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Multifunctional Carboxymethyl Chitosan Derivatives-Layered Double Hydroxides Hybrid Nanocomposites for Efficient Drug Delivery to the Posterior Segment of the Eye

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Document pages: 50 pages

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 hydroxides (LDH) and functional carboxymethyl chitosan (CMCS) derivatives was designed. Special substrates of peptide transporter-1 (Pept-1) and glutathione was modified on CMCS, respectively. CMCS-glutathione-glycylsarcosine (CMCG-GS) or CMCS-glutathione-valyl-valine (CMCG-VV)-LDH hybrid nanocomposites were prepared and structurally confirmed. The in vitro experiments on human conjunctival epithelial cells showed non-cytotoxicity (LDH concentration ≤ 100.0 μg mL) and enhanced permeability for the 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 AUC0-6h, 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 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 administrated drug delivery to the posterior segment of the eye.

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