Microvascular biodistribution of L19-SIP in angiogenesis targeting strategies.

Marcus Czabanka, Güliz Parmaksiz, Simon H Bayerl, Melina Nieminen, Eveline Trachsel, Hans D Menssen, Ralf Erber, Dario Neri, Peter Vajkoczy

Department of Neurosurgery, Universitätsmedizin Charitè, Campus Virchow Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany.

European journal of cancer (Oxford, England : 1990) 2011 May

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Various strategies using L19-mediated fibronectin targeting have become useful clinical tools in anti-tumour therapy and diagnostics. The aim of our study was to characterise the microvascular biodistribution and binding process during tumour angiogenesis and after anti-angiogenic therapy. SF126 glioma and F9 teratocarcinoma cells were implanted into dorsal skin fold chambers (SF126: n = 4; F9: n = 6). Using fluorescence and confocal intravital microscopy the biodistribution process was assessed at t = 0 h, t = 4 h and t = 24 h after intravenous application of Cy3-L19-SIP. Sunitinib treatment was applied for six days and microscopy was performed 2 and 6 days after treatment initiation. Analysed parameters included: vascular and interstitial binding, preferential binding sites of L19-SIP, microvascular blood flow rate, microvascular permeability. Histological analysis included CD31 and DAPI. L19-SIP showed a specific and time-dependent neovascular binding with a secondary extravasation process reaching optimal vascular/interstitial binding ratio 4 hours after iv administration (F9: L19-SIP: vascular binding: 74.6 ± 14.5; interstitial binding: 46.8 ± 12.1; control vascular: 22,2 ± 16.6). Angiogenic sprouts were preferred binding sites (F9: L19-SIP: 188 ± 15.5; RTV: 90.6 ± 13.5). Anti-angiogenic therapy increased microvascular hemodynamics (SF126: Su: 106.6 ± 13.3 μl/sec; Untreated: 19.7 ± 9.1 μl/sec) and induced increased L19-SIP accumulation (SF 126: t24; Su: 92.6 ± 2.7; Untreated: 71.9 ± 5.9) in therapy resistant tumour vessels. L19-SIP shows a time and blood-flow dependent microvascular biodistribution process with angiogenic sprouts as preferential binding sites followed by secondary extravasation of the antibody. Microvascular biodistribution is enhanced in anti-angiogenic-therapy resistant tumour vessels. Copyright © 2011 Elsevier Ltd. All rights reserved.

Citation

Marcus Czabanka, Güliz Parmaksiz, Simon H Bayerl, Melina Nieminen, Eveline Trachsel, Hans D Menssen, Ralf Erber, Dario Neri, Peter Vajkoczy. Microvascular biodistribution of L19-SIP in angiogenesis targeting strategies. European journal of cancer (Oxford, England : 1990). 2011 May;47(8):1276-84