Article
In vivo biodistribution and microvascular binding of a high-affinity monoclonal antibody fragment F8-SIP against the extra-domain A of fibronectin
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Published: | May 20, 2009 |
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Objective: The human monoclonal antibody fragment F8-SIP (small immunoprotein) is specific to the angiogenic marker EDA domain of fibronectin. The aim of our study was to characterize microvascular binding and biodistribution characteristics of F8-SIP.
Methods: SF126 cells were implanted into dorsal skin chamber (DSC) preparations of nude mice. Microvascular and interstitial accumulation of F8-SIP and microvascular blood flow rates were analyzed at t=0h, t=2h, t=4h, and t=24h after intra-arterial application of fluorescence labeled F8-SIP (n=5 per group) by intravital microscopy. Host vasculature of mice without tumor bearing DSCs were used as control group.
Results: F8-SIP binds specifically to tumor vessels reaching its maximum binding capacity 4 hours after injection (t=0h: 26.12±10.89 vs. t=4h: 91.46±6.19; p<0.05). In control vasculature no binding was observed. Extravasation of F8-SIP into the tumor interstice was observed reaching its maximum 4 hours after injection (t=0h: 19.25±9.45 vs. t=4h: 60.41±7.77; p<0.05). Microvascular binding was flow-dependent with significantly increased binding in high flow-blood vessels (HF≥60nl/sec) compared to low flow-blood vessels (LF≤20nl/sec) by 44% at t=2h and by 22% at t=4h, respectively. F8-SIP binding preferentially occurred in angiogenic sprouts (AS) compared to remaining tumor vasculature (RTV) 2 hours after injection (AS: 115.14±12.38 vs. RTV: 77.86±11.25; p<0.05).
Conclusions: F8-SIP represents a useful tool to specifically target tumor microvessels. Microvascular binding occurs in a time- and blood flow dependent manner with preferential binding sites. Our results provide biodistribution characteristics that might be used for future clinical applications.