Toxicity and intraocular properties of a novel long-acting anti-proliferative and anti-angiogenic compound IMS2186.
OBJECTIVE
To investigate the intraocular properties and toxicity of IMS2186, a small molecule developed as an anti-choroidal neovascularization (anti-CNV) drug.


METHODS
Cellular toxicity and mechanism of action was tested on cell lines in vitro. Intraocular studies used rabbits for drug dissolution as well as toxicity and rats for the treatment study as well as the toxicity confirmation study. Rabbits' eyes were injected with 2.5 mg of IMS2186 and observed for 36 weeks. Laser-induced CNV in rats was treated with IMS2186, Kenalog, or phosphate-buffered saline (pBS). Fluorescein angiography (FA) and immunohistochemical processing of the globes was performed.


RESULTS
The anti-proliferative IC(50) of IMS2186 for human fibroblast cells was 1.0-3.0 microM and 0.3-3.0 microM for human cancer cells; the IC(50) of IMS2186 to inhibit endothelial tube formation was 0.1-0.3 microM. The IC(50) of IMS2186 for inhibiting the production of pro-inflammatory cytokines was 0.3-1 microM. The IC(50) of IMS2186 for inhibiting macrophage migration was 1 micrM. These biological properties were not species specific. IMS2186 can be formulated as a suspension for long-lasting release and when delivered intraocularly, no intraocular toxicity was observed by slit lamp exam, fundus exam, intraocular pressure measurements, or by electroretinography. FA showed a reduction in the leakage in eyes treated with IMS2186 and triamcinolone acetonide; DAPI staining also showed significantly less cellularity in IMS2186-treated lesions as compared to PBS (p = 0.0025).


CONCLUSIONS
IMS2186 may be a safe intraocular therapeutic agent for intraocular proliferation and angiogenesis.
Falkenstein
Iryna A
IA
Joan and Irwin Jacobs Retina Center, Department of Ophthalmology, Shiley Eye Center, University of California, San Diego, California, USA.
Cheng
Lingyun
L
Wong-Staal
Flossie
F
Tammewar
Ajay M
AM
Barron
Erin C
EC
Silva
Gabriel A
GA
Li
Qi-Xiang
QX
Yu
Dehua
D
Hysell
Michelle
M
Liu
Guohong
G
Ke
Ning
N
Macdonald
James E
JE
Freeman
William R
WR
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D020256:Choroidal Neovascularization / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002867:Chromones / Q000494:pharmacology / Q000633:toxicity*; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004596:Electroretinography / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D005451:Fluorescein Angiography; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells / Q000187:drug effects; D010857:Pigment Epithelium of Eye / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011914:Rats, Inbred BN; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014471:Umbilical Veins / Q000166:cytology; D014945:Wound Healing / Q000187:drug effects
C531080:3-(1-(3-hydroxy-4-methoxyphenyl)methylidene)-6-methylchroman-4-one; D020533:Angiogenesis Inhibitors; D002867:Chromones; D015232:Dinoprostone