Abstract
We attempted to prepare ophthalmic in situ gel formulations containing lanosterol (Lan) nanoparticles (LA-NPs/ISG) and investigated the characteristics, delivery pathway into the lens, and anti-cataract effects of LA-NPs/ISG using SCR-N (rats with slight lens structure collapse) and SCR-C (rats with a combination of remarkable lens structure collapse and opacification). LA-NPs/ISG was prepared by bead milling of the dispersions containing 0.5% Lan powder, 5% 2-hydroxypropyl-β-cyclodextrin, 0.5% methylcellulose, 0.005% benzalkonium chloride, and 0.5% mannitol. The particle size distribution of Lan was 60–250 nm. The LA-NPs/ISG was gelled at 37 °C, and the LA-NPs/ISG was taken into the cornea by energy-dependent endocytosis and then released to the intraocular side. In addition, the Lan contents in the lenses of both SCR-N and SCR-C were increased by the repetitive instillation of LA-NPs/ISG (twice per day). The space and structure collapse in the lens of SCR-N with aging was attenuated by the instillation of LA-NPs/ISG. Moreover, the repetitive instillation of LA-NPs/ISG attenuated the changes in cataract-related factors (the enhancement of nitric oxide levels, calpain activity, lipid peroxidation levels, Ca2+ contents, and the decrease of Ca2+-ATPase activity) in the lenses of SCR-C, and the repetitive instillation of LA-NPs/ISG delayed the onset of opacification in the SCR-C. It is possible that the LA-NPs/ISG is useful in maintaining lens homeostasis.
Highlights
A cataract is a form of ophthalmic disease involving the collapse of tissue structure via crystallin aggregation and lens opacification by excessive collapse, and it is the leading global cause of human blindness
Researchers recently demonstrated that lanosterol (Lan), which is a key early rate-limiting step in the biosynthesis of cholesterol, disrupted the aggregation of γD-crystalline by binding to the hydrophobic dimerization interface in humans [5], and it played a key role in the prevention of cataract formation in animal models [6]
We found that energy-dependent endocytosis was related to the transcorneal penetration of ophthalmic formulations containing nanoparticles [16,18], and the instillation of ophthalmic formulations containing nanoparticles can deliver the drug into the lens [18]
Summary
A cataract is a form of ophthalmic disease involving the collapse of tissue structure via crystallin aggregation and lens opacification by excessive collapse, and it is the leading global cause of human blindness. Researchers recently demonstrated that lanosterol (Lan), which is a key early rate-limiting step in the biosynthesis of cholesterol, disrupted the aggregation of γD-crystalline by binding to the hydrophobic dimerization interface in humans [5], and it played a key role in the prevention of cataract formation in animal models [6]. Eye drops are accepted by many patients because of their safety and simplicity, and they are considered the preferred route for therapy of ophthalmic diseases. The low bioavailability of eye drops is a problem in cataract therapy. The barriers of the tear film and cornea are related to topical ocular drug delivery [7], and it is important to design a drug delivery system to improve bioavailability
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