Influence of the Size and Charge of Carbon Quantum Dots on Their Corneal Penetration and Permeation Enhancing Properties

Abstract

Reaching the corneal endothelium through the topical administration of therapeutic drugs remains a challenge in ophthalmology. Besides, endothelial cells are not able to regenerate, and diseases at this site can lead to corneal blindness. Targeting the corneal endothelium implies efficient penetration through the three corneal layers, which still remains difficult for small molecules. Carbon quantum dots (CQDs) have demonstrated great potential for ocular nanomedicine. This study focuses on the corneal penetration abilities of differently charged CQDs and their use as permeation enhancers for drugs. Excised whole bovine eyes were used as an ex vivo model to investigate corneal penetration of CQDs derived from glucosamine using β-alanine, ethylenediamine, or spermidine as a passivation agent. It was found that negatively charged CQDs have limited corneal penetration ability, while positively charged CQDs derived from glucosamine hydrochloride and spermidine (CQD-S) penetrate the entire corneal epithelium all the way down to the endothelium. CQD-S were shown to enhance the penetration of FITC-dextran 150 kDa, suggesting that they could be used as efficient penetration enhancers for therapeutic delivery to the corneal endothelium.

Enhancing paracellular and transcellular permeability using nanotechnological approaches for the treatment of brain and retinal diseases

“…1) acts as a natural protection against microorganisms and confers mechanical stability to the eye; it is a highly complex structure made of different Corneal stroma is a highly hydrophilic tissue allowing the diffusion of hydrophilic drugs up to 500 kDa layers. 26 The cornea, a transparent and avascular tissue with an average thickness of 500 mm in humans consists of several layers: (i) the corneal epithelium consisting of flattened superficial cells, wing cells, and columnar basal cells, (ii) Bowman's layer, (iii) the corneal stroma, (iv) the Descemet's membrane and (v) the corneal endothelium. Drug delivery is restricted in the cornea due to the presence of intercellular TJs between epithelial and endothelial cells, completely hindering the diffusion of macromolecules via the paracellular route.…”

In Vitro and Ex Vivo Models for Assessing Drug Permeation across the Cornea

“…Using confocal microscopy, the presence of nanoparticles in the cornea was determined. Monitoring the intensity of fluorescence in the full-thickness cornea allowed for the detection of particle penetration in various layers of the cornea . It could be demonstrated that positively charged spermidine-derived carbon quantum dots (CQDs) were able to penetrate the corneal epithelium and reach the deepest layer of the cornea, the endothelium.…”

“…114 More recently, our research group used an ex vivo bovine whole-eye model (Figure 12B) for corneal penetration studies of nanoparticles, in conjugation with confocal microscopy. 160 Fresh bovine eyes were collected at a local slaughterhouse and transported in a cold, CO 2 -independent medium. The cornea was prepared for analysis by cleaning the whole bovine eye and removing excess tissue.…”

“…Monitoring the intensity of fluorescence in the full-thickness cornea allowed for the detection of particle penetration in various layers of the cornea. 160 It could be demonstrated that positively charged spermidine-derived carbon quantum dots (CQDs) were able to penetrate the corneal epithelium and reach the deepest layer of the cornea, the endothelium. Furthermore, these CQDs could be used as permeation enhancers to deliver macromolecules such as FITC dextran 150 kDa in the corneal endothelium.…”

“…Furthermore, these CQDs could be used as permeation enhancers to deliver macromolecules such as FITC dextran 150 kDa in the corneal endothelium. 160 The lack of perfusion lines mimicking aqueous humor circulation and tear flow is a limitation for investigating particle penetration of the cornea in these whole-eye models. Kutlehria et al 161 developed a whole-eye perfusion model, in which porcine eyes were perfused in the anterior chamber with KSF (keratinocyte serum-free) medium designed to mimic the aqueous humor.…”