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Size optimization of synthetic graft copolymers for in vivo angiogenesis imaging
R Weissleder1, A Bogdanov, C H Tung
1The Center for Molecular Imaging Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. weissleder@helix.mgh.harvard.edu
Abstract:
Angiogenesis is a critical step in tumor development and more than 25 angiogenesis inhibitors are currently in clinical trials. Noninvasive in vivo imaging of angiogenesis represents a unique opportunity of repeatedly quantitating microvascular parameters prior to and during anti-angiogenic treatments. While several imaging tracers have been proposed for MR and nuclear imaging, there does not exist any consensus of what constitutes an ideal size of an imaging agent. A series of synthetic pegylated DOTA derivatized graft copolymers (30, 60, 120 kDa) were synthesized and their in vivo behavior tested in two breast cancer models differing in vascular endothelial growth factor (VEGF) expression. Polymers were labeled with different lanthanides (Eu, Gd, Dy) and absolute blood and tumor concentrations were determined by ICP-AES measurements. DOTA and the 30 kDa polymers underwent renal clearance resulting in low plasma levels. Slow leakage across neovasculature into tumor interstitium was clearly dependent on the molecular mass of all tested agents in MCF-7 tumors. However, a cutoff was observed with minimal extravasation occurring at and above 120 kDa in well differentiated MCF-7 tumors. VEGF overexpression caused detectable differences in extravasation of all polymers, including the 120 kDa compound. We conclude that large molecular weight contrast agents with a molecular mass of <120 kDa extravasate from experimental tumor neovasculature and may not be an accurate marker for measuring true blood volume fractions when in vivo imaging is performed in the steady state.
Insights
Large contrast agents (<120 kDa) can leak from tumor blood vessels, potentially skewing imaging results. Careful selection of molecular weight is crucial for accurate in vivo angiogenesis imaging.
Area of Science:
- Biomedical imaging
- Nanotechnology
- Oncology
Background:
- Angiogenesis is vital for tumor growth, with numerous inhibitors in development.
- Noninvasive imaging of angiogenesis allows monitoring of anti-angiogenic therapies.
- The optimal size for in vivo imaging agents remains undefined.
Purpose of the Study:
- To synthesize and evaluate pegylated DOTA-derivatized graft copolymers of varying molecular weights (30, 60, 120 kDa) for angiogenesis imaging.
- To assess the in vivo behavior and extravasation of these agents in breast cancer models.
- To determine the influence of molecular weight and vascular endothelial growth factor (VEGF) expression on imaging agent performance.
Main Methods:
- Synthesis of pegylated DOTA-graft copolymers (30, 60, 120 kDa).
- In vivo testing in two breast cancer models with differing VEGF expression.
- Lanthanide labeling (Eu, Gd, Dy) and quantification of blood/tumor concentrations via ICP-AES.
- Analysis of polymer extravasation across tumor neovasculature.
Main Results:
- Polymers <120 kDa showed size-dependent leakage into tumor interstitium in MCF-7 tumors.
- Minimal extravasation was observed for agents ≥120 kDa in well-differentiated MCF-7 tumors.
- VEGF overexpression influenced extravasation across all tested polymer sizes, including the 120 kDa compound.
Conclusions:
- Large molecular weight contrast agents (<120 kDa) can extravasate from tumor neovasculature.
- These agents may not accurately reflect true blood volume fractions in steady-state in vivo imaging.
- Molecular weight is a critical factor in designing effective angiogenesis imaging agents.