Sunitinib malate-loaded biodegradable microspheres for the prevention of corneal neovascularization in rats

Yang, Jin; Luo, Lixia; Oh, You-Take; Meng, Tuo; Chai, Guihong; Xia, Shiyu; Emmert, David; Wang, Bing; Eberhart, Charles G.; Lee, Seulki; Stark, Walter J.; Ensign, Laura M.; Xu, Qingguo

doi:10.1016/j.jconrel.2020.08.019

Cited by 28 publications

(29 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We next sought to investigate the effect of subconjunctival injection volume on ocular pharmacokinetics. As the microcrystals have higher drug loading than typical polymeric microparticles, we were able to inject similar doses to what we have investigated previously for preventing corneal neovascularization [ 25 ] with as little as 5 µL. We compared different SPC microcrystal doses to determine a dose that would result in therapeutically relevant sunitinib concentrations in the retina [ 28 ].…”

Section: Resultsmentioning

confidence: 99%

“…Sunitinib was developed as a tyrosine kinase inhibitor, and thus, better known for its antiangiogenic properties via inhibition of vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR) [ 33 ]. We previously demonstrated that subconjunctival injection of polymeric microparticles to deliver sunitinib malate provided inhibition of corneal neovascularization in rats, whereas injection of free sunitinib malate in solution had no effect on neovascularization [ 25 ]. Based upon these results, we tested whether anterior subconjunctival injection of SPC microcrystals could inhibit corneal neovascularization.…”

Section: Resultsmentioning

confidence: 99%

“…It was previously shown that subconjunctival injection of water-soluble drugs leads to increased intraocular bioavailability, potentially due to the higher concentration gradient and increased transscleral drug penetration [ 41 , 42 , 43 , 44 ]. However, water-soluble drugs are cleared from the subconjunctival space within hours [ 25 ] limiting the duration of therapeutic effect that can be achieved. Thus, drug delivery formulations for subconjunctival injection would ideally encapsulate and provide sustained release of water-soluble drugs, but prior attempts at this approach have been difficult to achieve.…”

Section: Discussionmentioning

confidence: 99%

“…We previously described approaches for loading water soluble dexamethasone sodium phosphate and sunitinib malate into polymeric particles for subconjunctival injection, providing sustained prevention or treatment of corneal graft rejection [ 42 ], corneal neovascularization [ 25 , 45 ] and uveitis [ 24 ]. However, one potential drawback was relatively low drug loading in the range of 6–8% by weight.…”

Section: Discussionmentioning

confidence: 99%

“…Here, we describe an approach for formulating sunitinib for prolonged therapeutic effects with subconjunctival injection. We previously observed that the water-soluble salt form of drugs, including sunitinib malate, was preferred for achieving intraocular drug penetration upon subconjunctival injection [ 24 , 25 ]. However, high water solubility presents a challenge to achieving sustained drug release using conventional encapsulation approaches.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells

et al. 2021

Self Cite

View full text Add to dashboard Cite

Glaucoma is the leading cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) is one of the major risk factors for glaucoma onset and progression, and available pharmaceutical interventions are exclusively targeted at IOP lowering. However, degeneration of retinal ganglion cells (RGCs) may continue to progress despite extensive lowering of IOP. A complementary strategy to IOP reduction is the use of neuroprotective agents that interrupt the process of cell death by mechanisms independent of IOP. Here, we describe an ion complexation approach for formulating microcrystals containing ~50% loading of a protein kinase inhibitor, sunitinib, to enhance survival of RGCs with subconjunctival injection. A single subconjunctival injection of sunitinib-pamoate complex (SPC) microcrystals provided 20 weeks of sustained retina drug levels, leading to neuroprotection in a rat model of optic nerve injury. Furthermore, subconjunctival injection of SPC microcrystals also led to therapeutic effects in a rat model of corneal neovascularization. Importantly, therapeutically relevant retina drug concentrations were achieved with subconjunctival injection of SPC microcrystals in pigs. For a chronic disease such as glaucoma, a formulation that provides sustained therapeutic effects to complement IOP lowering therapies could provide improved disease management and promote patient quality of life.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells

et al. 2021

Self Cite

View full text Add to dashboard Cite

show abstract

Injectable Anti‐Inflammatory Supramolecular Nanofiber Hydrogel to Promote Anti‐VEGF Therapy in Age‐Related Macular Degeneration Treatment

et al. 2022

View full text Add to dashboard Cite

Age‐related macular degeneration (AMD) is a major cause of visual impairment and severe vision loss worldwide, while the currently available treatments are often unsatisfactory. Previous studies have demonstrated both inflammation and oxidative‐stress‐induced damage to the retinal pigment epithelium are involved in the pathogenesis of aberrant development of blood vessels in wet AMD (wet‐AMD). Although antivascular endothelial growth factor (VEGF) therapy (e.g., Ranibizumab) can impair the growth of new blood vessels, side effects are still found with repeated monthly intravitreal injections. Here, an injectable antibody‐loaded supramolecular nanofiber hydrogel is fabricated by simply mixing betamethasone phosphate (BetP), a clinic anti‐inflammatory drug, anti‐VEGF, the gold‐standard anti‐VEGF drug for AMD treatment, with CaCl2. Upon intravitreal injection, such BetP‐based hydrogel (BetP‐Gel), while enabling long‐term sustained release of anti‐VEGF to inhibit vascular proliferation in the retina and attenuate choroidal neovascularization, can also scavenge reactive oxygen species to reduce local inflammation. Remarkably, such BetP‐Gel can dramatically prolong the effective treatment time of conventional anti‐VEGF therapy. Notably, anti‐VEGF‐loaded supramolecular hydrogel based on all clinically approved agents may be readily translated into clinical use for AMD treatment, with the potential to replace the current anti‐VEGF therapy.

show abstract

Ferrostatin‐1‐loaded liposome for treatment of corneal alkali burn via targeting ferroptosis

Wang

Jiang

Zhong

et al. 2021

Bioengineering & Transla Med

View full text Add to dashboard Cite

Alkali burn is a potentially blinding corneal injury. During the progression of alkali burn‐induced injury, overwhelmed oxidative stress in the cornea triggers cell damage, including oxidative changes in cellular macromolecules and lipid peroxidation in membranes, leading to impaired corneal transparency, decreased vision, or even blindness. In this study, we identified that ferroptosis, a type of lipid peroxidation‐dependent cell death, mediated alkali burn‐induced corneal injury. Ferroptosis‐targeting therapy protected the cornea from cell damage and neovascularization. However, the specific ferroptosis inhibitor ferrostatin‐1 (Fer‐1) is hydrophobic and cannot be directly applied in the clinic. Therefore, we developed Fer‐1‐loaded liposomes (Fer‐1‐NPs) to improve the bioavailability of Fer‐1. Our study demonstrated that Fer‐1‐NPs exerted remarkable curative effects regarding corneal opacity and neovascularization in vivo. The efficacy was comparable to that of dexamethasone, but without appreciable side effects. The significant suppression of ferroptosis (induced by lipid peroxidation and mitochondria disruption), inflammation, and neovascularization might be the mechanisms underlying the therapeutic effect of Fer‐1‐NPs. Moreover, the Fer‐1‐NPs treatment showed no signs of cytotoxicity, hematologic toxicity, or visceral organ damage, which further confirmed the biocompatibility. Overall, Fer‐1‐NPs provide a new prospect for safe and effective therapy for corneal alkali burn.

show abstract

Sunitinib malate-loaded biodegradable microspheres for the prevention of corneal neovascularization in rats

Cited by 28 publications

References 49 publications

Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells

Ion-Complex Microcrystal Formulation Provides Sustained Delivery of a Multimodal Kinase Inhibitor from the Subconjunctival Space for Protection of Retinal Ganglion Cells

Injectable Anti‐Inflammatory Supramolecular Nanofiber Hydrogel to Promote Anti‐VEGF Therapy in Age‐Related Macular Degeneration Treatment

Ferrostatin‐1‐loaded liposome for treatment of corneal alkali burn via targeting ferroptosis

Contact Info

Product

Resources

About