TY - JOUR
T1 - Sunitinib malate-loaded biodegradable microspheres for the prevention of corneal neovascularization in rats
AU - Yang, Jin
AU - Luo, Lixia
AU - Oh, Yumin
AU - Meng, Tuo
AU - Chai, Guihong
AU - Xia, Shiyu
AU - Emmert, David
AU - Wang, Bing
AU - Eberhart, Charles G.
AU - Lee, Seulki
AU - Stark, Walter J.
AU - Ensign, Laura M.
AU - Hanes, Justin
AU - Xu, Qingguo
N1 - Funding Information:
This work has been supported by the Raymond Kwok Family Research Fund , the Andreas Dracopoulos Research fund , the George and Lavinia Blick Research Fund , the Eye Bank Association of America/Richard Lindstrom Research Grant 2013, Ralph E. Powe Junior Faculty Enhancement Award, the National Institutes of Health ( R01EY027827 , P30-EY001765 , UG3DA048768 ), the FDA ( HHSF223201810114C ), and an unrestricted departmental grant from Research to Prevent Blindness (RPB).
Publisher Copyright:
© 2020
PY - 2020/11/10
Y1 - 2020/11/10
N2 - 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.
AB - 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.
KW - Controlled drug release
KW - PLGA
KW - Subconjunctival injection
KW - Trans-scleral delivery
KW - Tyrosine kinase inhibitor
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U2 - 10.1016/j.jconrel.2020.08.019
DO - 10.1016/j.jconrel.2020.08.019
M3 - Article
C2 - 32822742
AN - SCOPUS:85089848827
VL - 327
SP - 456
EP - 466
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -