Diabetic eye: associated diseases, drugs in clinic, and role of self-assembled carriers in topical treatment

Figures & data

Table 1. Administration routes for delivery of drugs to the eye

Administration route	Advantages	Disadvantages
Topical	Noninvasive approach, well accepted by the patient	All barriers except the blood–eye barriers must be overcome Self-administration may be not feasible in all cases
Oral	High patient compliance, no corneal or anterior segment barriers	Systemic untoward effects, blood-retinal barrier, low on-site concentration
Intracameral	High drug concentration in the anterior chamber	Clinical injection
Subconjunctival	Scleral route to the retina, suitable for depot formulations	Clinical injection
Intravitreal	High drug concentration in the posterior segment, hydraulic pressure gradient	Clinical injection (more invasive than subconjunctival), dependent on vitreous diffusion, the visual axis can be obscured if the formulation is opaque
Retrobulbar	Low risk for intraorbital injury, low influence on IOP	Clinical injection, risk of optic nerve damage
Peribulbar	Low risk for intraorbital injury	Clinical injection
Posterior juxta scleral	Available for inserts	Retinal pigment epithelium is still a barrier

Table 2. Some active substances of medicines used to reduce the IOP. Data from the European Medicines Agency, https://www.ema.europa.eu/en/medicines

Drug class	Drug	Dosage form
Prostaglandin or analog	Travoprost	Eye drop
	Bimatoprost	Eye drop
	Latanoprost	Eye drop
	Unoprostone	Eye drop
Prostaglandin analog nitric oxide	Latanoprostene bunod	Eye drop
Rho kinase inhibitor	Netarsudil	Eye drop
	Ripasudil	Eye drop
Miotic agent	Pilocarpine	Eye drop
Cholinergic agonist	Carbachol	Eye drop or intraocular injection
Alpha-adrenergic agonist	Brimonidine	Eye drop
	Apraclonidine	Eye drop
Beta blocker	Betaxolol	Eye drop or oral tablet
	Timolol	Eye drop
	Carteolol	Eye drop
Carbonic anhydrase inhibitor	Methazolamide	Oral tablet
	Acetazolamide	Eye drop
	Brinzolamide	Eye drop
	Dorzolamide	Eye drop

Figure 1. Regional distribution of clinical trials related to diabetic eye. Data source: ClinicalTrials.gov. There were 657 outcomes for ‘diabetic eye’ on February 2021. Applied filters were Recruiting, Active not recruiting, Completed, Enrolling by invitation, and Terminated

Table 3. Pharmacological treatments in clinical trials for diabetes-related macular edema classified as a function of the administration route, drug/biologic active substance, and number of clinical studies

Administration route	Drug/Biologic class	Active substance	Number of clinical trials
Intravitreal	Antibodies or blockers	Aflibercept and biosimilars	42
		Anti-angiopoietin-2 antibody REGN910	1
		REGN910-3 (co-formulation of REGN910 and aflibercept)	1
		Anti-erythropoietin LKA651	1
		Anti-PlGF recombinant monoclonal antibody	1
		Anti-ROBO4 antibody DS-7080a	1
		Bevacizumab	16
		Bevasiranib	1
		Tofacitinib (BI 764,524)	1
		Conbercept (KH902)	1
		Faricimab	1
		Infliximab, anti-TNFα	1
		OPT-302, anti-VEGF-C and anti-VEGF-D	1
		Pegaptanib	7
		Ranibizumab	40
		Teprotumumab	1
	Small molecules	Dexamethasone	31
		Fluocinolone acetonide	9
		Triamcinolone acetonide	11
		Anti-VEGF drugs	7
		KVD001 plasma kallikrein inhibitor	2
		AR-13,503, small-molecule inhibitor of both Rho kinase and protein kinase C	1
		UBX1325, inhibitor of Bcl-xL (anti-apoptotic regulatory protein)	1
	Peptides	AXT107, tyrosine kinase blocking collagen IV–derived peptide	1
		Luminate (Alg-1001) integrin inhibitor	1
	Proteases	Ocriplasmin	1
	Gene therapy	ADVM-022 gene therapy (AAV.7m8-aflibercept)	1
		iCo-007, a single-stranded antisense that degrades messenger RNA (mRNA)	1
		PF-04523655, small-interfering RNA (siRNA)	1
Oral	Small molecules	GSK2798745, transient receptor potential vanilloid 4 (TRPV4) channel blocker	1
		Aliskiren	1
		Danazol	1
		Fenofibrate/pemafibrate	2
		Imatinib mesylate (YD312)	1
		Levosulpiride	1
		Minocycline	1
		MS-533 protein kinase inhibitor	1
		Ruboxistaurin	1
		Semaglutide	1
	Dietary supplements	Alzer®, Diamel®, others	2
Topical eyedrops	Small molecules	Bromfenac	1
		Dexamethasone	2
		Diclofenac	1
		EXN407, specific serine/threonine-protein kinase 1 (SRPK1) inhibitor	1
		FOV2304, inhibitor of bradykinin B1 receptor	1
		Fluocinolone acetonide	1
		Ketorolac	3
		Nepafenac	5
		OC-10X tubulin inhibitor	1
		Loteprednol etabonate	1
		Mecamylamine nonspecific nACh receptor blocker	1
		SF0166 small-molecule αvβ3 antagonist	1
		Vitamin E	2
	Peptides	Elamipretide (MTP-131), mitochondria-targeting peptide	1
Intravenous	Small molecules	Methotrexate	1
Intramuscular	Peptides	Octreotide acetate in microspheres	1
Episcleral	Small molecules	Dexamethasone implant	1
Subconjunctival	Antibody	Bevacizumab	1
	Small molecule	Rapamycin	2
Subcutaneous	Small molecule	Razuprotafib (AKB-9778), inhibitor of VE-PTP (vascular endothelial protein tyrosine phosphatase)	2
Sub-macular	Antibodies	Ranibizumab	1
Suprachoroidal	Gene therapy	RGX-314 (AAV8 vector containing a transgene for anti-VEGF fab)	1

Data source: ClinicalTrials.gov. Outcomes for ‘diabetic eye AND macular edema’ on February 2021. Applied filters were Recruiting, Active not recruiting, Completed, Enrolling by invitation, and Terminated.

Table 4. Pharmacological treatments in clinical trials for diabetes-related retinopathy classified as a function of the administration route, drug/biologic active substance, and number of clinical studies

Administration route	Drug/Biologic class	Active substance	Number of clinical trials
Intravitreal	Antibodies or blockers	Aflibercept and biosimilars	14
		Anti-PlGF recombinant monoclonal antibody	1
		Bevacizumab	14
		Tofacitinib (BI 764,524)	1
		Conbercept (KH902)	2
		Pegaptanib	2
		Ranibizumab	20
	Small molecules	Dexamethasone	3
		Triamcinolone acetonide	5
		Anti-VEGF Drugs	1
	Gene therapy	PF-04523655, small-interfering RNA (siRNA)	1
Oral	Small molecules	Acetazolamide	1
		Alpha-lipoic acid	1
		Aminoguanidine	1
		Brimonidine	1
		Darapladib	1
		Doxycycline	1
		Emixustat hydrochloride	1
		Empaglifozin	1
		Fenofibrate/pemafibrate	3
		Finerenone	1
		Melatonin	1
		RG7774	1
		Ruboxistaurin	2
		Semaglutide	1
		Sinemet	1
		Sulodexide	1
		Tientine	1
		Ubiquinone	1
	Dietary supplements	Alpha-lipoic acid, carotenoid vitamins, omega 3, multi-component nutritional supplement (vitamin C, mixed tocopherols/tocotrienols, vitamin D, fish oil, lutein, zeaxanthin, pine bark extract, benfotiamine, green tea extract, curcumin), Ocufolin®	5
Topical eyedrops	Small molecules	Anecortave acetate	1
		Citicoline	1
		Curcumin, homotaurine, and vitamin D3	1
		Dexamethasone	1
		Diclofenac	1
		Dorzolamide	1
		Ketorolac	3
		Latanoprost	2
		Napafenac	3
		OC-10X tubulin inhibitor	2
		Prednisolone acetate	2
		Squalamine lactate	1
		TG100801 multikinases inhibitor	1
	Peptides	Somatostatin (with brimonidine)	1
Intravenous	Protein	Pulsatile insulin	2
Intramuscular	Peptides	Octreotide acetate in microspheres	4
Subconjunctival	Small molecule	Rapamycin	1
Subcutaneous	Small molecule	Razuprotafib (AKB-9778), inhibitor of VE-PTP (vascular endothelial protein tyrosine phosphatase)	1
Suprachoroidal	Gene therapy	RGX-314 (AAV8 vector containing a transgene for anti-VEGF fab)	1

Data source: ClinicalTrials.gov. Outcomes for ‘diabetic eye AND retinopathy’ on February 2021. Applied filters were Recruiting, Active not recruiting, Completed, Enrolling by invitation, and Terminated.

Figure 2. Dependence of the architecture of the self-assembled nanocarrier on the critical packing parameter (CPP)

Figure 3. Progesterone (PG) apparent solubility in Soluplus and Pluronic F68 micelles, and permeability coefficients of cornea and sclera recorded for PG encapsulated in Soluplus 20% micelles or Pluronic F68 20% micelles. Reproduced from Alambiaga-Caravaca et al. [126] (Creative Commons Attribution License)

Table 5. Recent examples of self-assembled nanocarriers proposed for the topical ocular treatment of diabetic eye

Nanocarrier	Drug	Disease/Outcome	Reference
Polymeric micelles	Alpha-lipoic acid	Dry eye and diabetic retinopathy (bovine cornea). Soluplus micelles facilitated alpha-lipoic acid accumulation and pass across the tissue.	[99]
	Progesterone	Retina degeneration (rabbit, pig, cow). Soluplus and Pluronic micelles enhanced drug permeability through cornea with respect to sclera. Important interspecies differences.	[128]
	Dexamethasone, triamcinolone and triamcinolone acetonide	Macular edema (cell cultures). Micelles of copolymer of inulin derivatized with ethylenediamine and retinoic acid efficiently encapsulated the drugs, were internalized by different cell lines, and favored transcorneal permeation.	[130]
	Dexamethasone	Posterior uveitis (rabbit). Mixed micelles of polyoxyl 40 stearate and polysorbate 80 provided therapeutic levels in retina and choroid after one single instillation.	[132]
	Anti-angiogenic peptide aANGP	Diabetic retinopathy and macular edema (cell cultures). aANGP-micelles inhibited tube formation at 1000-fold lower concentration than free peptide.	[133]
	Glycyrrhizin and genistein	Wound healing in diabetic eye model (mice). Genipin-loaded glycyrrhizinate micelles down-regulated high mobility group box protein-1 (HMGB1) and its receptors for advanced glycation-end products (RAGEs) and toll-like receptors (TLRs), as well as inflammatory factor interleukin (IL)-6 and IL-1β, which favored diabetic corneal and nerve wound healing.	[134]
Liposomes	Citicoline	Diabetic retinopathy (mouse). Topical administration twice a day, for 15 days, prevented glial activation and neural apoptosis.	[138]
	Triamcinolone acetonide	Macular edema (patients). Drug-loaded QuSomes® instilled every 2 h decreased the central foveal thickness and increased the best-corrected visual acuity.	[141]
	Triamcinolone acetonide	Macular edema (rabbit). Chitosan-coated liposomes instilled five times a day provided efficient delivery to anterior and posterior segments due to enhanced cell uptake.	[142]
	Berberine hydrochloride	Macular edema (rabbit). PAMAM G3.0-coated liposomes promoted transcorneal permeability.	[143]
	Bevacizumab	Macular degeneration (rat and rabbit). Unilamellar vesicles with annexin A5 enhanced uptake and transcytosis through cornea, supplying therapeutic concentrations to the back of the eye.	[144]
	Transforming growth factor-β1 (TGF-β1)	Macular degeneration (rabbit). Unilamellar vesicles with annexin A5 provided therapeutic levels to the back of the eye.	[148]
	Thrombospondin (TSP)-1-derived peptide	Chronic ocular surface inflammation and tear film instability (ex vivo porcine cornea). Liposomes enhanced cornea permeation.	[149]
	Plasmid DNA	Gene therapy at retinal pigment epithelium (rat). Transferrin-modified small liposomes (<80 nm) selectively distributed to the retinal pigment epithelium. Larger liposomes could be targeted to choroidal endothelial cells.	[151]
Niosomes	Naltrexone·HCl	Diabetic keratopathy (bovine). Span 60 and cholesterol (30 mol%) niosomes sustainedly release the drug while still allowed for high cornea permeability.	[167]
	Flurbiprofen	Keratitis (rabbit). Span 60 and cholesterol (50 mol%) niosomes solely or dispersed in Carbopol gel enhanced drug ocular bioavailability.	[168]
	Latanoprost	Glaucoma (rabbit). One instillation of Span 60 and cholesterol (50:50 weight ratio) niosomes dispersed in Pluronic F127 gel decreased IOP for more than 48 h.	[169]

Figure 4. (a) Central foveal thickness (CFT), (b) best-corrected visual acuity (BCVA), and (c) intraocular pressure (IOP) recorded for patients with refractory pseudophakic cystoid macular edema during treatment with triamcinolone-loaded liposomes (one drop every 2 h for 90 days). Reproduced from Gonzalez-De la Rosa et al. [139] (Creative Commons License)

Figure 5. Main techniques used to prepare drug-loaded niosomes

Figure 6. Reduction in the intraocular pressure (IOP) observed after topical administration to normotensive rabbits of latanoprost-loaded niosome gel or conventional latanoprost eye drops. Error bars represent standard deviation of six replicates. Reproduced from Fathalla et al. [167] with permission from Taylor & Francis (http://www.tandfonline.com)

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