(187at) Injectable Thermosensitive Drug Delivery Platform for Use in Trauma Applications

Traumatic Optic Neuropathy (TON) is a rare neurodegenerative condition that develops because of trauma, primarily to the head or face, and is mainly characterized by injury to the optic nerve. Occurring in 0.5% to 5% of head injuries, TON affects both civilians (due to falls or accidents) and soldiers (blast-related injuries). Current management options have very limited evidence of success and include observation without any treatment, optic nerve decompression surgery, and high-dose corticosteroids. However, to date, there is no clear consensus on the optimal treatment strategy and their success remains controversial. With a recent push towards individualized TON treatment, research has focused on targeting TON pathological hallmarks using neuroprotective agents, anti-inflammatory compounds, RNAs for axon regeneration, and stem cell transplantation. While these are trying to target a single aspect of TON on their own, novel drug delivery systems show promise in strategically and simultaneously reducing reactive oxygen species (ROS) levels, inflammation, and axon degeneration. Therefore, there is a clear clinical opportunity to develop innovative treatments tailored to individual TON cases.

In this work, we fabricated and characterized an injectable drug delivery platform using Pluronic F127 and hyaluronic acid-based nanoparticles capable of scavenging reactive oxygen species (ROS). In situ gel formulations were fabricated using Pluronic F-127, a triblock co-polymer of Poly(ethylene oxide)-poly(propylene oxide)- poly(ethylene oxide), as a temperature sensitive material. Chitosan, alginate, and poly(acrylic acid) were selected as viscosity enhancing agents and were mixed individually with Pluronic F-127 at 1% w/w each. Pluronic F-127 concentrations were used at 12-20% (w/w). All fabricated formulations were evaluated for optical transparency using ultraviolet-visible spectroscopy. Similarly, to determine the impact of Pluronic F-127 concentration on the gelling temperature of the formulations, the dynamic viscoelastic behavior of the formulations was studied using rheology. Additionally, a copolymer of hyaluronic acid (HA) and poly(propylene sulfide) (PPS) was synthesized to form self-assembled nanoparticles. The copolymer synthesis was confirmed using ¹H NMR and the size and zeta potential of the nanoparticles was evaluated with dynamic light scattering. The ROS scavenging behavior of the nanoparticles was evaluated in vitro along with loading and release of small molecular weight cargo.

The gelling temperature of the biomaterial formulations decreased as the concentration of Pluronic F-127 increased. The formulations consisting of Pluronic F-127 with Chitosan and Pluronic F127 with poly(acrylic acid) exhibited fine tunability of their gelling points as Pluronic F-127 concentration increased. Similarly, all formulations exhibit a shear thinning behavior which makes them suitable as an injectable formulation through needles like the ones used in intravitreal injections. The formulations also exhibited controlled release of methylene blue as a model therapeutic and was dependent on the concentration of polymers used. Lastly, all the formulations exhibited excellent optical properties with light transmittance values above 80%. The nanoparticles fabricated are monodisperse and exhibit hydrodynamic sizes ranging from 100-280 nm.

Developing smart biomaterial formulations with excellent optical properties and tunable thermoresponsive behavior is a critical milestone in the development of drug delivery platforms used for TON. The results of this work show promise in creating an injectable thermosensitive formulation that could be used as a drug delivery platform for TON. Current and future work seeks to investigate drug loading and release from the in situ gels and nanoparticles with multiple therapeutic agents in a retinal cell model to achieve co-delivery of therapeutic agents.

Acknowledgements

This work is supported by funding from the Trauma Research and Combat Casualty Care Collaborative, An Initiative of the University of Texas System. JJR-C is supported by the NSF GRFP under Grant No. 2137420.