(265e) Fabrication of in Situ Gelling Formulations for the Topical Treatment of Age-Related Macular Degeneration

The World Health Organization estimates that in 2020 there were around 196 million people with age-related macular degeneration (AMD), which has become the leading cause of blindness in patients over 65 years of age [1]. This posterior eye segment disease is characterized by the development of vascularization at the choroid, the vascular bed of the retina. This neovascularization leads to the development of serious complications including macular edemas and retinal hemorrhages that can severely damage photoreceptors and therefore seriously impair a patient’s vision. Its current and only 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 from marginalized communities since the injections are extremely expensive, thus creating an important source of inequity in eyecare access [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]. Therefore, current research has shifted focus to the use of smart polymeric formulations in combination with nanotechnology to enhance ocular bioavailability. In this work, our goal is to develop a topical drug delivery platform for the treatment of posterior eye segment diseases like AMD. By leveraging mucoadhesive and environmentally responsive polymeric biomaterials in combination with anionic nanoparticles we seek to enhance ocular bioavailability 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 at body temperature (37 °C) was modulated to exhibit the same transition at the surface temperature 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 evaluated for optical transparency using ultraviolet-visible spectroscopy. To determine the impact of Pluronic F1-27 concentration on the gelling temperature of the formulations, four different concentrations were tested and the impact of adding a mucoadhesive agent on the dynamic viscoelastic behavior of the formulations was studied using rheometry. With this same technique, the viscosity of the formulations was measured to ensure all formulations remained below thresholds for ocular tolerance. Similarly, self-assembled anionic nanoparticles were synthesized as potential anti-VEGF nanocarriers via carbodiimide coupling of hyaluronic acid (HA) and perfluoroheptanoic acid (PFHA). Feed ratios of HA:PFHA were varied and their impact on nanoparticle size and charge was studied using dynamic light scattering. Future work will seek to develop a library of nanoparticles that can be combined with the in situ gel formulations to deliver ocular therapeutic agents of varying molecular weight such as ranibizumab (48kDa) and bevacizumab (149 kDa) [3]. 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.