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Daylight-Mediated, Passive, and Sustained Release of the Glaucoma Drug Timolol from a Contact Lens.

ABSTRACT: Timolol, a potent inhibitor of ?-adrenergic receptors (?ARs), is a first-line drug for decreasing the intraocular pressure (IOP) of patients with glaucoma. Timolol is administered using 0.5% eye-drop solutions at >3 × 10⁷ times the inhibitory concentration (k _i) for ?ARs. This high dose is wasteful and triggers off-target effects that increase medication noncompliance. Here, we introduce contact lenses that release timolol to the eye throughout the day during passive exposures to natural daylight at a more therapeutically relevant concentration (>3000 k _i). Timolol is coupled to the polymer of the contact lens via a photocleavable caged cross-linker and is released exclusively to the surrounding fluid after the 400-430 nm mediated cleavage of the cross-linking group. Studies conducted in a preclinical mouse model of glaucoma show photoreleased timolol is effective as authentic timolol in reducing IOP. Our studies highlight several advantages of daylight-mediated release of timolol from lenses compared to eye-drops. First, fitted contact lenses exposed to natural daylight release sufficient timolol to sustain the inhibition of ?ARs over a 10 h period. Second, the contact lenses inhibit ?ARs in the eye using only 5.7% of the timolol within a single eye-drop. Third, the lenses allow the patient to passively control the amount of timolol released from the lens-for example, early morning exposure to outdoor sunlight would release enough timolol to maximally reduce the IOP, whereas subsequent periodic exposures to indoor daylight would release sufficient timolol to overcome the effects of its spontaneous dissociation from ?ARs. Fourth, our lenses are disposable, designed for single day use, and manufactured at a low cost.

SUBMITTER: Mu C

PROVIDER: S-EPMC6311683 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Project description:Cataract is the leading cause of visual impairment, and posterior capsular opacification (PCO) is the most common long-term complication of modern cataract surgery, which can cause severe visual impairment after surgery. The proliferation, migration, and epithelial-mesenchymal transition (EMT) of residual lens epithelial cells (LECs) stimulated by growth factors and cytokines, are the key pathological mechanisms involved in the development of PCO. This study demonstrated that non-steroidal anti-inflammatory drug (NSAID), bromfenac, was capable of effectively inhibiting cell migration, overexpression of EMT markers, such as fibronectin (FN), matrix metalloproteinase 2 (MMP2), α-smooth muscle actin (α-SMA), and transcription factor Snail, and extracellular signal-regulated kinase (ERK)/glycogen synthase kinase-3β (GSK-3β) signaling induced by transforming growth factor-β2 (TGF-β2) in vitro. The inhibitory effect of bromfenac on TGF-β2-induced EMT was also verified on a primary lens epithelial cell model using human anterior capsules. Furthermore, based on ultrasonic spray technology, we developed a drug-eluting intraocular lens (IOL) using poly (lactic-co-glycolic acid) (PLGA) with sustained bromfenac release ability for the prevention of PCO development. In the rabbit models of cataract surgery, bromfenac-eluting IOL exhibited remarkable PCO prevention and inflammation suppression effects with excellent biocompatibility. In conclusion, bromfenac can inhibit TGF-β2-induced cell migration and the EMT of LECs via ERK/GSK-3β/Snail signaling. The present study offers a novel approach for preventing PCO through PLGA-based drug sustained-release IOLs. Graphical abstract TGF-β2 promoted migration and EMT of lens epithelial cells (LECs) through activation of ERK/GSK-3β/Snail signaling, which could be suppressed by bromfenac. Novel bromfenac-based drug-eluting IOLs exhibited excellent PCO prevention in vivo.Image 1 Highlights • Bromfenac inhibited TGF-β2-induced migration and EMT of LECs through ERK/GSK-3β/Snail signaling.• Drug-eluting IOLs with sustained bromfenac release were developed based on ultrasonic spray technology.• Bromfenac-eluting IOLs exhibited remarkable PCO prevention and inflammation suppression effects in vivo.• Bromfenac-eluting IOLs hold great potential for clinical application of PCO prevention.

Project description:Although once daily anti-glaucoma drug therapy is a current clinical reality, most therapies require multiple dosing and there is an unmet need to develop convenient, safe, and effective sustained release drug delivery systems for long-term treatment to improve patient adherence and outcomes. One of the first sustained release drug delivery systems was approved for the reduction of intraocular pressure in glaucoma patients. It is a polymeric reservoir-type insert delivery system, Ocusert™, placed under the eyelid and on the ocular surface for zero-order drug release over one week. The insert, marketed in two strengths, released pilocarpine on the eye surface. While many clinicians appreciated this drug product, it was eventually discontinued. No similar sustained release non-invasive drug delivery system has made it to the market to date for treating glaucoma. Drug delivery systems under development include punctal plugs, ring-type systems, contact lenses, implants, microspheres, nanospheres, gels, and other depot systems placed in the extraocular, periocular, or intraocular regions including intracameral, supraciliary, and intravitreal spaces. This article discusses the advantages and disadvantages of the various routes of administration and delivery systems for sustained glaucoma therapy. It also provides the reader with some examples and discussion of drug delivery systems that could potentially be applied for glaucoma treatment. Interestingly, one intracamerally injected implant, Durysta™, was approved recently for sustained intraocular pressure reduction. However, long-term acceptance of such devices has yet to be established. The ultimate success of the delivery system will depend on efficacy relative to eye drop dosing, safety, reimbursement options, and patient acceptance. Cautious development efforts are warranted considering prior failed approaches for sustained glaucoma drug delivery. Neuroprotective approaches for glaucoma therapy including cell, gene, protein, and drug-combination therapies, mostly administered intravitreally, are also rapidly progressing towards assessment in humans.

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Daylight-Mediated, Passive, and Sustained Release of the Glaucoma Drug Timolol from a Contact Lens.

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