Non-invasive imaging of barriers to drug delivery in tumors.
Solid tumors often develop high interstitial fluid pressure (IFP) as a result of increased water leakage and impaired lymphatic drainage, as well as changes in the extracellular matrix composition and elasticity. This high fluid pressure forms a barrier to drug delivery and hence, resistance to therapy. We have developed techniques based on contrast enhanced magnetic resonance imaging for mapping in tumors the vascular and transport parameters determining the delivery efficiency of blood borne substances. Sequential images are recorded during continuous infusion of a Gd-based contrast agent and analyzed according to a new physiological model, yielding maps of microvascular transfer constants, as well as outward convective interstitial transfer constants and steady state interstitial contrast agent concentrations both reflecting IFP distribution. We further demonstrated in non small cell human lung cancer xenografts the capability of our techniques to monitor in vivo collagenase induced increase in contrast agent delivery as a result of decreased IFP. These techniques can be applied to test drugs that affect angiogenesis and modulate interstitial fluid pressure and has the potential to be extended to cancer patients for assessing resistance to drug delivery.
Hassid
Yaron
Y
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
Eyal
Erez
E
Margalit
Raanan
R
Furman-Haran
Edna
E
Degani
Hadassa
H
D000465:Algorithms; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002196:Capillaries / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D045744:Cell Line, Tumor; D017364:Collagenases / Q000008:administration & dosage / Q000494:pharmacology; D045604:Extracellular Fluid / Q000187:drug effects / Q000502:physiology; D005119:Extravasation of Diagnostic and Therapeutic Materials / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D019786:Gadolinium DTPA / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000378:metabolism*; D011312:Pressure; D014183:Transplantation, Heterologous
D004364:Pharmaceutical Preparations; D017364:Collagenases; D019786:Gadolinium DTPA