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
Jakub Rudovský
Mauro Botta
Petr Hermann
Kenneth I. Hardcastle
Ivan Lukeš
Silvio Aime
10.1021/bc060149l.s001
https://acs.figshare.com/articles/journal_contribution/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/3070069
A series of dendrimeric conjugates based on a PAMAM (polyamidoamine) backbone with macrocyclic Gd−DO3A-P<sup>ABn</sup> 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-P<sup>BnN{CS}</sup>)<sub>8</sub>, G2−(Gd−DO3A-P<sup>BnN{CS}</sup>)<sub>16</sub>, and G4−(Gd−DO3A-P<sup>BnN{CS}</sup>)<sub>59</sub>
showed relaxivities of 10.1, 14.1, and 18.6 s<sup>-1</sup> mM<sup>-1</sup> 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-P<sup>BnN{CS}</sup>)<sub>16</sub> conjugate. As confirmed by <sup>1</sup>H 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 <sup>17</sup>O
NMR and <sup>1</sup>H 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, <sup>298</sup>τ<sub>M</sub>, for the conjugates studied was ca. 45−70 ns, which is longer than the value found
for the monomeric model compound Gd−DO3A-P<sup>ABn</sup> (16 ns) but short enough so as not to limit the relaxivity.
The global rotational correlation time, <sup>298</sup>τ<sub>Rg</sub>, 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 <i>S</i><sup>2</sup> (∼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-P<sup>BnN{CS}</sup>)<sub>8</sub> 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 <sup>1</sup>H
relaxometric data obtained for the G2−(Gd−DO3A-P<sup>BnN{CS}</sup>)<sub>16</sub>−poly(Lys)<sub>59</sub> adduct. Importantly, it was proved
that the adduct formation did not hamper the water exchange process.
2006-07-19 00:00:00
correlation time
water exchange
Global Motion
PAMAM Dendrimeric Conjugates
298τ Rg
Gd
multiparametrical data evaluation
adduct formation
dendrimeric conjugates
relaxivity
Internal Rotation
DOTA
monophosphinated analogue
G 2 dendrimer
thiourea linker
20 MHz
3.1 ns
1 H relaxometric data
298τ M
1 H NMR titration
water exchange process
Fast Water ExchangeA series
conjugate solutions
1 H NMRD relaxometric studies
water residence lifetime