bc060149l_si_001.pdf (442.15 kB)
PAMAM Dendrimeric Conjugates with a Gd−DOTA Phosphinate Derivative and Their Adducts with Polyaminoacids: The Interplay of Global Motion, Internal Rotation, and Fast Water Exchange
journal contribution
posted on 2006-07-19, 00:00 authored by Jakub Rudovský, Mauro Botta, Petr Hermann, Kenneth I. Hardcastle, Ivan Lukeš, Silvio AimeA series of dendrimeric conjugates based on a PAMAM (polyamidoamine) backbone with macrocyclic Gd−DO3A-PABn complexes (monophosphinated analogue of DOTA) was prepared. The chelates were covalently
attached to the G1-, G2-, and G4-PAMAM dendrimers through a thiourea linker in high loads (>90%). The
prepared conjugates G1−(Gd−DO3A-PBnN{CS})8, G2−(Gd−DO3A-PBnN{CS})16, and G4−(Gd−DO3A-PBnN{CS})59
showed relaxivities of 10.1, 14.1, and 18.6 s-1 mM-1 at 20 MHz and 37 °C and pH = 7.5, respectively. A
variable-pH study (range 2−12) revealed up to 30% increase in the relaxivity at low pH for the G2−(Gd−DO3A-PBnN{CS})16 conjugate. As confirmed by 1H NMR titration of the unmodified G2 dendrimer, this is due to
protonation of core tertiary amines leading to a more open and rigid structure. The variable-temperature 17O
NMR and 1H NMRD relaxometric studies confirmed that the relaxivity is not controlled by water exchange but
by rotational dynamics. A multiparametrical data evaluation using the Lipari−Szabo approach revealed that the
water residence lifetime, 298τM, for the conjugates studied was ca. 45−70 ns, which is longer than the value found
for the monomeric model compound Gd−DO3A-PABn (16 ns) but short enough so as not to limit the relaxivity.
The global rotational correlation time, 298τRg, varied from 1.5 to 3.1 ns and seemed to indicate a sufficiently slow
molecular tumbling to achieve the high relaxivities measured; however, the rigidity factor S2 (∼0.26), describing
the internal flexibility, was far from optimum. The overall relaxivity was significantly increased (e.g. by a factor
of 1.8 for the G1−(Gd−DO3A-PBnN{CS})8 conjugate) when a positively charged polyaminoacid like poly(Arg) or
poly(Lys) was added to the conjugate solutions. The electrostatic interactions partially “freeze” the internal mobility
of the conjugate and also slow down global motion. This assumption was confirmed by an evaluation of 1H
relaxometric data obtained for the G2−(Gd−DO3A-PBnN{CS})16−poly(Lys)59 adduct. Importantly, it was proved
that the adduct formation did not hamper the water exchange process.
History
Usage metrics
Categories
Keywords
correlation timewater exchangeGlobal MotionPAMAM Dendrimeric Conjugates298τ RgGdmultiparametrical data evaluationadduct formationdendrimeric conjugatesrelaxivityInternal RotationDOTAmonophosphinated analogueG 2 dendrimerthiourea linker20 MHz3.1 ns1 H relaxometric data298τ M1 H NMR titrationwater exchange processFast Water ExchangeA seriesconjugate solutions1 H NMRD relaxometric studieswater residence lifetime
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC