Evaluation of Gd(III)DTPA-terminated poly(propylene imine) dendrimers as contrast agents for MR imaging.
Different generations of Gd(III)DTPA-terminated poly(propylene imine) dendrimers {G1 [n = 4 Gd(III) ions per molecule], G3 (n = 16) and G5 (n = 64)} and reference Gd(III)DTPA complex [G0 (n = 1)] were characterized in terms of (i) longitudinal (r1) and transverse (r2) relaxivities in mouse blood plasma, (ii) concentration detection limits in vitro and (iii) in vivo contrast-enhanced MR imaging (CE-MRI) in mice at 1.5 T. Serial and dynamic CE-MRI were performed to monitor the distribution of MRI contrast agent in the heart, arteries, renal system, liver, spleen, bladder and tumor periphery. The relaxivities increased non-linearly with molecular weight (for G0 ionic r1 = 8.1 mM(-1) s(-1) and ionic r2 = 8.6 mM(-1) s(-1) to G5 19.3 and 25.0, respectively). The minimal detectable dendrimer concentration was more than two orders of magnitude lower for G5 (8.1 x 10(-8) M) than for G0 (3.1 x 10(-5) M). Sub-millimeter-sized blood vessels were well visualized with serial CE-MRI with each contrast agent. Dynamic CE-MRI showed timely renal clearance for all contrast agents, but a stronger and a prolonged blood signal enhancement for the higher generations of the dendritic contrast agent. Moreover, G0 and G1 showed a rapid tumor wash-in and wash-out, whereas G3 and G5 displayed a more gradual and prolonged tumor wash-in. In conclusion, both G0 and dendritic contrast agents G1, G3 and G5 are well suited for non-tissue-specific MRI of sub-millimeter-sized blood vessels and evaluating tumor microcirculatory characteristics in mice. Higher generations of dendritic contrast agents display lower concentration detection limits, which suggests their future use for molecular imaging.
Langereis
Sander
S
Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, Eindhoven, The Netherlands.
de Lussanet
Quido G
QG
van Genderen
Marcel H P
MH
Meijer
E W
EW
Beets-Tan
Regina G H
RG
Griffioen
Arjan W
AW
van Engelshoven
Jos M A
JM
Backes
Walter H
WH
D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D003287:Contrast Media; D019786:Gadolinium DTPA; D007089:Image Enhancement / Q000379:methods*; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D003287:Contrast Media; D019786:Gadolinium DTPA