.3390/pharmaceutics12020093

Eugene P Chung, Alesia V Prakapenka + Show 4 more

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https://doi.org/10.3390/pharmaceutics12020093

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Abstract

Alternative routes of administration are one approach that could be used to bypass the blood–brain barrier (BBB) for effective drug delivery to the central nervous system (CNS). Here, we focused on intranasal delivery of polymer nanoparticles. We hypothesized that surface modification of poly(lactic-co-glycolic acid) (PLGA) nanoparticles with rabies virus glycoprotein (RVG29) would increase residence time and exposure of encapsulated payload to the CNS compared to non-targeted nanoparticles. Delivery kinetics and biodistribution were analyzed by administering nanoparticles loaded with the carbocyanine dye 1,1′-Dioctadecyl-3,3,3′,3′-Tetramethylindotricarbocyanine Iodide (DiR) to healthy mice. Intranasal administration yielded minimal exposure of nanoparticle payload to most peripheral organs and rapid, effective delivery to whole brain. Regional analysis of payload delivery within the CNS revealed higher delivery to tissues closest to the trigeminal nerve, including the olfactory bulb, striatum, midbrain, brainstem, and cervical spinal cord. RVG29 surface modifications presented modest targeting benefits to the striatum, midbrain, and brainstem 2 h after administration, although targeting was not observed 30 min or 6 h after administration. Payload delivery to the trigeminal nerve was 3.5× higher for targeted nanoparticles compared to control nanoparticles 2 h after nanoparticle administration. These data support a nose-to-brain mechanism of drug delivery that closely implicates the trigeminal nerve for payload delivery from nanoparticles via transport of intact nanoparticles and eventual diffusion of payload. Olfactory and CSF routes are also observed to play a role. These data advance the utility of targeted nanoparticles for nose-to-brain drug delivery of lipophilic payloads and provide mechanistic insight to engineer effective delivery vectors to treat disease in the CNS.

Highlights

Delivery of therapeutic molecules to the central nervous system (CNS) is severely limited by the blood–brain and blood–spinal cord barriers (BBB and BSCB)
To develop a brain-targeted nanoparticle system for intranasal administration, we focused on a 29 amino acid peptide component of rabies virus glycoprotein (RVG29)
Our results demonstrate that surface modification of nanoparticles with RVG29 can achieve to specific tissues within the CNS following intranasal administration by mechanisms that are distinct from intravenously administered nanoparticles

Summary

Introduction

Delivery of therapeutic molecules to the central nervous system (CNS) is severely limited by the blood–brain and blood–spinal cord barriers (BBB and BSCB). These barriers are comprised of tight junctions and efflux pumps that restrict parenchymal penetration of all but a fraction of small, lipophilic molecules. Intranasal administration has been shown to have several key advantages over systemic administration, including avoidance of first-pass metabolism and ease of administration [8] This can enable better drug delivery to the brain, since substances have the potential for more direct access to the CNS than if they had been administered by routes that encounter first-pass metabolism. A variety of intranasal therapeutics have been clinically tested or approved for use in humans [10]

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