Specific targeting of tumor angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner.
Angiogenesis is essential for the development of malignant tumors and provides important targets for tumor diagnosis and therapy. To noninvasively assess the angiogenic profile of tumors, novel alpha(v)beta(3) integrin-targeted ultrasmall superparamagnetic iron oxide particles (USPIOs) were designed and their specific uptake by endothelial cells was evaluated in vitro and in vivo. USPIOs were coated with 3-aminopropyltrimethoxysilane (APTMS) and conjugated with Arg-Gly-Asp (RGD) peptides. Accumulation in human umbilical vein endothelial cells (HUVECs) was evaluated using Prussian blue staining, transmission electron microscopy, magnetic resonance (MR) imaging, and inductively coupled plasma mass spectrometry. Uptake of RGD-USPIO by HUVECs was significantly increased when compared with unlabeled USPIO and could be competitively inhibited by addition of unbound RGD. The ability of the RGD-USPIO to noninvasively distinguish tumors with high (HaCaT-ras-A-5RT3) and lower (A431) area fractions of alpha(v)beta(3) integrin-positive vessels was evaluated using a 1.5-T MR scanner. Indeed, after RGD-USPIO injection, there was a more pronounced decrease in T(2) relaxation times in HaCaT-ras-A-5RT3 tumors than in A431 tumors. Furthermore, T(2)*-weighted images clearly identified the heterogeneous arrangement of vessels with alpha(v)beta(3) integrins in HaCaT-ras-A-5RT3 tumors by an irregular signal intensity decrease. In contrast, in A431 tumors with predominantly small and uniformly distributed vessels, the signal intensity decreased more homogeneously. In summary, RGD-coupled, APTMS-coated USPIOs efficiently label alpha(v)beta(3) integrins expressed on endothelial cells. Furthermore, these molecular MR imaging probes are capable of distinguishing tumors differing in the degree of alpha(v)beta(3) integrin expression and in their angiogenesis profile even when using a clinical 1.5-T MR scanner.
Zhang
Chunfu
C
Junior Group Molecular Imaging, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
Jugold
Manfred
M
Woenne
Eva C
EC
Lammers
Twan
T
Morgenstern
Bernd
B
Mueller
Margareta M
MM
Zentgraf
Hanswalter
H
Bock
Michael
M
Eisenhut
Michael
M
Semmler
Wolfhard
W
Kiessling
Fabian
F
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000098:blood supply* / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D005290:Ferric Compounds / Q000493:pharmacokinetics*; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis / Q000378:metabolism*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000098:blood supply* / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000175:diagnosis / Q000378:metabolism; D009842:Oligopeptides / Q000493:pharmacokinetics*; D010316:Particle Size; D011437:Propylamines / Q000493:pharmacokinetics; D012821:Silanes / Q000493:pharmacokinetics
D005290:Ferric Compounds; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D011437:Propylamines; D012821:Silanes; C088294:3-aminopropyltrimethoxysilane; C000499:ferric oxide; C047981:arginyl-glycyl-aspartic acid