Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity.
We have performed a long-term study into the use of a lipophilic amino-acid dendrimer to deliver an anti-vascular endothelial growth factor (VEGF) oligonucleotide (ODN-1) into the eyes of rats and inhibit laser-induced choroidal neovascularization (CNV). In addition, the uptake, distribution and retinal tolerance of the dendrimer plus oligonucleotide conjugates were examined. Analysis of fluorescein angiograms of laser photocoagulated eyes revealed that dendrimer plus ODN-1 significantly inhibited (P<0.05) the development of CNV for 4-6 months by up to 95% in the initial stages. Eyes similarly injected with ODN-1 alone showed no significant difference (P>0.05) in mean severity score at 2 months (2.86+/-0.09), 4 months (2.15+/-0.17) or 6 months (2.7+/-0.12) compared to the vehicle-injected controls. Furthermore, we showed that intravitreally injected ODN-1 tagged with 6-fam was absorbed by a wide area of the retina and penetrated all of the retinal cell layers to the retinal pigment epithelium. Ophthalmological examinations indicated that the dendrimers plus ODN-1 conjugates were well tolerated in vivo, which was later confirmed using immunohistochemistry, which showed no observable increase in antigens associated with inflammation. We conclude that the use of such dendrimers may provide a viable mechanism for the delivery of therapeutic oligonucleotides for the treatment of angiogenic eye diseases.
Marano
R J
RJ
Department of Molecular Ophthalmology, Lions Eye Institute, Nedlands, WA, Australia.
Toth
I
I
Wimmer
N
N
Brankov
M
M
Rakoczy
P E
PE
D000818:Animals; D002829:Choroid / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000000981:diagnostic imaging / Q000378:metabolism / Q000628:therapy*; D050091:Dendrimers / Q000008:administration & dosage* / Q000737:chemistry; D005451:Fluorescein Angiography; D005629:Frozen Sections; D015316:Genetic Therapy / Q000379:methods*; D007150:Immunohistochemistry / Q000379:methods; D007267:Injections; D007834:Lasers; D008856:Microscopy, Fluorescence; D023421:Models, Animal; D009841:Oligonucleotides / Q000008:administration & dosage*; D011859:Radiography; D051381:Rats; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D014822:Vitreous Body
D050091:Dendrimers; D009841:Oligonucleotides; D042461:Vascular Endothelial Growth Factor A