Sustained Release from Biodegradable Microparticles of Bioactive Cysteinyl Leukotriene Receptor Antagonists for the Treatment of Ocular Neovascularisation

Abstract

Purpose: There is an unmet need in ocular neovascular-based diseases to improve current delivery modalities to the eye. This is highlighted by the requirement of current gold-standard anti-VEGF drugs to be administered bi-/monthly by intravitreal injection. Our objective is to enhance the delivery of bespoke novel anti-angiogenic drugs using biodegradable sustained-release devices.

Methods: Two novel VEGF-independent, cysteinyl leukotriene receptor antagonists (Quininib [QB] & Quininib-12 [QB12]) previously identified as anti-angiogenic in zebrafish, cells and mice were formulated into biodegradable PLGA and alginate microparticles. Drug-loaded microparticles were characterised in terms of shape, size and loading efficiency. Drug release from microparticle subtypes was determined by in vitro release studies using HPLC. The Efficacy of released drug was evaluated in vitro with tubule formation assays, ex vivo with rodent aortic rings and in vivo using larval zebrafish angiogenesis assays.

Results: QB & QB12 were successfully formulated into PLGA and alginate microspheres of ~1-2 µm. Notably, in vitro release studies demonstrate high concentrations of QB drug released from PLGA and alginate microparticles for up to one month. Importantly, QB released from microparticles retained anti-angiogenic efficacy in vivo. We are currently evaluating if these microparticles inhibit HMEC-1 tubule formation and reduce sprouting angiogenesis from rodent aortic rings. Future directions will test the safety, pharmacokinetics and efficacy of these Quininib-loaded microparticle formulations in rodent models.

Conclusions: We successfully encapsulated small molecule cysteinyl leukotriene receptor antagonists into slow release preparations. The ultimate goal is to determine if these encapsulated anti-angiogenic drugs offer an improved sustained and effective treatment for ocular neovascularisation.