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Sunitinib malate-loaded biodegradable microspheres for the prevention of corneal neovascularization in rats
Jin Yang1, Lixia Luo2, Yumin Oh3
1Department of Ophthalmology, Myopia Key Laboratory of Health PR, Eye & ENT Hospital of Fudan University, Shanghai 200031, China; Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; The Center for Nanomedicine at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
Abstract:
Corneal neovascularization (NV) predisposes patients to compromised corneal transparency and visional acuity. Sunitinib malate (Sunb-malate) targeting against multiple receptor tyrosine kinases, exerts potent antiangiogenesis. However, the rapid clearance of Sunb-malate eye drops administered through topical instillation limits its therapeutic efficacy and poses a challenge for potential patient compliance. Sunb-malate, the water-soluble form of sunitinib, was shown to have higher intraocular penetration through transscleral diffusion following subconjunctival (SCT) injection in comparison to its sunitinib free base formulation. However, it is difficult to load highly water-soluble drugs and achieve sustained drug release. We developed Sunb-malate loaded poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres (Sunb-malate MS) with a particle size of approximately 15 μm and a drug loading of 7 wt%. Sunb-malate MS sustained the drug release for 30 days under the in vitro infinite sink condition. Subconjunctival (SCT) injection of Sunb-malate MS provided a prolonged ocular drug retention and did not cause ocular toxicity at a dose of 150 μg of active agent. Sunb-malate MS following SCT injection more effectively suppressed the suture-induced corneal NV than either Sunb-malate free drug or the placebo MS. Local sustained release of Sunb-malate through the SCT injection of Sunb-malate MS mitigated the proliferation of vascular endothelial cells and the recruitment of mural cells into the cornea. Moreover, the gene upregulation of proangiogenic factors induced by the pathological process was greatly neutralized by SCT injection of Sunb-malate MS. Our findings provide a sustained release platform for local delivery of tyrosine kinase inhibitors to treat corneal NV.
Insights
Sustained release of sunitinib malate microspheres via subconjunctival injection effectively treats corneal neovascularization (NV) by prolonging drug retention and reducing ocular toxicity. This platform offers a promising approach for managing NV.
Area of Science:
- Ophthalmology
- Biomaterials Science
- Pharmacology
Background:
- Corneal neovascularization (NV) impairs vision by compromising corneal transparency.
- Sunitinib malate, an antiangiogenic drug, faces challenges with topical eye drop delivery due to rapid clearance and limited efficacy.
- Achieving sustained drug release for water-soluble drugs like sunitinib malate via subconjunctival injection is difficult.
Purpose of the Study:
- To develop and evaluate sunitinib malate-loaded poly(D,L-lactic-co-glycolic acid) (PLGA) microspheres (Sunb-malate MS) for sustained subconjunctival delivery.
- To assess the efficacy of Sunb-malate MS in suppressing suture-induced corneal NV.
- To investigate the ocular toxicity and drug retention of Sunb-malate MS after subconjunctival injection.
Main Methods:
- Sunb-malate MS were formulated with a particle size of ~15 μm and 7 wt% drug loading.
- In vitro drug release studies were conducted under infinite sink conditions, showing sustained release for 30 days.
- Corneal NV was induced by sutures in rabbits, and the efficacy of SCT-injected Sunb-malate MS was compared to free drug and placebo MS.
Main Results:
- Sunb-malate MS demonstrated sustained drug release for 30 days in vitro.
- Subconjunctival injection of Sunb-malate MS provided prolonged ocular drug retention without toxicity at 150 μg.
- Sunb-malate MS significantly suppressed corneal NV, reduced vascular endothelial and mural cell proliferation, and neutralized proangiogenic factors.
Conclusions:
- Sunb-malate MS provide a viable sustained release platform for subconjunctival delivery of sunitinib malate.
- This approach effectively mitigates corneal neovascularization with improved ocular drug retention and safety.
- The developed microsphere system holds promise for treating corneal NV and potentially other ocular diseases requiring local sustained drug delivery.
