(483e) Topical Drug Delivery Formulations for Treatment of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) has become the leading cause of blindness in patients over 65 years of age and is estimated to currently affect over 190 million patients worldwide [1]. The wet form of AMD is characterized by the development of vascularization at the choroid, the vascular bed of the retina, which leads to the development of serious complications including macular edemas and retinal hemorrhages. These can severely damage photoreceptors and therefore seriously impair a patient’s vision, significantly lowering their quality of life. Its current form of treatment is through monthly intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) to slow down retinal blood vessel growth. However, in addition to being highly inconvenient and uncomfortable, intravitreal injections also pose a significant financial burden to patients and a barrier to access for those from marginalized communities since the injections are extremely expensive and must be administered in a clinical setting [2,3]. As a result, topical treatments for AMD have been sought after as a less invasive and more accessible alternative. However, a key challenge to this treatment form is that the bioavailability of drugs administered to the eye via topical formulations is very low, with only 5-10% of the active therapeutic entering the eye [4]. To solve this, current research has shifted focus to the use of smart polymeric formulations in combination with nanotechnology to enhance ocular bioavailability. In this work, we develop a topical drug delivery platform for the treatment of posterior eye segment diseases like AMD. By leveraging mucoadhesive and stimuli-responsive polymeric biomaterials in combination with anionic nanoparticles, we seek to enhance ocular bioavailability of drugs and ultimately deliver therapeutic agents to the posterior segment of the eye via the less invasive topical route.

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. The ability of this material to undergo a phase transition in response to changes in temperature was finely modulated to exhibit such transition at the temperature of the surface of the eye (35 °C). Chitosan, alginate, and poly(acrylic acid) were selected as mucoadhesive agents and were mixed with the Pluronic F-127 material at 2 different concentrations to obtain mucoadhesive and temperature sensitive formulations. The formulations were characterized using ultraviolet-visible spectroscopy and rheology to assess both the viscoelastic behavior of the formulations and their optical properties. Similarly, Poly(lactic-co-glycolic) acid (PLGA) and hyaluronic acid (HA)-based nanoparticles were synthesized and fabricated via self-assembly as promising anti-VEGF nanocarriers. Feed ratios of hydrophilic to hydrophobic blocks of the copolymers were varied and their impact on nanoparticle size and charge was studied using dynamic light scattering. Additionally, both PLGA and HA nanoparticles were loaded with fluorescein isothiocyanate-tagged bovine serum albumin (FITC-BSA) as a model molecule of anti-VEGF. Loaded particles were used to evaluate loading efficiency and protein release using UV-Vis. Finally, the cytocompatibility and efficacy of the system was evaluated using human corneal epithelial cells in vitro. The results of this work show promise in creating a topical ocular drug delivery platform that can be used for posterior eye segment diseases like Age-Related Macular Degeneration which affect millions of people worldwide.

This work was supported by the NIH (R01-EB022025), the Cockrell Family Chair Foundation, the Office of the Dean of the Cockrell School of Engineering at the University of Texas at Austin (UT) for the Institute for Biomaterials, Drug Delivery, and Regenerative Medicine, and the UT-Portugal Collaborative Research Program. JJR-C was supported by the National Science Foundation Graduate Research Fellowship under Grant No. 2137420.

References

[1] World Health Organization, World report on vision, (2019).

[2] J. Silver, Drugs for Macular Degeneration, Price Discrimination, and Medicare’s Responsibility Not to Overpay, JAMA. 312 (2014) 23–24. https://doi.org/10.1001/jama.2014.6672.

[3] Ranibizumab (Lucentis) versus bevacizumab (Avastin): modelling cost effectiveness | British Journal of Ophthalmology, (n.d.). https://bjo.bmj.com/content/91/9/1244.long (accessed December 7, 2022).

[4] G. Orive, E. Santos-Vizcaino, J.L. Pedraz, R.M. Hernandez, J.E. Vela Ramirez, A. Dolatshahi-Pirouz, A. Khademhosseini, N.A. Peppas, D.F. Emerich, 3D cell-laden polymers to release bioactive products in the eye, Progress in Retinal and Eye Research. 68 (2019) 67–82. https://doi.org/10.1016/j.preteyeres.2018.10.002.