Abstract
Age-related macular degeneration (AMD) is a leading cause of vision loss, the treatment of which may require monthly intravitreal injections. This is a burden on patients and health services, and new delivery modalities that reduce injection frequency are required. To that end, we investigated the suitability of a novel reverse thermoresponsive polymer (RTP) as an ocular drug-delivery vehicle. In this work, we detail the structure and synthesis of a novel RTP, and determine drug release curves for two drugs commonly used in the treatment of AMD, bevacizumab and aflibercept. Biocompatibility of the RTP was assessed in vitro in human and rat cell lines and in vivo following intravitreal injection in rats. Bevacizumab demonstrated a more appropriate release profile than aflibercept, with 67% released within 14 days and 78% released in total over a 183-day period. No toxic effects of RTP were seen in human or rat cells in up to 14 days of co-culture with RTP. Following intravitreal injection, intraocular pressure was unaffected by the presence of RTP and no changes in retinal function or structure were observed at 1 week or 1 month post-injection. RTP injection did not cause inflammation, gliosis or apoptosis in the retina. This work demonstrates the potential suitability of the novel RTP as a sustained-release vehicle for ocular drug delivery for anti-neovascular therapies. Optimization of polymer chemistry for optimal drug loading and release is needed.
Highlights
Age-related macular degeneration (AMD) is the leading cause of blindness in Australians over the age of 60 years
In a subset of patients with the most aggressive form of the disease abnormal blood vessels grow beneath the retina and the associated leakage of fluid and blood reduces vision and predisposes to scarring and permanent retinal damage (Shao et al, 2016). The treatment of this form of the disease has been revolutionized by the development of drugs targeting vascular endothelial growth factor (VEGF) (Schachat, 2013), which is produced by the diseased retina and which drives the development of abnormal blood vessels
reverse thermoresponsive polymer (RTP) does not affect the viability of rat and human cell lines To evaluate in vitro biocompatibility of RTP, rat R12 fibroblasts and human SHSY-5Y cells were incubated with RTP (15 mL) for 28 and 11 days respectively
Summary
Age-related macular degeneration (AMD) is the leading cause of blindness in Australians over the age of 60 years. The need for frequent eye injections imposes significant social costs upon patients and exposes them to the cumulative risk of sight-threatening complications of the procedure (Ramsey et al, 2014; Nuzzi and Tridico, 2015; Eadie et al, 2017). In light of this increasing demand, it is necessary to develop a sustained-release intraocular drug delivery vehicle to reduce the frequency of eye injections
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