Table 3.

Immunomodulatory agents using nanotechnology-based drug delivery systems for allergic conjunctivitis.

Experimental Models	Drug	Findings
Excised rabbit corneas [77]	Tacrolimus loaded PLGA nanoparticles (PLGA-NPs) via topical eye drops	Enhanced transcorneal uptake of tacrolimus. The t1/2 of tacrolimus carried by PLGA-NPs was 1.77-fold greater than conventional eye drops while more than two-fold higher of AUC0-inf, AUMC0-inf and MRT0-inf were detected in aqueous humor samples. Effective concentration in cornea and conjunctiva was able to be maintained at 24 h after topical instillation. No adverse effects observed clinically in corneas, conjunctiva, and iris.
Ex-vivo goat eyes for transcorneal permeation study; Rabbits for precorneal retention study [67]	Proglycosomes modified liposomal tacrolimus topical eye drops	5-fold and 13-fold corneal permeation than conventional liposomes and tacrolimus eye drops, respectively. Incorporation of proglycosomes enhanced the drug encapsulation, decreased the vesicle aggregation and increased the liposomal elasticity, thereby enhancing the transocular permeation. Tear samples exhibited prolonged precorneal retention for up to 8 h, with improved intraocular drug levels which exceeded therapeutic levels.
Rabbit corneal epithelial cells for in-vitro study Rabbit corneas for ex-vivo study [79]	Cyclosporin (CsA)-loaded solid lipid nanoparticles	High encapsulation efficiency at 95.6%. The CsA release was lipase/co-lipase complex dependent. The solid lipid nanoparticles improved penetration of CsA across the excised rabbit corneas.
Phase III, multicenter, randomized, double-masked, vehicle-controlled trial [42]	CsA cationic nanoemulsion eye drops	CsA cationic emulsions significantly improved patients’ symptoms, signs and quality of life after 4 months’ course of treatment in both high-dose (four times daily) and low-dose (twice daily) groups compared to vehicle group.
In-vitro study in human corneal epithelial cells; in vivo study in rabbits [37]	CsA-loaded mPEG-PLA nanomicelles via topical instillation	High encapsulation efficiency of CsA nanomicelles of 98.51% with an average particle size of 57 nm. The stability was greatly influenced by the light and temperature. Initial quick drug release of about 73% for 36 h, followed by a prolonged release up to 92 h, achieving total drug release close to 89%. No inflammatory response on cornea, conjunctiva, sclera or iris, but significant in vitro cytotoxicity was present after 24 h of incubation with corneal epithelial cells.

Abbreviation: mPEG-PLA: lyophilized methoxy poly(ethylene glycol)-poly(lactide).