Ten Years of Knowledge of Nano-Carrier Based Drug Delivery Systems in Ophthalmology: Current Evidence, Challenges, and Future Prospective

Figures & data

Figure 1 Structural particularities of the eye. The eye can be divided into two parts of the anterior segment and the posterior segment. There are many barriers to drug delivery to the retina. Drugs cannot be easily delivered to the retina by topical administration, such as eye drops, because of the presence of tear drainage and peribulbar and choroidal blood flow. In contrast, systemically administered drugs rarely enter the retina because of the presence of the blood - aqueous barrier and the inner and outer blood-retinal barriers.

Figure 2 Electrospun nanofibers - A promising solid in-situ gel. (A) The diagram of study on electrospun nanofibers; (B) 3D diagram of the spinning solution composition and the product characteristics; (C) 3D X-ray images of the electrospun nanofibers: (black) grayscale and (color) fiber size distribution image with scale bar; (D) overlay of regular (photo) and fluorescence images of porcine eyes treated with fluorescein sodium eye drops (5 µg/mL) (left), and with pullulan-gellan gum nanofiber lens (0.0001% fluorescein sodium) (right) after different spray applications. Reprinted from Eur J Pharm Biopharm, 146, Göttel B. Electrospun nanofibers - A promising solid in-situ gelling alternative for ocular drug delivery, 125–132, Copyright 2020, with permission from Elsevier.⁷²

Table 1 Nanocarriers to Deliver Anti-Conjunctivitis Agents

Study	Drug	Vehicle/Carriers	Production Method(s)	Results	Conclusion
E. Sanchez-Lopez, et al^Citation159 2020	Dexibuprofen	PLGA^⁎ nanoparticles	Solvent displacement method	Polyethylene glycol (PEG) increased the interaction between Dexibuprofen-NPs and customized corneal membrane.	These formulations containing DXI PLGA 15% PEG prepared using Lutrol as a surfactant were able to release DXI more effectively for the treatment of ocular inflammation.
X. Gai, et al^Citation160 2018	Ibuprofen	Liposomal	Ethanol injection method	Ibuprofen cationic liposomes could significantly prolong the T max to 100 min and the AUC to 1.53-folds, which indicated that the ibuprofen cationic liposomes could improve the precorneal retention time and bioavailability of ibuprofen.	The ibuprofen cationic liposomes probably are a promising application in ocular drug delivery system.
Y. Xu, et al^Citation84 2017	Tacrolimus	PLGA nanoparticles	Emulsification-diffusion method	PLGA-NPs improved corneal, conjunctival and aqueous humor bioavailability of Tacrolimus.	The PLGA-NPs significantly enhanced ocular bioavailability of TAC than that of aqueous suspension.
V. Garg, et al^Citation85 2017	Tacrolimus	Proglycosomes	Film hydration method	Incorporation of proglycosomes enhanced the drug encapsulation, decreased the vesicle aggregation and increased the liposomal elasticity, thereby enhancing the transocular permeation.	The developed proglycosomes are prospective carriers for enhanced ocular delivery of tacrolimus.
H. Chen, et al^Citation82 2016	Flurbiprofen	Chitosan-coated liposomal	Modified ethanol injection method	Flurbiprofen-loaded deformable liposomes could prolong pre-corneal retention and improve transcorneal penetration. Edge activator, Solutol HS-15, could potentiate its flexibility and penetrability.	Chitosan-coated deformable liposomes appear to be a novel ophthalmic drug delivery system with the potential to overcome the limitations of conventional eye drops.

Abbreviation: ⁎PLGA, poly (lactic-co-glycolic acid).

Figure 3 Tacrolimus is a common immune modulator that has been loaded onto Poly(lactic-co-glycolic acid) nanoparticle. Hypothetical representation of the location of propylene glycol in the vesicles and its effects as a novel drug delivery system for tacrolimus. Reprinted from Colloids Surf B Biointerfaces, 157, Garg V, Suri R, Jain GK, Kohli K. Proglycosomes: a novel nano-vesicle for ocular delivery of tacrolimus, 40–47, Copyright 2017, with permission from Elsevier.⁸⁵

Abbreviation: PNVs, Proglycosomes nano-vesicles.

Table 2 Nanocarriers to Deliver Anti-Dry Eye Agents

Study	Experimental Models	Drug	Vehicle/Carriers	Production Method(s)	Results	Conclusion
N. Nagai, et al^Citation93 2020	N-acetylcysteine-treated rabbit model	Rebamipide	Nanoparticles	Breakdown method	The rebamipide solid nanoparticle-based ophthalmic formulation increased mucin levels in the lacrimal fluid and healed tear film breakup levels in vivo.	This novel sustained-release drug delivery route and creation of a nano-formulation can be used to design further studies aimed at therapy for dry eye.
F. Yu, et al^Citation161 2019	Dry eye murine model	Glycol chitosan cerium oxide	Nanoparticles	Unspecified	Glycol chitosan cerium oxide nanoparticles not only ameliorate symptoms but also reverse pathological changes at the cellular and molecular levels in dry eye.	Glycol chitosan cerium oxide nanoparticles are an effective treatment for dry eye and may represent a potential new class of drug for dry eye disease.
Y. J. Li, et al^Citation92 2019	Rabbits model	Amfenac	Poly(catechin) capped-gold nanoparticles	Unspecified	Poly (catechin) capped-gold nanoparticles (Au@Poly-CH NPs) not only act as an anti-oxidant to suppress ROS-mediated processes, but also serve as a drug carrier of AF for a synergistic effect on anti-inflammation.	Au@Poly-CH NPs loaded with NSAIDs is a promising multifunctional nanocomposite for treating various inflammation- and oxidative stress-related diseases.
H. Y. Huang, et al^Citation162 2018	New Zealand White rabbits	Hyaluronic acid	Nanoparticles	Self-assembly method	Large amounts of gelatin-epigallocatechin gallate nanoparticles (GEH-NPs) accumulated in the cytoplasm of human corneal epithelium cells and the ocular surfaces of rats and rabbits, indicating the advantage of GEH NPs for ocular delivery of medication.	GEH NPs are potentially valuable as a new therapeutic agent delivered in eye drops for treating dry eye syndrome.
H. Kang, et al^Citation91 2016	New Zealand albino rabbits	Cyclosporine A	Micelle solutions	Simple method	The number of goblet cells in rabbit conjunctivas after the administration of cyclosporine A-micelle solutions was significantly higher than that with Restasis.	The potential use of a novel MS for the ophthalmic delivery of CsA in treating dry eyes.
C. Di Tommaso, et al^Citation163 2011	Female albino New Zealand rabbits	Cyclosporin A	polymeric micelles	Co-solvent method	After incubation with methoxy poly (ethylene glycol)-hexylsubstituted poly(lactides) (MPEG-hexPLA) micelle formulations, the activation of caspase-dependent and -independent apoptosis as well as autophagy was evaluated using immunohistochemistry for localizing antibodies	MPEG-hexPLA micelles are promising drug carriers for ocular diseases involving the activation of cytokines

Table 3 Nanocarriers to Deliver Anti-Glaucoma Agents

Study	Experimental Models	Drug	Vehicle/Carriers	Production Method(s)	Results	Conclusion	Future Direction
Schnichels S, et al^Citation164 2020	DBA/2J mice model	Travoprost	Lipid DNA nanoparticles	Self-assembly of DNA amphiphiles	Travoprost nanoparticles deliver at least twice the amount of the drug at every time-point investigated compared to the pristine drug.	There is applicability of a DNA-based drug delivery system in the field of ophthalmology for the treatment of glaucoma.	In the future, a combination therapy relying on DNA-based NPs and different aptamers might be feasible.
Orasugh JT, et al^Citation165 2019	In vitro gel	Pilocarpine	Cellulose nanocrystals	Acid hydrolysis process	Have higher sustained drug release and less toxicity.	Cellulose nanocrystals have a significant effect on the gelation behavior, gel strength, and drug release kinetics of poloxamer copolymer-cellulose nanocrystals formulations.	Unspecified
Sánchez-López E, et al^Citation102 2018	Morrison`s ocular hypertension model in Dark Agouti (DA) rats	Memantine	PLGA nanoparticles	Modification of the double emulsion solvent evaporation technique	Well tolerated in vitro (human retinoblastoma cells) and in vivo (Draize test); Reduced RGC loss in vivo.	Topical MEM-NP is safe, well tolerated, and, most promisingly, neuroprotective in an experimental glaucoma model.	Unspecified
Fahmy HM, et al^Citation166 2018	White albino rabbits	Latanoprost	Liposomes	Film hydration method	Reduced the IOP in glaucomatous white albino rabbits, which lasted for 8 hours.	Lip (LAT + TQ) and Lip (LAT) were the most effective tested formulations, which provided in vivo sustained drug release and showed the maximum IOP lowering effect up to 84 h as compared to other tested formulations.	None of the prepared liposome formulations succeeded in improving the glaucoma-induced oxidative stress damage.
Wang F, et al^Citation167 2018	White New Zealand rabbits	Brinzolamide	Nanoliposomes	Thin-film dispersion method	Reduced IOP in less than 1 hour, reached peak efficacy at 2 hours, and sustained release effect for 12 hours.	The HP-β-CD/BRZ loaded nanoliposomes might have a promising future as a NODDS for glaucoma treatment.	Further studies are still required to investigate the in vitro release properties of BCL and elucidate how the release profile affects the therapeutic efficacy of BCL.
Tan G, et al^Citation42 2017	New Zealand albino rabbits	Timolol maleate	Chitosan coated liposomes	Ammonium sulfate gradient coupled with a pH-gradient	Significantly reduced the IOP.	CHL is a potentially useful carrier for ocular drug delivery, which could improve the efficacy of TM.	The formulation reported here will be the subject of future studies aimed at improving its clinical use.
Rathod LV, et al^Citation168 2017	Goat eyes and albino rabbits	Acetazolamide	Nanoparticles	Solvent displacement method	Displayed better permeability and flow across corneal tissue in vitro.	The nanoparticles impregnated ocular inserts can act as potential platform for delivering drug to posterior segment of eye not only for glaucoma but also for other eye diseases.	Unspecified
Ikuta Y, et al^Citation169 2017	Male Sprague-Dawley rats	Brinzolamide	Nanoparticles	Reprecipitation method	Increases the eye penetration rate and resulted in high drug efficacy.	The nano-eye-drops may have applications as a next-generation ophthalmic treatment.	Unspecified
Kouchak M, et al^Citation170 2016	Albino rabbits	Dorzolamide hydrochloride	Nanoliposomes	Reverse-phase evaporation vesicle method	Had greater IOP lowering activity and more prolonged effects.	It could be a candidate for the treatment of ocular hypertension.	Assay of DRZ in aqueous humor following drug instillation into rabbit eye should be done before clinical trials as well.
Bravo-Osuna I, et al^Citation99 2016	New Zealand white rabbits	Acetazolamide	Dendrimers	Hydrosilylation of Boc-protected allylamine and followed by deprotection with HCl	Demonstrated rapid (1 hour post-instillation) and sustained (up to 7 hours) hypotensive effect, reaching a peak 22.6% IOP reduction in normotensive rabbit eyes.	Carbosilane dendrimers can be used in a safe range of concentrations to enhance the bioavailability of drugs topically administered in the eye.	Unspecified
Yu S, et al^Citation171 2015	New Zealand rabbits	Timolol maleate	Liposome	pH-gradient method	Reduced the IOP and the effective time was significantly longer.	Liposome incorporated ion sensitivity in situ gels has a potential ability for ophthalmic delivery.	Future work will research the pathway and mechanism of the cellular uptake of TM L-ISG.
Rodriguez-Aller M, et al^Citation98 2015	New Zealand rabbits	Latanoprost	Cyclodextrins	Unspecified	Improved solubility and stability in vitro. In vivo evaluation of ocular tolerability revealed that ocular irritation was 15.5% with the commercially marketed formulation of latanoprost and 9.5% with the latanoprost-propylamino-ß-CD formulation.	The latanoprost-propylamino-β-CD formulation was demonstrated to successfully address the main stability, solubility, and tolerance limitations of topical ocular latanoprost therapy for glaucoma.	Unspecified
Wong TT, et al^Citation97 2014	Human	Latanoprost	Nanoliposome	Gradient method	Good tolerance with no evident safety issues or adverse events.	This study provided the evidence and support for further clinical studies of liposomal latanoprost in the treatment of glaucoma.	The authors were planning additional controlled clinical studies.
Singh J, et al^Citation172 2014	Rabbits model	Acetazolamide	Polymeric nanoparticles	Nanoprecipitation method	Sustained release effects and increased transcorneal permeation in vivo.	NP-ISG5 may offer intensive management of glaucoma via higher permeation, prolonged precorneal residence time and sustained drug release along with higher in vitro efficacy, safety and patient compliance.	These systems are emerging as vehicles for the treatment of diseases of posterior portion of eye which is not possible by topical delivery through conventional systems.
Tuomela A, et al^Citation173 2014	Wistar rats	Brinzolamide	Nanocrystal	Top-down wet milling technique	The IOP lowering effect was investigated using a modern rat ocular hypertensive model and elevated IOP reduction was seen in vivo with all the formulations. The reduction achieved in experimentally elevated IOP was comparable to that obtained with a commercial product.	Various BRA nanocrystal formulations which all showed advantageous dissolution and absorption behavior were successfully formulated.	Unspecified
Mishra V, et al^Citation174 2014	New Zealand albino rabbits	Acetazolamide	Poly(propylene imine) dendrimer nanoarchitectures	Unspecified	The sustained and prolonged reduction in IOP suggested that drug entrapped in dendrimers can be used for higher retention in ocular cul-de sac.	The PPI dendrimer based formulation seems to enhance the ocular drug residence time and exhibits better intraocular pressure lowering effect for glaucoma treatment	Unspecified
Jung HJ, et al^Citation175 2013	Beagle dogs	Timolol	Nanoparticles of PGT (propoxylated glyceryl triacylate)	Thermal polymerization of a mixture of timolol base and PGT.	Sustained release of the timolol.	Preliminary in vivo animal studies demonstrate safety and efficacy of the particle loaded lenses treating glaucoma.	Further in vivo safety and pharmacokinetics and pharmacodynamics tests particularly with lenses in which particles are loaded prior to lens fabrication are necessary to evaluate the potential of the proposed approach for glaucoma therapy.
Wu W, et al^Citation176 2013	New Zealand rabbits	Brinzolamide	Liquid crystalline nanoparticles	Modified emulsification method	Had advantages such as lower doses but maintaining the effectiveness, better ocular bioavailability, and patient compliance compared with Azopt^®.	BLZ LCNPs would be a promising delivery system used for the treatment of glaucoma	Unspecified
Natarajan JV, et al^Citation177 2012	New Zealand White rabbits	Latanoprost	Egg PC liposomes	Hydration method	A greater sustained IOP lowering effect compared with daily administration of topical latanoprost beyond 90 days.	A single injection of latanoprost-loaded Egg PC liposomes can lower the IOP for up to 90 days, with a greater IOP lowering effect than daily topical administration of latanoprost.	Further detailed studies on the pharmacodynamics of these liposomes within the ocular tissues will determine its future potential clinical application.

Figure 4 Cerium (III) chloride (CeCl₃)-loaded mesoporous silica (CeCl₃@mSiO₂) nanoparticles. A type of cerium (III) chloride (CeCl₃)-loaded mesoporous silica (CeCl₃@mSiO₂) nanoparticles designed and to prevent the formation of diabetic cataract in vitro and in vivo using a well-established rat model of streptozotocin-induced diabetes. (A) Schematic diagram of CeCl₃@mSiO₂ nanoparticle preparation; (B) The morphology of the mSiO₂ nanoparticles under transmission electron microscopy (spherical, uniform and monodisperse morphology with an average diameter of 85 nm); (C) A line graph, showing the time course of changes in the cataract degrees in different groups of animals; (D) various degrees of cataract and representative images of H&E-stained sections of the lens tissue in experimentally induced diabetic animals 8 weeks after treatment with vehicle or 10 and 20 mg/kg CeCl₃@mSiO₂ nanoparticles, respectively. Reprinted from Nanomed, 13, Yang J, Gong X, Fang L, et al. Potential of CeCl3@mSiO2 nanoparticles in alleviating diabetic cataract development and progression, 147–1155, Copyright 2017, with permission from Elsevier.¹¹⁰

Table 4 Nanocarriers to Deliver Anti-Age-Related Macular Degeneration Agents

Study	Experimental Models	Drug	Vehicle/Carriers	Production Method(s)	Results	Conclusion	Future Direction
Tang M, et al^Citation178 2018	An Alkali-Burn Corneal Neovascularization Model in the Mouse	Silicon	Nanoparticles	Photochemical method.	SiNPs-RGD features efficacious antiangiogenic ability; SiNPs-RGD can label angiogenic blood vessels and has neovascularization suppression effects.	the SiNPs-RGD as a novel class of high-quality theranostic probe is suitable for simultaneous diagnosis and treatment in ocular neovascular diseases	Unspecified
Wang Y, et al^Citation116 2016	Balb/c mice and Sprague-Dawley rats	LPD-mediated gene delivery	Lipid-based nanoparticles	A two-step packaging technology employing a multilayering method	Cell-specific promoters enable lipid-based nanoparticles to deliver genes to specific retinal cells in vivo.	This work will inspire investigators in the field of lipid nanotechnology to couple cell-specific promoters to drive expression in a cell- and tissue-specific manner.	The formulated lipid nanoparticles may be appropriate for use with other tissues for the purposes of gene delivery with tissue-specific promoters.
Huu VA, et al^Citation179 2015	Sprague-Dawley rats	Nintedanib	Nanoparticle	Light-sensitive polymer	Stably retain encapsulated molecules in the vitreous; released cargo in response to UV exposure up to 30 weeks post-injection; light-triggered release of nintedanib 10 weeks post-injection suppresses CNV in vivo.	Light-sensitive nanoparticles are biocompatible and cause no adverse effects on the eye as assessed by electroretinograms (ERG), corneal and retinal tomography, and histology.	Whether light can trigger release of multiple therapeutic doses of BIBF1120.
Luo L, et al^Citation180 2013	C57BL/6J mice and Cynomolgus macaque monkeys	RGD- targeted	PLGA nanoparticles	Emulsion solvent evaporation method	Improved with nearly 40% restoration of visual loss induced by CNV.	These findings offer a nanoparticle-based platform for targeted, vitreous-sparing, extended-release, nonviral gene therapy.	Further studies would be necessary before concluding this delivery system is completely safe.
Iwase T, et al^Citation181 2013	Pathogen-free C57BL/6 mice and Dutch belted rabbits	Doxorubicin	Poly(sebacic acid)–polyethylene glycol nanoparticles	Oil-in-water emulsion method	Reduced HIF-1-responsive gene products, strongly suppressed CNV, and no retinal toxicity; suppressed NV for at least 35 days in vivo; sustained release in vivo for at least 105 days.	A novel HIF-1-inhibitor-polymer conjugate formulated into controlled-release particles maximizes efficacy and duration of activity, minimizes toxicity, and provides a promising new chemical entity for treatment of ocular NV.	A single-agent that targets multiple pro-angiogenic effectors is expected to have substantial benefits from a clinical perspective and could provide a major step forward the treatment of highly prevalent neovascular diseases of the eye.
Kyosseva SV, et al^Citation182 2013	Mutant mice with targeted deletion of the Vldlr gene	Cerium oxide	Nanoparticles	Simple wet chemistry methods	Many cell signaling, cellular development, growth and proliferation, and tissue development were affected; inhibited the activation of ERK 1/2, JNK, p38 MAP kinase, and Akt.	Nanoceria may represent a novel therapeutic strategy to treat AMD, RAP, and other neurodegenerative diseases.	Unspecified
Yandrapu SK, et al^Citation183 2013	Rat model	Bevacizumab	PLGA nanoparticles	Emulsion solvent evaporation method	In vitro release of bevacizumab from NP in PMP was sustained for 4 months.	NP in PMP is a novel sustained release system for protein drugs to reduce frequency of protein injections in the therapy of back of the eye diseases.	NPinPMP will sustain drug levels much further in vivo, which will be assessed in future studies.
Jo DH, et al^Citation184 2012	C57BL/6 mice	Silicate	Nanoparticles	Reverse microemulsion method	No direct toxicity; reduced anomalous retinal angiogenesis in vivo; inhibited in vitro VEGF-induced angiogenesis via suppression of VEGF receptor-2 phosphorylation and blocking ERK 1/2 activation.	SiNPs could be an inhibitor of the potency and safety of retinal neovascularization that is mediated by VEGF	Biodegradation and biodistribution of NPs might be investigated before clinical application
Iezzi R, et al^Citation185 2012	Royal College of Surgeons (RCS) rat retinal degeneration model	Hydroxyl-terminated polyamidoamine	Nanodevices	Unspecified	Sustained release effects over 90 days. One intravitreal injection of 1 mg of FA conjugated to 7 mg of the dendrimer was able to arrest retinal degeneration, preserve photoreceptor outer nuclear cell counts, and attenuate activated microglia, for an entire month.	PAMAM dendrimers (with no targeting ligands) have an intrinsic ability to selectively localize in activated microglia, and can deliver drugs inside these cells for a sustained period for the treatment of retinal neuro-inflammation.	This approach can have significant implications in the treatment of neuro-inflammation in other neurodegenerative diseases such as cerebral palsy, autism, and Alzheimer’s disease.
Liu HA, et al^Citation186 2011	Brown-Norway rats	PEGylated liposome-protamine-hyaluronic acid nanoparticles (PEG-LPH-NP) loaded with siRNA (PEG-LPH-NP-S)	Liposome-polymer hybrid nanoparticles	Post-insertion method	Protected siRNA load and facilitated the intracellular delivery of siRNA, the expression inhibition of VEGFR1, and the reduction of CNV area in vivo.	PEG-LPH-NP may be a promising lipid nanoparticle system for the siRNA treatment of CNV.	Unspecified
Jin J, et al^Citation119 2011	Brown Norway rats	Plasminogen kringle	PLGA nanoparticle	Emulsion–diffusion–evaporation technique with some modifications	Intense K5 expression was detected in the retina 2 weeks after the injection of K5-NP. Areas of CNV were significantly decreased in the K5-NP treatment group compared with that in the control-NP group. The K5-NP injection also significantly reduced vascular permeability.	K5 has a novel anti-inflammatory activity. K5-NP mediates a sustained inhibitory effect on CNV	The receptor and signaling pathway mediating the anti-inflammatory activity of K5, however, remains to be defined.
Zhang C, et al^Citation187 2010	Brown Norway rats	PshHIF-1α	PLGA nanoparticle	Water-in-oil-in-water (W/O/W) multiple emulsion technique	Expression of GFP preferentially localized in the retinal pigment epithelium cell layer and lasted for 4 weeks; reduced the mean thickness of the CNV lesions in vivo.	pshHIF-1α NPs may act as a novel therapeutic option to transfer specific pDNA and inhibit the formation of experimental CNV.	The efficacy of this method is not clear yet and needs further determination.

Abbreviations: IOP, intraocular pressure; AMD, age-related macular degeneration; RAP, retinal angiomatous proliferation; CNV, choroidal neovascularization.

Table 5 Nanocarriers to Deliver Anti-Uveitis Agents

Study	Experimental Models	Drug	Vehicle/Carriers	Production Method(s)	Results	Conclusion
Nikita, et al^Citation132 2021	Unspecified	Everolimus	PVCL-PVA-PEG nanomicellar	Unspecified	Have high encapsulation efficiency and sustained release of everolimus; have higher permeation across goat cornea than everolimus suspension.	Everolimus nanomicelles could be considered a promising topical drug delivery nanocarrier for treating uveitis.
Garg V, et al^Citation188 2021	Endotoxin-Induced Uveitis in Rabbit	Tacrolimus	Proglycosome nano-vesicles	Propylene glycol modified lipid vesicles	PNV treatment not only subsides clinical symptoms of uveitis but also prevents breakdown of blood aqueous barrier.	Tacrolimus loaded PNVs are a potential new topical treatment for uveitis.
Gaballa SA, et al^Citation134 2020	Rabbits’ model	Beclomethasone Dipropionate	Cubosomes/Cubosomal Gels	Top-down technique	Transcorneal permeation parameters Papp, flux and AUC0-10h, were markedly enhanced up to 4-, 5.8-and 5.5-fold, respectively.	Cubosomes/Cubo-gel could be an auspicious ocular delivery system for BDP that was able to effectively treat uveitis.
Nirbhavane P, et al^Citation131 2020	LPS induced inflamed cells	Triamcinolone acetonide	Cationic nanostructured lipid carriers	Hot microemulsion method	Sustained release effects in vitro; no cytotoxicity; retained inside the cells for 24 h; reduced the TNF-α level in LPS induced inflamed cells.	cTA-NLC could be a promising option for the topical treatment of uveitis.
Coburn PS, et al^Citation189 2019	A murine sterile endophthalmitis model	Gatifloxacin	Rabbit nanosponges	Biomimetic erythrocyte-derived nanosponge	Reduced the hemolytic activity of a diverse array of PFTs; human nanosponges alone protected mouse retinas following intraocular infection with E. faecalis and S. pneumoniae but not B. cereus or MSSA.	Clinical improvements in intraocular infections following nanosponge treatment were dependent on the complexity and types of toxins produced. Nanosponges might serve as an adjunctive therapy for the treatment of ocular infections.
Chennamaneni SR, et al^Citation190 2013	New Zealand White (NZW) rabbits	Dexamethasone	PLGA nanoparticles	Standard oil-in-water (o/w) emulsion-solvent extraction method	DXM flow was bidirectional in the endocapsular space and it was found in the anterior and posterior chambers after up to 6 weeks after WHAT?.	The feasibility of drug delivery from the capsular bag to the anterior and posterior segments effectively compared to topical alternatives.
Elbialy NS, et al^Citation191 2013	Male New Zealand white rabbits	Prednisolone acetate	Liposomes	Film hydration method	Have higher entrapment efficiency and slower release rate; higher concentration of PSA in aqueous humor.	pSUV and pMLV are effective carriers for PSA and have a good potential as drug delivery systems in the ocular therapy

Table 6 Nanocarriers to Deliver Anti-VEGF Agents

Study	Disease	Experimental Models	Drug	Vehicle/Carriers	Production Method(s)	Results	Mean Particle Size (nm)	Future Direction
Formica ML, et al^Citation147 2021	Neovascular ocular pathologies	HUVEC	Bevacizumab and triamcinolone	Lipid mix and stabilizers	Phase inversion temperature	Enhanced antiangiogenic properties in HUVEC	113–182	Unspecified
Liu J, et al^Citation192 2019	CNV	Rabbit mode	Bevacizumab and dexamethasone	PLGA-nanoparticles	Emulsion-solvent evaporation	Sustained release effects in vitro; enhanced efficacy inhibiting tube formation and VEGF secretion in HUVEC; increased antiangiogenic efficacy of CNV in a rabbit model.	190–222	Merit future investigation to validate and improve clinical use in treating AMD and other angiogenesis-dependent diseases.
Sun JG, et al^Citation149 2019	Corneal neovascularization and an oxygen-induced retinopathy	Mice model	Bevacizumab	Mesoporous silica nanoparticles	Nanocasting	Sustained release effects in vitro; enhanced antiangiogenic properties in HUVEC; enhanced antiangiogenic efficacy in vivo.	140	Unspecified
Savin CL, et al^Citation193 2019	DR	Rabbit model	Bevacizumab	Chitosan grafted polyethylene glycol) methacrylate nanoparticles	Double crosslinking (ionic and covalent) process in reverse emulsion	Sustained release effects in vitro; enhanced efficacy as antiangiogenic in vivo.	200–900	Unspecified
Ugˇurlu N, et al^Citation194 2019	Eye posterior segment neovascularization	Rabbit model	Bevacizumab	Chitosan nanoparticles	Ionic gelation	Sustained release effects in vitro; high intravitreal drug concentration after subtenon injection in vivo.	188	Further studies are warranted to evaluate the stability of antibody-loaded nanoparticles and the anti-angiogenesis of bevacizumab loaded nanoparticles.
Luis de Redín I, et al^Citation150 2019	Corneal neovascularization	Rat model	Bevacizumab	Human serum albumin nanoparticles	Desolvation followed by freeze-drying	Sustained release effects in vivo; formulation remained in eye for more than 4 hours post-topical administration; improved antiangiogenic efficacy in vivo.	310	Unspecified
Juan M. Llabot, et al^Citation195 2019	Corneal neovascularization	Unspecified	Bevacizumab and suramin	Human serum albumin nanoparticles	Desolvation	Sustained release effects in vivo; bevacizumab released from Nps-Ga was characterized by a small burst effect followed by a sustained release rate.	158–210	Unspecified
Zhang XP, et al^Citation196 2018	Oxygen-induced retinopathy and corneal neovascularization	Mice model	Bevacizumab	PLGA-nanoparticles	Double-emulsion solvent evaporation	Sustained release effects in vitro; increased half-life of drug and enhanced antiangiogenic efficacy in vivo; enhanced antiangiogenic properties in HUVEC.	133	Unspecified
Yan J, et al^Citation197 2018	Neovascular age-related macular degeneration	Human umbilical vein endothelial cells	Ranibizumab	Ring opening polymerization, following addition of iron oxide nanoparticles	PLGA-PEGylated magnetic nanoparticles	Inhibition of the tube formation in HUVEC	5–10	Unspecified
D. K. Karumanchi, et al^Citation198 2018	Unspecified	Rabbit model	Bevacizumab	Phospholipids and lipids of different chain size	Lipid hydration and extrusion	Sustained release effects in vivo; slow release and retained antibody activity after intravitreal administration in vivo.	120–385	Unspecified
Mu H, et al^Citation199 2018	CNV	Rabbit model	Bevacizumab	Phospholipids and lipids of different chain size, albumin and PVA	Double emulsification	Sustained release effects in vivo; prolonged residency time in eye after intravitreal injection in vivo; enhanced antiangiogenic efficacy in a laser-induced CNV.	1190–4360	Unspecified
Pandit J, et al^Citation200 2017	VEGF related retinal disease	Goat and pig	Bevacizumab	Chitosan-coated PLGA nanoparticles	Emulsion-solvent evaporation	Increased drug transscleral permeation; enhanced bioadhesion in vivo.	222	Further studies concerning the cytotoxicity and concentration dependent reduction of the VEGF concentration in DR model were underway.
Sousa F, et al^Citation201 2017	VEGF related retinal disease	HUVEC	Bevacizumab	PLGA-nanoparticles	Double-emulsion solvent evaporation	Sustained pH-dependent bevacizumab release in vitro.	198	The mechanisms underlying bevacizumab delivery at the sub-cellular level are certainly needed.
Elsaid N, et al^Citation202 2016	Macular diseases	HUVEC	Ranibizumab	PLGA microparticles entrapping chitosan nanoparticles	Chitosan crosslinking –modified double emulsion method	Sustained release effects in vivo; enhanced antiangiogenic properties in HUVEC.	17–350	Unspecified
Varshochian R, et al^Citation48 2015	Eye posterior segment neovascularization	Rabbit mode	Bevacizumab	PLGA-albumin nanoparticles	Double-emulsion solvent evaporation	Sustained release bevacizumab for about 2 months after intravitreal injection and increased half-life of drug in vivo.	190	Unspecified
Lu Y, et al^Citation203 2014	Diabetic retinopathy	Rabbit model	Bevacizumab	Chitosan nanoparticles	Unspecified	Sustained release effects in vivo; inhibition of VEGF expression in vivo.	88.9	The preparation of nanoparticle should be optimized to achieve the goal of reducing intravitreal injection and the occurrence of complications in clinical practices.

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