A Hybrid Genipin-Cross-Linked Hydrogel/Nanostructured Lipid Carrier for Ocular Drug Delivery: Cellular, ex Vivo, and in Vivo Evaluation

We developed a hybrid nanostructured lipid carrier/dual pH- and thermo-sensitive hydrogel (NLC-Gel) for ocular delivery of quercetin (QN). The hydrogel consisted of carboxymethyl chitosan (CMCS) and poloxamer 407 (P407) was crosslinked using a naturally occurring crosslinker genipin (GP), while the hydrogel crosslinked using glutaraldehyde (GA) as a control. NLC loaded with quercetin/hydrogel crosslinked by genipin hybrid drug delivery system (QN-NLC-Gel-GP) exhibited better cytocompatibility and lower ocular irritation than its glutaraldehyde counterpart. The levels of cellular uptake in NLC and NLC-Gel groups were improved. The results of fluorescence imaging and ex vivo transcorneal study indicated NLC could facilitate transcorneal penetration of lipophilic molecules and incorporation into the hydrogel could increase precorneal residence time of NLC. Area under the curve (AUC) of quercetin in NLC-Gel group was 4.4-fold versus that in eye drops group, because of longer precorneal retention time. In summ...