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

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.

Neuroinflammation Treatment via Targeted Delivery of Nanoparticles

“…Deeper understanding of neuroinflammatory pathways and CNS cellular biology have led to the development of methods to modify nanoparticle surface with ligands that increase cell specificity and CNS penetration. These include modifications with integrin-binding peptides (Juthani et al, 2020), antibodies (Cerqueira et al, 2012), psychostimulant or psychotropic drugs (Aparicio-Blanco et al, 2019;Saha et al, 2020), B-CNS-B receptor ligands (Hoyos-Ceballos et al, 2020), and neurotropic viruses (Chung et al, 2020). Surface functionalization to improve cell-specificity has been performed on a variety of nanoparticles including liposomes, inorganic nanoparticles, polymeric nanoparticles, and dendrimers (Charabati et al, 2019).…”

Intranasal 17β-Estradiol Modulates Spatial Learning and Memory in a Rat Model of Surgical Menopause

“…In general, the greatest E2 delivery to each brain area was observed at the earliest time point collected, 0.5 h, followed by a rapid decrease for each treatment formulation. E2 concentration in the trigeminal nerves, one of the potential pathways for agent uptake into the brain with intranasal delivery [ 20 ], tended to have slower clearance across the three evaluated time points as compared to the olfactory bulbs, another potential pathway for agent uptake into the brain with intranasal delivery ( Figure 2 ). Focusing on the two regions of interest, E2 in the dorsal hippocampus 0.5 h following Treatment C administration was significantly greater than that of Treatment A ( p < 0.05; Figure 4 ).…”

“…The intranasal route of administration circumvents first-pass metabolism and can facilitate specific accumulation of agents in brain versus peripheral tissue compared to other administration routes, including subcutaneous, oral, and intravenous [ 16 , 17 , 18 , 19 , 20 ]. Several clinical trials have evaluated the efficacy of intranasal administration of multiple types of hormones (e.g., oxytocin, testosterone, E2, gonadotropins) to treat vasomotor symptoms, infertility, voice quality, and other target symptoms [ 21 , 22 , 23 , 24 , 25 , 26 ].…”

Poly(lactic-co-glycolic Acid) Nanoparticle Encapsulated 17β-Estradiol Improves Spatial Memory and Increases Uterine Stimulation in Middle-Aged Ovariectomized Rats

“…Our goal was to develop better E2 delivery approaches that will maximize the potential of hormone therapy in menopause. Here, we focused on poly(lactic-co-glycolic) acid (PLGA) nanoparticles as customizable drug carriers (Chasin and Langer, 1990;Danhier et al, 2012;Fazil et al, 2012;Cook et al, 2015;Householder et al, 2015;Mir et al, 2017;Prakapenka et al, 2017;Chung et al, 2020). PLGA is biocompatible, biodegradable, and FDAapproved for use in the clinic in both implanted and injectable forms (Chasin and Langer, 1990;Anderson and Shive, 1997;Danhier et al, 2012).…”

“…For instance, surfacemodification of E2 PLGA nanoparticles with Tween R 80 was found to significantly increase E2 levels in the brain relative to non-surface-modified E2 PLGA nanoparticles (Mittal et al, 2011). We have studied peptide strategies for achieving active targeting of hydrophobic molecules across the blood brain barrier (Cook et al, 2015;Chung et al, 2020); such a strategy could eventually be used to design a brain-selective hormone therapy.…”