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Xiaohui Zhang, Austin Bohner, Sailaja Bondalapati, Santosh Kumar Kumar Muddana, Hironori Uehara, Bonnie Archer, Balamurali Ambati; Dose-Efficacy and Safety of Targeted Intraceptor Flt23k Nanoparticle in Mice. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3322.
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© ARVO (1962-2015); The Authors (2016-present)
Previously we demonstrated that targeted Arg-Gly-Asp (RGD) intraceptor Flt23k nanoparticle (RGD.Flt23k.NP) inhibits choroidal neovascularization (CNV) in murine and monkey models. The present study measures the dose response and efficacy of intravenously administered RGD.Flt23k.NP on regression of laser-induced CNV in mice to establish its safety and tolerability.
To determine whether RGD.Flt23k.NP nanoparticles exhibit dose dependent inhibition and regression of laser-induced CNV, Anesthetized, 6-8 week old maleC57Bl/6J mice received laser injury in both eyes. One week after laser injury, mice were treated with 0 (PBS), 1, 3, 10, 20, 30, or 40µg RGD.Flt23k.NP suspension via tail vein (n = 7 mice). CNV size was assessed by fluorescein angiography (FA) and optical coherence tomography (OCT) at baseline (post laser 1 week) and 2 weeks after treatment. To assess safety and tolerability of the Flt23k nanoparticles, we intravenously injected 5 male and 5 female mice with a single treatment of RGD.Flt23k.NP. based on the above dose-efficacy assay. Systemic toxicity was evaluated after one month by assaying hematology, histology, immune responses, and changes in mortality and body weight. The control groups included untreated C57BL/6J and C57BL/6J mice receiving an identical dose of RGD delivery blank nanoparticles (RGD.Bk.NP).
Compared to CNV volumes 1 week post laser (baseline) v, the CNV volumes evaluated at 2 weeks were decreased by 4.19%, 9.43%, 9.61%, 22.52%, 27.18%, 29.70%, and 39.81%, corresponding to: PBS, 1, 3, 10, 20, 30 and 40 µg of plasmid respectively. We choose a plasmid dose of 30 µg to evaluate safety in mice. The treated mice showed equivalent mortality to controls, while body weights were not statistically different. The concentration of hemoglobin in red blood cells was 2.59 ± 0.27 g/dl, 2.62 ± 0.34 g/dl, and 2.60 ± 0.21 g/dl in the wildtype, RGD.Bk.NP, and RGD.Flt23k.NP groups respectively. The concentration of complement C3 in plasma was 581.45 ± 82.07 µg/ml, 633.13 ± 95.82 µg/ml, and 614.60 ± 102.05 µg/ml in wildtype, RGD.Bk.NP, and RGD.Flt23k.NP groups respectively. Both the concentrations of hemoglobin and complement C3 were not statistically different between RGD.Flt23k.NP and control groups.
Intraceptor Flt23k nanoparticles dose-dependently improve recovery from CNV injury and are well tolerated with no obvious systemic defects.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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