Comparison of the Macromolecular MR Contrast Agents with Ethylenediamine-Core versus Ammonia-Core Generation-6 Polyamidoamine Dendrimer

Abstract

Two novel macromolecular MRI contrast agents based upon generation-6 polyamidoamine dendrimers (G6) of presumed similar molecular size, but of different molecular weight, were compared in terms of their blood retention, tissue distribution, and renal excretion. Two G6s with either ammonia core (G6A) or with ethylenediamine core (G6E), which possessed 192 and 256 exterior primary amino groups, respectively, were used. These dendrimers were reacted with 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M). The G6--1B4M conjugates were reacted with (153)Gd for studying biodistribution and blood clearance or Gd(III) for the MRI study. 3D-micro-MR angiography of the mice were taken with injection of 0.033 mmol of Gd/kg of G6A--(1B4M-Gd)(192) or G6E--(1B4M-Gd)(256) using a 1.5-T superconductive MRI unit. Although numerous fine vessels of approximately 100 microm diameter were visualized on subtracted 3D-MR-angiography with both G6A--(1B4M-Gd)(192) and G6E--(1B4M-Gd)(256), (153)Gd-labeled saturated G6E-(1B4M)(256) remained in the blood significantly more than (153)Gd-labeled saturated G6A--(1B4M)(192) at later than 15 min postinjection (p < 0.01). In addition, G6E--(1B4M-Gd)(256) visualized these finer vessels longer than G6A--(1B4M-Gd)(192). The G6A--(1B4M-Gd)(192) showed higher signal intensity in the kidney on the dynamic MR images and brighter kidney images than G6E--(1B4M-Gd)(256). In conclusion, the G6A--(1B4M-Gd)(192) was observed to go through glomerular filtration more efficiently than G6E--(1B4M-Gd)(256) resulting faster clearance from the blood and higher renal accumulation, even though both of G6--1B4M conjugates have almost similar molecular size and same chemical structure. In terms of the ability of intravascular contrast agents, G6E--(1B4M-Gd)(256) was better due to more Gd(III) atoms per molecule and longer retention in the circulation than G6A--(1B4M-Gd)(192).

Macromolecular MRI Contrast Agents with Small Dendrimers: Pharmacokinetic Differences between Sizes and Cores

“…The resulting preparation was purified by diafiltration using a Centricon 30 (Amicon Co., Beverly, MA) for the generation-4 dendrimers and a Centricon 10 (Amicon Co.) for the generation-2 and -3 dendrimers. Over 98% of the amine groups on the dendrimers were reacted with the 1B4M as well as found not to contain free 1B4M chelates as determined by both a 153 Gdlabeling assay as previously described (9) and an analysis by size-exclusion HPLC (SE-HPLC) using a TSK G3000 SW column (TosoHaas, Philadelphia, PA; 0.1 M PBS; 0.01 M KCl; pH 7.4; 1 mL/min) using a UV detector at 280 nm absorbance.…”

Preparation and Long-Term Biodistribution Studies of a Pamam Dendrimer G5–Gd-BnDOTA Conjugate for Lymphatic Imaging

“…The behavior of the dendrimeric Gd(III) agents in vivo is affected by modification of the dendrimer properties, such as their size [9,10], core [11] and the exterior shell chemistry [12,13]. One concern about dendrimeric Gd(III) agents is the potential for retention in organs making them difficult to translate clinically.…”

MRI with Gadolinium‐Based Nanoparticles

“…For instance, G4 ppI dendrimers with their higher hydrophobicity than pAMAM have been shown to accumulate significantly more in mice liver, allowing visualization of micrometastatic tumors of 0.3 mm diameter [94]. The nature of the core can also be critical in the development of a better blood pool agent as demonstrated by a study by Kobayashi et al showing that the replacement of the ammonia core by an ethylenediamine leads to longer blood retention and slower renal uptake [95]. ultimately, circulation and excretion properties can be modulated by modification in the surface of dendrimers.…”