Ocular Drug Delivery: Advancements and Innovations

Abstract

Ocular drug delivery has been significantly advanced for not only pharmaceutical compounds, such as steroids, nonsteroidal anti-inflammatory drugs, immune modulators, antibiotics, and so forth, but also for the rapidly progressed gene therapy products. For conventional non-gene therapy drugs, appropriate surgical approaches and releasing systems are the main deliberation to achieve adequate treatment outcomes, whereas the scope of "drug delivery" for gene therapy drugs further expands to transgene construct optimization, vector selection, and vector engineering. The eye is the particularly well-suited organ as the gene therapy target, owing to multiple advantages. In this review, we will delve into three main aspects of ocular drug delivery for both conventional drugs and adeno-associated virus (AAV)-based gene therapy products: (1) the development of AAV vector systems for ocular gene therapy, (2) the innovative carriers of medication, and (3) administration routes progression.

Keywords: adeno-associated virus; administration routes; gene therapy; medication carriers; non-viral vectors; ocular drug delivery.

Figure 1

Anatomical barriers of the eye. (A) In the anterior of the eye, the blood–aqueous barrier, consisting of the iris/ciliary blood vessels and nonpigmented ciliary epithelium, limits access to the anterior of the eye and prevents therapeutic entry to the intraocular environment. (B) In the posterior of the eye, the blood-retinal barrier, comprised of the retinal capillary endothelial cells and retinal pigment epithelium cells, prevents therapeutics from entering the posterior segment from the bloodstream.

Figure 2

Schematic of the wild type and recombinant AAV genome. The wild type AAV genome comprised four known open reading frames, rep (blue), cap (green), MAAP (burgundy), and AAP (purple), flanked by inverted terminal repeats (ITRs, grey color). The rep gene encodes four regulatory proteins: Rep78, Rep68, Rep52, and Rep40. Cap gene encodes viral proteins, VP1, VP2, and VP3. Rep and cap genes are removed from the genome of recombinant AAV, instead the transgene expression cassette was inserted, flanked by ITRs. Created with BioRender.com.

Figure 3

The structure of organic nanoparticles (NPs). (A) Solid lipid nanoparticles (SLNs) range from 50 to 1000 nm and consist of a solid crystal lipid core that is stabilized by surfactant, which acts as an emulsifier. Rather than a simple phospholipid bilayer, the exterior of an SLN feature a bilayer of physiologic lipids, such as triglycerides and cholesterol. (B) Nanostructured lipid carriers (NLCs) range from 30 to 100 nm in size and have a similar outer layer to SLNs and contain a surfactant that acts as an emulsifier, but they utilize an irregular solid lipid crystal matrix and a liquid lipid (oil) core. (C) Polymeric nanoparticles range from 1 to 1000 nm. They utilize a polymetric core that can be loaded with active compounds to produce countless variations of the nanoparticle. (D) Dendrimers are organic polymers, which consist of a central core from which ‘branches’ extend outwards to form a spherical shape. They range from 1 to 10 nm in size.

Figure 4

The structures of nanomicelles., liposomes, and niosomes (A) Surfactant micelles are grouped molecules of amphipathic lipids that create a hydrophobic core. Their sizes can vary but generally range from 10–100 nm. (B) Polymeric micelles contained amphiphilic copolymer that, when exposed to water, automatically forms a core/shell structure that can be loaded with insoluble drugs. They are typically between 10–100 nm in size. (C) Liposomes consist of an amphiphilic phospholipid bilayer that encloses hydrophilic substances and are typically between 25 and 2500 nm in size. (D) Niosomes are composed of non-ionic surfactant that form a vesicle to transport aqueous material. They are typically between 25 and 100 nm in size.

Figure 5

Drug administration routes to the anterior segment of the eye. (A) Subconjunctival injections are a type of periocular route of administration where the drug is injected under the conjunctiva (epibulbar) or underneath the conjunctiva lining the eyelid (subpalpebral). Intracameral injection delivers medication directly to the anterior chamber/aqueous humor of the eye. Topical administration is most used in drop form and delivers the solution to the exterior of the eye. Intrastromal injection administers the drug directly to the thick, fibrous stroma of the cornea. (B) Figure 3B depicts the layers of the tear film and cornea. The tear film stretches from the lipid layer to the mucous layer and the cornea from the corneal epithelium to the endothelium.

Figure 6

Drug administration routes to the posterior anatomy of the eye. (A) Intravitreal injections administer the drug directly to the vitreous humor. Suprachoroidal injections deliver directly into the suprachoroidal space. Implants are non-biodegradable systems often anchored to the sclera or injected into the vitreous that release drugs at a predetermined rate. Subretinal injections target the subretinal space or the area directly between retinal pigment epithelium (RPE) cells and photoreceptors. (B) The posterior anatomy of the eye consists of the vitreous humor and the retina, which contains layers of terminally differentiated cells used for light perception.