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Potential Drug Delivery Approaches for XFS-associated and XFS-associated Glaucoma

Kulkarni, Shreya S. BPharm*; Kompella, Uday B. PhD, FARVO*,†,‡

doi: 10.1097/IJG.0000000000000109
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Key tissue targets in treating exfoliation syndrome (XFS) and the associated glaucoma include lens, iris, and ciliary body, which produce the exfoliative material, and the trabecular meshwork, which may be impaired by the exfoliative material. In addition to antiglaucoma drug therapy, strategies for treating the disease include approaches for preventing formation of exfoliative material as well as those aimed at digesting exfoliative material. A variety of drug molecules including small molecules, protein drugs, and nucleic acids are potential candidates for treating XFS. Potential drug classes include antioxidants, lysyl oxidase-like 1 enhancers, antifibrotics, anti-inflammatory agents, proteases, and chaperones. However, the delivery of these agents to the target tissues in the anterior segment is hindered by protective static and dynamic barriers of the eye. Thus, unique drug delivery approaches are needed for each drug type (small molecules, proteins, and nucleic acids). In addition, there is a need for sustaining drug therapy for treating XFS, which can potentially be addressed by using nanoparticles, microparticles, implants, and contact lens delivery systems. This article provides an overview of drug delivery challenges and opportunities in treating XFS with the focus being on nanomedicines.

*Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences

Departments of Ophthalmology

Bioengineering, University of Colorado Anschutz Medical Campus, Aurora, CO

Disclosure: The authors declare no conflict of interest.

Reprints: Uday B. Kompella, PhD, FARVO, Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, 12850 East Montview Boulevard, C238-V20, Aurora, CO 80045 (e-mail: uday.kompella@ucdenver.edu).

Received July 29, 2014

Accepted August 1, 2014

Exfoliation syndrome (XFS) is a genetic, age-related, and potentially environment-related disease.1,2 It is characterized by the production of glycoproteinaceous, fibrillar exfoliative material by the iris pigment epithelium, ciliary epithelium, or the lens epithelium and deposition of this material on the structures of the anterior segment of the eye.2 The exfoliative material is commonly deposited on the anterior lens capsule (phacopathy), iris (iridopathy), trabecular meshwork (trabeculopathy), ciliary body (cyclopathy), zonular fibers (zonulopathy), and occasionally the cornea.3 Phacopathy is characterized by phacodonesis, subluxation, nuclear cataract, and zonular dialysis; iridopathy is characterized by vasculopathy that involves blood-aqueous barrier defect, pseudouveitis, anterior chamber hypoxia, capillary hemorrhage, iris rigidity, posterior synechiae, poor mydriasis, asymmetric pupillary action, and melanin liberation.3 Trabeculopathy is characterized by the buildup of protein fibrils in the trabecular meshwork that can lead to blockade of normal drainage of the aqueous humor.3 This, in turn, elevates intraocular pressure (IOP) and leads to the development of XFS-associated glaucoma. Increased IOP can eventually damage the optic nerve, resulting in loss of vision.4 Hence, based on the pathophysiology of the disease, the key target tissues in the treatment of XFS and XFS glaucoma appear to be the lens, iris, and the ciliary body, which produce the exfoliative material, in addition to trabecular meshwork where exfoliative material deposits may lead to obstruction of fluid flow.

The clinical treatment for XFS glaucoma is required to be more aggressive in contrast to primary open-angle glaucoma because of high IOP at onset, faster progression rate, and poor prognosis associated with XFS glaucoma.5,6 Although miotics (pilocarpine), β-blockers (timolol), and prostaglandin analogs (latanoprost, bimatoprost, and travoprost) are useful first-line treatments in reducing IOP, laser trabeculoplasty and filtration surgery are often required for treating XFS glaucoma.7 However, the surgical procedures are also associated with relapse due to continued production and deposition of exfoliative material, and involve the risk of surgical complications.8,9 Hence, in treating XFS glaucoma, there is a need for treating the underlying primary cause. Figure 1 summarizes the causes that predispose a person toward developing XFS.

FIGURE 1

FIGURE 1

Key strategies for treating the root cause of the disease include approaches for preventing formation exfoliative material or those aimed at digesting exfoliative material. On the basis of changes in biomarkers in association with XFS, potential treatment modalities include antioxidants like superoxide dismutase, catalase, and vitamin C, lysyl oxidase-like 1 (LOXL1) enhancers (polypeptides and nucleic acids), antifibrotics-like inhibitors of transforming growth factor (TGF-β1), anti-inflammatory agents, antiaggregation agents like protein chaperones (clusterin and crystallins) and small molecule chaperones (quinacrines, curcumin, and chlorpromazine), proteases (MMP-2 and MMP-9) to cleave fibrillins, and signaling molecules related to extracellular matrix to facilitate clearance of exfoliative material.7 Thus, correcting the causes of XFS may require the delivery of a variety of therapeutic agents including conventional small molecules as well as macromolecules such as proteins and nucleic acids. However, the delivery of these agents to the target tissues in the anterior segment is hindered by protective static and dynamic barriers of the eye.

Key static barriers for anterior segment drug delivery include the corneal epithelium, stroma, and endothelium and the blood-aqueous barrier formed by the ciliary epithelium. The dynamic barriers include conjunctival vascular and lymphatic clearance mechanisms, and nasolacrimal drainage.10,11 The target tissues may also possess efflux transporters for drug molecules, reducing drug bioavailability. Further, metabolic enzymes that form a part of the defensive barriers are responsible for degrading drug molecules (especially protein and nucleic acid drugs), thereby reducing their bioavailability and efficacy.11

Nanosystems endowed with characteristics such as rapid uptake, slow release, and targeting ability can potentially overcome drug delivery barriers in delivering the therapeutic agents for treating XFS and XFS glaucoma. These systems include polymeric nanoparticles, nanomicelles, dendrimers, and films which can then be delivered topically or via minimally invasive approaches.11 The design of the nanosystem needs to be suitably modified depending on the drug type (small molecules, proteins, and nucleic acids), target tissue, and route of administration.

Small molecules are routinely administered as eye drops for drug delivery to the anterior segment. However, drug delivery from eye drops is impeded by poor solubility and permeability of the drug, resulting in inadequate delivery. These shortcomings can be overcome by designing nanosized delivery systems which enhance drug solubility, mucoadhesion, and corneal penetration. For instance, poly(amidoamine) (PAMAM) dendrimers are mucoadhesive,12 enhance drug solubility,13 and improve corneal penetration of drug molecules.14 Sustained delivery of small molecule antiglaucoma agents is critical in the treatment of XFS glaucoma due to persistent IOP elevation. The 2 major barriers for sustained delivery include rapid precorneal clearance (half-life of about 1 min) of drug solutions. PAMAM dendrimers sustain drug release and exhibit prolonged residence on eye surface following topical eye drop administration in a rabbit model.15 Thus, dendrimer nanoparticle formulations are suitable for achieving multiple drug delivery objectives including mucoadhesion and prolonged precorneal residence, enhanced drug solubility, and enhanced and sustained drug delivery to treat diseases of the eye. In addition, nanoparticles loaded in contact lenses are useful for sustaining antiglaucoma drug delivery and efficacy in vivo. Although nanoparticles by themselves can prolong precorneal drug residence time, drug retention on eye surface can be further prolonged by loading nanoparticles in extended-wear contact lenses. For example, timolol containing propoxylated glyceryl triacylate nanoparticles when loaded in silicone-hydrogel contact lenses (5% particle loading), sustained timolol release for a month in vitro and exhibited sustained IOP reduction in beagle dogs.16 Other possible delivery solutions for sustaining drug release include the use of contact lenses loaded with plain drug, implants, punctal plugs, and gel formulations.11

Although small molecule delivery to anterior segment tissues has been extensively studied, delivery of macromolecules is more challenging and may specially benefit from application of nanotechnologies. Sustained release of protein drugs is associated with problems such as physical and chemical instability during manufacture, on shelf, and in vivo; leading to aggregation, incomplete release, and loss in activity and immunogenicity. Protein stabilization can be achieved either by engineering proteins with enhanced stability and reduced immunogenicity or by stabilizing the protein formulations by including additives such as sugars, surfactants, and salts. An alternate solution could be the use of nanoparticles in porous microparticles (NPinPMP). NPinPMP is a novel delivery system for sustained delivery of protein drugs developed by Yandrapu et al.17 NPinPMP uses supercritical infusion and pressure quench technology for preparing nanoparticles loaded with protein drugs. The technology has been developed for bevacizumab, a protein drug that was coated on poly(lactic acid) (PLA) nanoparticles, which were further encapsulated into porosifying PLGA microparticles by exposing the mixture to supercritical carbon dioxide. In vitro release of bevacizumab from NPinPMP was sustained for 4 months and NPinPMP were found to release bevacizumab for at least 2 months when administered intravitreally in rats as opposed to drug levels from the solution which reached baseline at 2 weeks. Fluorescence spectroscopy, size-exclusion chromatography, circular dichroism spectroscopy, SDS-PAGE, and ELISA studies indicated that the released bevacizumab was present in the monomeric form and was able to maintain its conformation and activity. The NPinPMP technology can be evaluated for protein delivery to the anterior segment.

Similar to protein delivery, nucleic acid delivery is also confounded with delivery issues such as poor cell entry and enzymatic instability due to the ubiquitous nucleases. Surface modification of nanoparticles has proven to be a useful approach for rapid and efficient delivery of intact nanoparticles to cornea and conjunctiva. Deslorelin and transferring conjugation has been shown to enhance corneal epithelial uptake of polystyrene nanoparticles in ex vivo bovine eye model.18 The total corneal uptake in 5 minutes was found to be approximately 2.4%, 9%, and 16% with plain, deslorelin-functionalized, and transferrin-functionalized nanoparticles, respectively. Nanoparticles not only help protect nucleic acids from degradation by nucleases and enhance their cell entry, but also may aid in targeting them to the nucleus. Transferrin or arginine-glycine-aspartic acid (RGD) peptide or transferrin and RGD dual-functionalized poly(lactide coglycolide) nanoparticles have been developed to achieve back-of-the-eye delivery of an antivascular endothelial growth factor intraceptor plasmid in the treatment of choroidal neovascularization.19 Intravenously administered functionalized nanoparticles increased both the retinal delivery of nanoparticles and the subsequent intraceptor gene expression in retinal vascular endothelial cells, photoreceptor outer segments, and retinal pigment epithelial cells, when compared to nonfunctionalized nanoparticles. Such functionalized nanoparticles can also be used for delivering nucleic acids to the anterior segment tissues.

In conclusion, treating the root cause is a prerequisite in the treatment of XFS and XFS glaucoma. Correcting the primary cause requires the delivery of a variety of therapeutic agents including both conventional small molecules and macromolecules. However, the delivery of these agents to the target tissues in the anterior segment is hindered by protective static and dynamic barriers of the eye. Nanosystems seem to be good candidates for overcoming these barriers and can potentially be used for successful delivery of therapeutic agents for treating XFS-associated and XFS-associated glaucoma.

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Keywords:

exfoliation syndrome; therapeutic agents; drug delivery

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