Inhibition of in vitro VEGF expression and choroidal neovascularization by synthetic dendrimer peptide mediated delivery of a sense oligonucleotide

Marano, Robert J.; Wimmer, Norbert; Kearns, Philip S.; Thomas, Bradley G.; Tóth, István; Brankov, Meliha; Rakoczy, P. Elizabeth

doi:10.1016/j.exer.2004.06.023

Cited by 86 publications

(68 citation statements)

References 26 publications

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“…However, in the groups that were injected with dendrimer plus ODN-1, the level of CNV development was significantly reduced (Po0.05) at the initial 2-month period compared to the controls. This result was in accordance with our previous study 12 and indicates that the dendrimer not only protects ODN-1 from the effects of nucleases but also mediates its delivery to the site of activity. Further evaluation at the 4-month time point later revealed that the level of CNV inhibition was reduced but still statistically significant (Po0.05).…”

Section: Discussionsupporting

confidence: 93%

“…In this study, we extend the initial research of Marano et al 12 and examine the issue of longevity of dendrimer plus ODN-1 conjugates. The duration of the study was extended to 6 months, and the efficacy of the conjugates to inhibit laser-induced CNV was examined at various time points.…”

Section: Introductionmentioning

confidence: 82%

“…Previously in our laboratories, we have sought to overcome both of these problems with the introduction of a dendrimer-mediated delivery system for ODN-1, an anti-VEGF sense oligonucleotide, initially in vitro and subsequently in vivo. 12,13 In this instance, the dendrimer under investigation provided the conjugated ODN-1 a high degree of protection against nucleases in addition to effecting efficient delivery to the target site. However, the effective time of this protection, and its comparison to other methods of improving longevity had not yet been fully explored.…”

Section: Discussionmentioning

confidence: 99%

“…Rats were injected in both eyes with either ODN-1 or ODN-1 conjugated to a previously described dendrimer. 12 CNV was induced using the laser photocoagulation method 17 at 2, 4 and 6 months post injection. The eyes were subsequently examined using CFP, FA, histology and immunohistochemistry and evaluated for the extent of neovascularization in addition to uptake, distribution and toxicity of both ODN-1 alone and dendrimer plus ODN-1.…”

Section: Discussionmentioning

confidence: 99%

“…More recently, we described the synthesis and use of lipophilic amino-acid dendrimers that enhanced the delivery of ODN-1 into the retinal tissue of rats. 12,13 In addition, the data from this earlier study suggested that the dendrimers served as a protective agent against the effects of nucleases while enabling ODN-1 to interact with its target site within the gene.…”

Section: Introductionmentioning

confidence: 87%

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Dendrimer delivery of an anti-VEGF oligonucleotide into the eye: a long-term study into inhibition of laser-induced CNV, distribution, uptake and toxicity

et al. 2005

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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 (Po0.05) 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 (P40.05) in mean severity score at 2 months (2.8670.09), 4 months (2.1570.17) or 6 months (2.770.12) 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. Gene Therapy (2005) 12, 1544-1550.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 87%

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