title: Targeted Intraceptor Nanoparticle for Neovascular Macular Degeneration: Preclinical Dose Optimization and Toxicology Assessment.
abstract: Neovascular age-related macular degeneration (AMD) is treated with anti-VEGF intravitreal injections, which can cause geographic atrophy, infection, and retinal fibrosis. To minimize these toxicities, we developed a nanoparticle delivery system for recombinant Flt23k intraceptor plasmid (RGD.Flt23k.NP) to suppress VEGF intracellularly within choroidal neovascular (CNV) lesions in a laser-induced CNV mouse model through intravenous administration. In the current study, we examined the efficacy and safety of RGD.Flt23k.NP in mice. The effect of various doses was determined using fluorescein angiography and optical coherence tomography to evaluate CNV leakage and volume. Efficacy was determined by the rate of inhibition of CNV volume at 2 weeks post-treatment. RGD.Flt23k.NP had peak efficacy at a dose range of 30-60 μg pFlt23k/mouse. Using the lower dose (30 μg pFlt23k/mouse), RGD.Flt23k.NP safety was determined both in single-dose groups and in repeat-dose (three times) groups by measuring body weight, organ weight, hemoglobin levels, complement C3 levels, and histological changes in vital organs. Neither toxicity nor inflammation from RGD.Flt23k.NP was detected. No side effect was detected on visual function. Thus, systemic RGD.Flt23k.NP may be an alternative to standard intravitreal anti-VEGF therapy for the treatment of neovascular AMD.
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Austin
authors.initials: A
authors.lastname: Bohner
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Sai
authors.initials: S
authors.lastname: Bhuvanagiri
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Hironori
authors.initials: H
authors.lastname: Uehara
authors.affiliation: University of Colorado School of Pharmacy, Mail Stop C238, 12850 E. Montview Blvd. V20-4129, Aurora, CO 80045, USA.
authors.forename: Arun Kumar
authors.initials: AK
authors.lastname: Upadhyay
authors.affiliation: Department of Pathology, University of Utah and Associated Regional and University Pathologists (ARUP) Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108, USA.
authors.forename: Lyska L
authors.initials: LL
authors.lastname: Emerson
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Sailaja
authors.initials: S
authors.lastname: Bondalapati
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Muddana
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Fang
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA; State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.
authors.forename: Miaoling
authors.initials: M
authors.lastname: Li
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Zoya
authors.initials: Z
authors.lastname: Sandhu
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Alya
authors.initials: A
authors.lastname: Hussain
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Lara S
authors.initials: LS
authors.lastname: Carroll
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Tiem
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Archer
authors.affiliation: University of Colorado School of Pharmacy, Mail Stop C238, 12850 E. Montview Blvd. V20-4129, Aurora, CO 80045, USA.
authors.forename: Uday
authors.initials: U
authors.lastname: Kompella
authors.affiliation: Singapore Eye Research Institute, Singapore 169856, Singapore.
authors.forename: Rajkumar
authors.initials: R
authors.lastname: Patil
authors.affiliation: Moran Eye Center, University of Utah, 65 Mario Capecchi Dr., Salt Lake City, UT 84132, USA. Electronic address: bala.ambati@utah.edu.
authors.forename: Balamurali K
authors.initials: BK
authors.lastname: Ambati
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry; D000818:Animals; D002829:Choroid / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D020256:Choroidal Neovascularization / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D003176:Complement C3 / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D004353:Drug Evaluation, Preclinical; D005260:Female; D005786:Gene Expression Regulation; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D058449:Intravitreal Injections; D007834:Lasers; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D003176:Complement C3; D004337:Drug Carriers; D006454:Hemoglobins; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: RGD.Flt23k.NP efficacy; RGD.Flt23k.NP safety; age-related macular degeneration