title: Imaging the extracellular pH of tumors by MRI after injection of a single cocktail of T1 and T2 contrast agents.
abstract: The extracellular pH (pH(e) ) of solid tumors is acidic, and there is evidence that an acidic pH(e) is related to invasiveness. Herein, we describe an MRI single-infusion method to measure pH(e) in gliomas using a cocktail of contrast agents (CAs). The cocktail contained gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaminophosphonate (GdDOTA-4AmP) and dysprosium-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetrakis(methylenephosphonic acid) (DyDOTP), whose effects on relaxation are sensitive and insensitive to pH, respectively. The Gd-CA dominated the spin-lattice relaxivity ΔR(1) , whereas the Dy-CA dominated the spin-spin relaxivity ΔR(2)*. The ΔR(2)* effects were used to determine the pixel-wise concentration of [Dy] which, in turn, was used to calculate a value for [Gd] concentration. This value was used to convert ΔR(1) values to the molar relaxivity Δr(1) and, hence, pH(e) maps. The development of the method involved in vivo calibration and measurements in a rat brain glioma model. The calibration phase consisted of determining a quantitative relationship between ΔR(1) and ΔR(2)* induced by the two pH-independent CAs, gadolinium-diethylenetriaminepentaacetic acid (GdDTPA) and DyDOTP, using echo planar spectroscopic imaging (EPSI) and T(1) -weighted images. The intensities and linewidths of the water peaks in EPSI images were affected by CA and were used to follow the pharmacokinetics. These data showed a linear relationship between inner- and outer-sphere relaxation rate constants that were used for CA concentration determination. Nonlinearity in the slope of the relationship was observed and ascribed to variations in vascular permeability. In the pH(e) measurement phase, GdDOTA-4AmP was infused instead of GdDTPA, and relaxivities were obtained through the combination of interleaved T(1) -weighted images (R(1) ) and EPSI for ΔR(2)*. The resulting r(1) values yielded pH(e) maps with high spatial resolution.
authors: H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Gary.Martinez@moffitt.org.
authors: Gary V
authors: GV
authors: Martinez
authors: Xiaomeng
authors: X
authors: Zhang
authors: María L
authors: ML
authors: García-Martín
authors: David L
authors: DL
authors: Morse
authors: Mark
authors: M
authors: Woods
authors: A Dean
authors: AD
authors: Sherry
authors: Robert J
authors: RJ
authors: Gillies
references: Magn Reson Med. 2003 May;49(5):817-21
references: 12704763
references: NMR Biomed. 2003 Aug;16(5):276-85
references: 14648888
references: Nat Rev Cancer. 2004 Nov;4(11):891-9
references: 15516961
references: NMR Biomed. 1997 Dec;10(8):411-22
references: 9542738
references: Cancer Res. 2009 Mar 15;69(6):2260-8
references: 19276390
references: Magn Reson Med. 1995 Jan;33(1):34-40
references: 7891533
references: J Magn Reson Imaging. 1999 Jul;10(1):1-7
references: 10398971
references: Magn Reson Imaging. 2003 Feb;21(2):85-93
references: 12670594
references: Magn Reson Med. 1998 Mar;39(3):417-28
references: 9498598
references: NMR Biomed. 2005 Jun;18(4):235-41
references: 15759296
references: J Nucl Med. 2008 Jun;49 Suppl 2:24S-42S
references: 18523064
references: Magn Reson Med. 1999 Apr;41(4):743-50
references: 10332850
references: Magn Reson Med. 1994 Dec;32(6):749-63
references: 7869897
references: Magn Reson Imaging. 2005 Jun;23(5):619-27
references: 16051036
references: Magn Reson Med. 2003 Dec;50(6):1120-6
references: 14648559
references: NMR Biomed. 2002 Apr;15(2):114-9
references: 11870907
references: Magn Reson Med. 2009 Mar;61(3):615-25
references: 19235262
references: Magn Reson Med. 2003 Jun;49(6):1067-76
references: 12768585
references: Radiology. 1994 Sep;192(3):733-8
references: 8058941
references: Cancer Res. 2001 Sep 1;61(17):6524-31
references: 11522650
references: Magn Reson Med. 1998 Jul;40(1):36-42
references: 9660550
references: Magn Reson Med. 2003 Dec;50(6):1151-69
references: 14648563
references: Nat Med. 2003 Aug;9(8):1085-90
references: 12872167
references: Magn Reson Med. 2003 Feb;49(2):249-57
references: 12541244
references: Inorg Chem. 2007 Jun 25;46(13):5260-70
references: 17539632
references: Magn Reson Med. 2006 Feb;55(2):309-15
references: 16402385
references: Magn Reson Med. 1999 Sep;42(3):467-78
references: 10467291
references: NMR Biomed. 2005 Aug;18(5):285-92
references: 15973657
references: Nature. 2008 Jun 12;453(7197):940-3
references: 18509335