Ocular drug delivery for bioactive proteins

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Recent advances in biotechnology enabled commercial production of humanized monoclonal antibodies. In the field of ophthalmology, ranibizumab and bevacizumab, anti-VEGF antibodies, are highly recognized as first-choice drugs to treat age-related macular degeneration, which is one of the major causes of legal blindness in developed countries. Infliximab is a monoclonal antibody against TNF-α and is effective in treating autoimmune diseases such as Behçet's disease. Thus, these drugs proved the potential of antibodies as molecularly targeted therapies for the treatment of a variety of ocular diseases. A variety of cytokines may also possess great potential as therapeutics, exemplified by interferon for the treatment of chronic hepatitis C, multiple sclerosis, and other systemic diseases. However, intraocular delivery of bioactive proteins remains a critical problem to be overcome. The cornea, sclera, tear turnover, frontward current of aqueous humor, the blood–aqueous barrier and blood–retinal barrier strictly limit penetration and diffusion of the drug into the chorioretinal tissue. Therefore, ranibizumab and bevacizumab are intravitreally injected, with the possibility of rare but serious adverse events such as endophthalmitis. Moreover, repeated injections are required to keep therapeutic concentrations in the eye. In addition, intravitreal injections may be less effective on eyes after vitrectomy because the residence time of intravitreally injected drugs is remarkably shortened. Generally, cytokines have a short half-life of bioactivity in the body, which may limit their suitability as a drug. One of strategies to overcome these limitations may be the development of intraocular drug-delivery systems. However, previously developed devices may be applicable only to deliveries of steroids and other small compounds. In this review, we aim to summarize possible strategies involving controlled release and drug targeting of bioactive proteins on the basis of polyion complexation or metal coordination and other gelling agents to prolong residence time of intravitreally injected drugs.

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