Insight into the Effect of Nanoparticles Physicochemical Properties on Ocular Uptake and Transport

Abstract

The growing population of people suffering from various eye disease has become a concern for ophthalmologists and drug delivery scientists. Currently, the majority of marketed ophthalmic formulations are in the form of topical eye drops. Despite the popularity among the patients, topical formulations suffer from low bioavailability resulting from short residence time on the surface of the eye and poor penetration into ocular tissue due to presence of ocular surface barriers. To overcome the limitations of conventional topical formulations, nanoparticles drug delivery systems have attracted attention for enhancing therapeutic efficacy of ocular formulations by providing prolonged retention on the surface of the eye, improved permeability into intraocular tissues, sustained release of drug, and targeted therapy. Although various types of nanoparticles have been considerably investigated for ocular drug delivery applications, there is still a knowledge gap in understanding of how the physicochemical properties of nanoparticles affect the uptake and transport process into the ocular tissues. Also, the dominant mechanisms of nanoparticle entry into the eye through the corneal route is not fully understood. To address the current gap, this research explores the effect of nanoparticles size and surface chemistry on cellular uptake and its mechanisms as well as transport into the eye. To achieve this goal, PLGA nanoparticles of varying size within the applicable range for topical ocular drug delivery (100, 150, 200, 250 nm) were fabricated and surface modified with anionic and cationic mucoadhesive polymers (PLGA/ALG NPs and PLGA/CHS NPs) and non-ionic mucopenetrative polymer (PLGA/PEG) to create a variety of surface chemistries with wide range of surface charge. Nanoparticles physicochemical properties were characterized in terms of size, zeta potential, morphology, colloidal stability, and in vitro interaction with simulated ocular solution. An in vitro model of ocular surface barriers based on immortalized human cornea epithelial cells integrated with simulated mucosal solution were employed for in vitro evaluation of nanoparticles interactions cornea and tear film. Prior to any interaction with the cells, nanoparticles cytotoxicity was studied using colorimetric MTT assay to investigate the tolerability of cornea cells to different concentrations of nanoparticles. The in vitro model was also employed to study the uptake and uptake mechanisms of nanoparticles by the cornea cells and how different experimental conditions including time, temperature, and nanoparticles concentrations affect the uptake process. Once the energy dependency of nanoparticle uptake by the cornea cells were confirmed, pharmacological endocytosis inhibitors were applied to the in vitro model for direct probing of dominant endocytosis pathways. In addition, an ex vivo model ocular surface barriers were established using freshly excised porcine cornea and simulated mucosal solution to evaluate nanoparticles transcorneal permeation and distribution into the cornea tissue. This research provides solid foundation for design of nanoparticle-based ocular drug delivery system with desirable physicochemical properties with potential capability to improve the delivery process into the eye through the corneal route by targeting specific and dominant internalization pathway.