Harnessing competing endocytic pathways for overcoming the tumor-blood barrier: magnetic resonance imaging and near-infrared imaging of bifunctional contrast media.
Ovarian cancer is the most lethal gynecologic malignancy, often diagnosed at advanced stage leading to poor prognosis. In the study reported here, magnetic resonance imaging and near-infrared reflectance imaging were applied for in vivo analysis of two competing endocytic pathways affecting retention of bifunctional daidzein-bovine serum albumin (BSA)-based contrast media by human epithelial ovarian carcinoma cells. Suppression of caveolae-mediated uptake using nystatin or by BSA competition significantly enhanced daidzein-BSA-GdDTPA/CyTE777 uptake by tumor cells in vitro. In vivo, perivascular myofibroblasts generated an effective perivascular barrier excluding delivery of BSA-GdDTPA/CyTE777 to tumor cells. The ability to manipulate caveolae-mediated sequestration of albumin by perivascular tumor myofibroblasts allowed us to effectively overcome this tumor-stroma barrier, increasing delivery of daidzein-BSA-GdDTPA/CyTE777 to the tumor cells in tumor xenografts. Thus, both in vitro and in vivo, endocytosis of daidzein-BSA-GdDTPA/CyTE777 by ovarian carcinoma cells was augmented by albumin or by nystatin. In view of the cardinal role of albumin in affecting the availability and pharmacokinetics of drugs, this approach could potentially also facilitate the delivery of therapeutics and contrast media to tumor cells.
Migalovich
Helena Sheikhet
HS
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel.
Kalchenko
Vyacheslav
V
Nevo
Nava
N
Meir
Gila
G
Kohen
Fortune
F
Neeman
Michal
M
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D001692:Biological Transport; D004705:Endocytosis / Q000502:physiology*; D005260:Female; D006801:Humans; D007529:Isoflavones / Q000378:metabolism / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D009761:Nystatin / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000473:pathology*; D004369:Pentetic Acid / Q000378:metabolism; D012710:Serum Albumin, Bovine / Q000493:pharmacokinetics; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D007529:Isoflavones; D009761:Nystatin; D012710:Serum Albumin, Bovine; C004742:daidzein; D004369:Pentetic Acid