Nanoparticle formulations that allow for sustained delivery and brain targeting of the neuropeptide oxytocin

Abstract

Oxytocin is a promising candidate for the treatment of social-deficit disorders such as Autism Spectrum Disorder, but oxytocin cannot readily pass the blood-brain barrier. Moreover, oxytocin requires frequent dosing as it is rapidly metabolized in blood. We fabricated four polymeric nanoparticle formulations using poly(lactic-co-glycolic acid) (PLGA) or bovine serum albumin (BSA) as the base material. In order to target them to the brain, we then conjugated the materials to either transferrin or rabies virus glycoprotein (RVG) as targeting ligands. The formulations were characterized in vitro for size, zeta potential, encapsulation efficiency, and release profiles. All formulations showed slightly negative charges and sizes ranging from 100 to 278 nm in diameter, with RVG-conjugated BSA nanoparticles exhibiting the smallest sizes. No formulation was found to be immunogenic or cytotoxic. The encapsulation efficiency was ≥ 75% for all nanoparticle formulations. Release studies demonstrated that BSA nanoparticle formulation exhibited a faster initial burst of release compared to PLGA particles, in addition to later sustained release. This initial burst release would be favorable for clinical dosing as therapeutic effects could be quickly established, especially in combination with additional sustained release to maintain the therapeutic effects. Our size and release profile data indicate that RVG-conjugated BSA nanoparticles are the most favorable formulation for brain delivery of oxytocin.

The role of oxytocin in regulation of appetitive behaviour, body weight and glucose homeostasis

“…In some cases, modifications have been made to the disulfide bond (essential for biological activity) to alter its activity and stability. Recent findings indicate that when encapsulated into a nanoparticle formulation, OXT may have improved stability and passage across the BBB . One other modification has been to replace the Pro 7 of OXT with either N ‐( p ‐fluorobenzyl)glycine or N ‐(3‐hydroxypropyl)glycine, which yielded long‐lasting effects in an animal model of social behaviour .…”

Omega-3 Fatty Acids as Druggable Therapeutics for Neurodegenerative Disorders

“…Moreover, although these studies provide a compelling basis for the use of dietary O3FA for neurodegenerative disorders, the use of natural compounds for neurodegenerative disorders is often limited by their poor bioavailability and limited penetration across the BBB. The recent development of targeted CNS drug delivery systems [66][67][68] has aided in improving the CNS bioavailability of natural compounds such as O3FA [69,70]. In addition, molecular docking studies with natural compounds have also helped in better characterizing ligand/receptor interactions and selecting compounds with higher activity at desired targets, thereby aiding the development of natural products against neurodegenerative disorders [71].…”

Oxytocin Receptor Signaling in Vascular Function and Stroke

“…While rodent and non-human primate studies have found no long-term negative consequences, the delivery of OXT or an analog has not been tested and the chance of hemorrhagic transformation in stroke means it could be highly dangerous to use for this specific application (Choi et al, 2011;Downs et al, 2015). Finally, the use of nanoparticles as a carrier method to enhance BBB penetrance of peptides is an exciting addition to therapeutic research that could revolutionize CNS drug delivery including OXT or an OXTR agonist (Zaman et al, 2018;Oppong-Damoah et al, 2019). While further investigation is needed, there is hope this can provide an effective, noninvasive, and safe option for OXTR modulation.…”