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Jeffrey L Cleland, Rishi Sharma, Santiago Appiani, Justin Prater, M. Grazia Spiga, David Culp; Suppression of Murine Choroidal Neovascularization After Systemic Administration of a Targeted Anti-VEGF Therapy. Invest. Ophthalmol. Vis. Sci. 2020;61(7):3974.
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To evaluate the efficacy of hydroxyl dendrimers covalently conjugated with analogs of sunitinib in a mouse model of laser-induced choroidal neovascularization (CNV).
Hydroxyl dendrimers (~14000 Da, 4 nm), which selectively target inflammation, were covalently conjugated to analogs of sunitinib, an FDA-approved potent VEGF receptor tyrosine kinase inhibitor. Conjugates were made with a cleavable sunitinib analog (D-CSA) or a non-cleavable sunitinib analog (D-NSA) and drug release was evaluated at 37oC in PBS, pH 7.4 or citrate buffer, pH 5.5 with esterase. Laser-induced CNV was performed in both eyes of C57BL/6 mice (n=8/group) 24 hr prior to dose administration. Mice were administered IV (100 µL) vehicle, D-CSA (5.25 (low) or 26.25 (high) mg/kg sunitinib equivalent), D-NSA (6.3 (low) or 15.75 (high) mg/kg sunitinib equivalent), or free sunitinib (32.5 mg/kg) or administered aflibercept intravitreally (IVT; 1 µL, 40 µg). The CNV area was measured 7 days after laser treatment by both fluorescein angiography and flat-mounts of the sclera-choroid/RPE complexes stained with isolectin IB4.
D-CSA was prepared with 5 sunitinib analogs per dendrimer (10.5% w/w) and D-NSA was prepared with 7 sunitinib analogs per dendrimer (12.6% w/w). Over 6 days in vitro, D-CSA released ~65% of the sunitinib at pH 5.5 with esterase (intracellular conditions) and ~15% release of sunitinib occurred over 24 hr at pH 7.4 (plasma conditions). As expected, D-NSA did not release the sunitinib analog. Statistically significant reductions in the CNV area were observed for IVT aflibercept and both IV dose levels of D-CSA and D-NSA but not free sunitinib (even at 5-fold higher doses compared to low dose D-CSA), compared with vehicle control (Figure below). Further studies evaluating lower D-CSA and D-NSA dose levels and IP administration in this murine model are planned.
Hydroxyl dendrimers conjugated with sunitinib analogs administered systemically inhibit CNV comparable to IVT aflibercept and free sunitinib. The non-cleavable sunitinib analog efficacy in CNV area reduction suggests that sunitinib release from the dendrimer may not be required. Previous studies have shown hydroxyl dendrimers and dendrimer-drug conjugates are retained in CNV lesions > 28 days and systemically cleared intact within 24 hr in mice and humans without detectable liver or other off-target toxicity.
This is a 2020 ARVO Annual Meeting abstract.
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