Utilizing targeted gene therapy with nanoparticles binding alpha v beta 3 for imaging and treating choroidal neovascularization |
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Authors: | Salehi-Had Hani Roh Mi In Giani Andrea Hisatomi Toshio Nakao Shintaro Kim Ivana K Gragoudas Evangelos S Vavvas Demetrios Guccione Samira Miller Joan W |
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Institution: | Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America. |
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Abstract: | PurposeThe integrin αvβ3 is differentially expressed on neovascular
endothelial cells. We investigated whether a novel intravenously injectable
αvβ3 integrin-ligand coupled nanoparticle (NP) can target choroidal
neovascular membranes (CNV) for imaging and targeted gene therapy.MethodsCNV lesions were induced in rats using laser photocoagulation. The utility of
NP for in vivo imaging and gene delivery was evaluated by
coupling the NP with a green fluorescing protein plasmid (NP-GFPg).
Rhodamine labeling (Rd-NP) was used to localize NP in choroidal flatmounts.
Rd-NP-GFPg particles were injected intravenously on weeks 1, 2, or 3. In the
treatment arm, rats received NP containing a dominant negative Raf mutant
gene (NP-ATPμ-Raf) on days 1, 3, and 5. The change in CNV size and
leakage, and TUNEL positive cells were quantified.ResultsGFP plasmid expression was seen in vivo up to 3 days after
injection of Rd-NP-GFPg. Choroidal flatmounts confirmed the localization of
the NP and the expression of GFP plasmid in the CNV. Treating the CNV with
NP-ATPμ-Raf decreased the CNV size by 42% (P<0.001). OCT
analysis revealed that the reduction of CNV size started on day 5 and
reached statistical significance by day 7. Fluorescein angiography grading
showed significantly less leakage in the treated CNV (P<0.001). There
were significantly more apoptotic (TUNEL-positive) nuclei in the treated
CNV.ConclusionSystemic administration of αvβ3 targeted NP can be used to label the
abnormal blood vessels of CNV for imaging. Targeted gene delivery with
NP-ATPμ-Raf leads to a reduction in size and leakage of the CNV by
induction of apoptosis in the CNV. |
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