Multifunctional carboxymethyl chitosan derivatives-layered double hydroxide hybrid nanocomposites for efficient drug delivery to the posterior segment of the eye

Abstract

Efficient ocular drug delivery to the posterior segment of the eye by topical administration is a great challenge to pharmacologists. To explore drug delivery system of organic-inorganic hybrid nanocomposites for the efficient delivery of dexamethasone disodium phosphate (DEXP), a targeted hybrid nanocomposite based on layered double hydroxide (LDH) and functional carboxymethyl chitosan (CMCS) derivatives was designed. A special substrate of peptide transporter-1 (PepT-1) and glutathione was modified on CMCS. CMCS-glutathione-glycylsarcosine (CMCG-GS) and CMCS-glutathione-valyl-valine (CMCG-VV)-LDH hybrid nanocomposites were prepared and structurally confirmed. The in vitro experiments on human conjunctival epithelial cells showed noncytotoxicity (LDH concentration ≤100.0 µg/mL) and enhanced permeability for hybrid nanocomposites. Additionally, cellular uptake of the CMCG-GS-DEXP-LDH (10:1) nanocomposite eye drops involved clathrin-mediated endocytosis and PepT-1 mediated actively targeting transport. Results of the in vivo precorneal retention study showed an 8.35-fold, 2.87-fold and 2.58-fold increase of AUC0–6 h, Cmax and MRT for CMCG-GS-DEXP-LDH (10:1) hybrid nanocomposite eye drops, respectively, compared to that of the commercial product. Fluorescence imaging of fluorescein isothiocyanate isome (FITC)-loaded LDH hybrid nanocomposites demonstrated that FITC could diffuse into the choroid-retina with the shelter of LDH and CMCG-GS. The presence of a strong fluorescence signal of FITC-conjugated LDH hybrid nanocomposites in the sclera revealed that integral LDH nanocarrier reached the sclera. In the tissue distribution evaluation of rabbit's eyes, DEXP of CMCG-GS-DEXP-LDH (10:1) nanocomposites group retained in the target of the choroid-retina for 3 h with final concentration at 120.04 ng/g. Furthermore, the results of fluorescence imaging and tissue distribution suggested that the intraocular transport pathway for the hybrid nanocomposites is the conjunctival-scleral route. Consequently, the developed hybrid nanocomposites offer a simple and efficient strategy for topically administered drug delivery to the posterior segment of the eye. Statement of SignificanceEfficient ocular drug delivery to the posterior segment of the eye by topical administration is a great challenge to pharmacologists. In this manuscript, hybrid nanocomposite based on layered double hydroxide (LDH) and functional carboxymethyl chitosan (CMCS) derivatives were designed. The multifunctional properties of these hybrid nanocomposites were attributed to active targeting, bioadhesive capacity and penetration enhancement. Visualization of transport routes of fluorescein isothiocyanate-conjugated LDH hybrid nanocomposites demonstrated that the integral LDH nanocarrier reached the sclera through the conjunctival-scleral pathway, and the loaded drug could further diffuse to the retina. The multifunctional CMCS derivatives-LDH hybrid nanocomposites could be applied for the efficient drug delivery to the posterior segment of the eye through noninvasive topical instillation.