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 and poloxamer 407 (P407) was cross-linked using a naturally occurring cross-linker genipin (GP), while the hydrogel cross-linked using glutaraldehyde was used as a control. NLC loaded with quercetin/hydrogel cross-linked by a 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 that NLC could facilitate transcorneal penetration of lipophilic molecules and incorporation into the hydrogel could increase the precorneal residence time of NLC. The area under the curve of quercetin in the NLC-Gel group was 4.4-fold that in the Eye drops group because of a longer precorneal retention time. In summary, the developed drug delivery system has enormous potential for ophthalmic applications.