Purchase this article with an account.
Nadir Alikacem, Toyohisa Yoshizawa, Kevin D. Nelson, Charles A. Wilson; Quantitative MR Imaging Study of Intravitreal Sustained Release of VEGF in Rabbits. Invest. Ophthalmol. Vis. Sci. 2000;41(6):1561-1569.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
purpose. To determine whether sustained elevation of vascular endothelial growth
factor (VEGF) in the vitreous cavity causes retinal hyperpermeability[
blood–retinal barrier (BRB) breakdown] before the development of
retinal neovascularization (NV) and to document the kinetics of the
integrity of BRB breakdown versus time.
methods. Poly(l-lactide-co-glycolide)-based devices
loaded with VEGF were implanted intravitreally in rabbit eyes.
Contrast-enhanced magnetic resonance imaging (MRI) methods were used to
identify and quantitate the retinal permeability at various time points
after implantation. This was done with the newly developed MR tracer
AngioMARK (Epix Medical, Boston, MA). After the MRI measurements,
fundus photography and fluorescein angiography (FA) also were performed
on the same set of animals.
results. At 3 days after implantation, the MR images showed a significant
retinal leakage into the vitreous cavity (BRB breakdown) of the
VEGF-implanted eyes. To quantitate this leakage, the permeability
surface area product (PS) was measured. At 3 days, the mean PS product
was 1.25 ± 0.25 × 10−5 cm3/min.
Based on the VEGF in vitro release study, this 3-day BRB breakdown
corresponded to a total sustained release of 7.42 ± 0.54 μg/ml
of VEGF. The fundus and FA photographs of these VEGF-implanted eyes
taken at 4 days after implantation also showed a considerable level of
retinal vascular dilation and tortuosity. By 12 days after
implantation, the mean PS product decreased to 5.83 ± 1.38 × 10−6 cm3/min. However, the retinal NV was
observed only after the second week after implantation. By this time, a
total of 10.70 ± 0.92 μg/ml of VEGF was released in a sustained
fashion. Also, after the retinal NV development, retinal detachment
also was observed. The control eyes, however, which were implanted with
blank devices, remained unchanged and normal during the entire course
of this study (PS = 5.57 ± 0.66 × 10−7 cm3/min).
conclusions. The findings indicate that sustained delivery of elevated amounts of
VEGF in the vitreous cavity induces a BRB breakdown even earlier than 3
days after implantation. This was achieved after a total sustained
release of 7.42 ± 0.54 μg/ml of VEGF. This retinal leakage
regressed by more than half by the time the retinal NV developed.
Furthermore, a retinal detachment occurred after this retinal NV. These
results are similar to proliferative diabetic retinopathy (PDR). The
sustained elevation of VEGF in the vitreous cavity of rabbit eyes is
potentially a good model to test VEGF antagonists to treat or prevent
PDR in humans. The quantifiable change of BRB breakdown by the
contrast-enhanced MRI method is ideal to assess the therapeutic
intervention in vivo without killing the animal and may prove to be
clinically useful in humans.
This PDF is available to Subscribers Only