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A liposomal Gd contrast agent does not cross the mouse placental barrier.

ABSTRACT: The trans-placental permeability of liposomal Gadolinium (Gd) nanoparticle contrast agents was evaluated in a pregnant mouse model. Pregnant Balb/c mice at 16.5 (±1) days of gestation were imaged using a 3D Spoiled Gradient Echo method at 9.4 T using two contrast agents: a clinically approved Gd chelate, Multihance(®) (gadobenate dimeglumine), and a novel experimental liposomal Gd agent. A Dynamic Contrast Enhancement (DCE) protocol was used to capture the dynamics of contrast entry and distribution in the placenta, and clearance from circulation. A blinded clinical radiologist evaluated both sets of images. A reference region model was used to measure the placental flow and physiological parameters; volume transfer constant (K(trans)), efflux rate constant (K(ep)). The Gd content of excised placentae and fetuses was measured, using inductively coupled plasma mass spectrometry (ICP-MS). MRI images of pregnant mice and ICP-MS analyses of placental and fetal tissue demonstrated undetectably low transplacental permeation of the liposomal Gd agent, while the clinical agent (Multihance) avidly permeated the placental barrier. Image interpretation and diagnostic quality was equivalent between the two contrast agents. Additional testing to determine both maternal and fetal safety of liposomal Gd is suggested.

SUBMITTER: Shetty AN

PROVIDER: S-EPMC4906290 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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A liposomal Gd contrast agent does not cross the mouse placental barrier.

Shetty Anil N AN Pautler Robia R Ghaghada Ketan K Rendon David D Gao Haijun H Starosolski Zbigniew Z Bhavane Rohan R Patel Chandreshkumar C Annapragada Ananth A Yallampalli Chandrasekhar C Lee Wesley W

Scientific reports 20160614

The trans-placental permeability of liposomal Gadolinium (Gd) nanoparticle contrast agents was evaluated in a pregnant mouse model. Pregnant Balb/c mice at 16.5 (±1) days of gestation were imaged using a 3D Spoiled Gradient Echo method at 9.4 T using two contrast agents: a clinically approved Gd chelate, Multihance(®) (gadobenate dimeglumine), and a novel experimental liposomal Gd agent. A Dynamic Contrast Enhancement (DCE) protocol was used to capture the dynamics of contrast entry and distribu ...[more]

PMID: 27298076

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Project description:A linear polyamidoamine (PAA) named BAC-EDDS, containing metal chelating repeat units composed of two tert-amines and four carboxylic groups, has been prepared by the aza-Michael polyaddition of ethylendiaminodisuccinic (EDDS) with 2,2-bis(acrylamido)acetic acid (BAC). It was characterized by size exclusion chromatography (SEC), FTIR, UV-Vis and NMR spectroscopies. The pKa values of the ionizable groups of the repeat unit were estimated by potentiometric titration, using a purposely synthesized molecular ligand (Agly-EDDS) mimicking the structure of the BAC-EDDS repeat unit. Dynamic light scattering (DLS) and ζ-potential analyses revealed the propensity of BAC-EDDS to form stable nanoaggregates with a diameter of approximately 150 nm at pH 5 and a net negative charge at physiological pH, in line with an isoelectric point <2. BAC-EDDS stably chelated Gd (III) ions with a molar ratio of 0.5:1 Gd (III)/repeat unit. The stability constant of the molecular model Gd-Agly-EDDS (log K = 17.43) was determined as well, by simulating the potentiometric titration through the use of Hyperquad software. In order to comprehend the efficiency of Gd-BAC-EDDS in contrasting magnetic resonance images, the nuclear longitudinal (r1) and transverse (r2) relaxivities as a function of the externally applied static magnetic field were investigated and compared to the ones of commercial contrast agents. Furthermore, a model derived from the Solomon-Bloembergen-Morgan theory for the field dependence of the NMR relaxivity curves was applied and allowed us to evaluate the rotational correlation time of the complex (τ = 0.66 ns). This relatively high value is due to the dimensions of Gd-BAC-EDDS, and the associated rotational motion causes a peak in the longitudinal relaxivity at ca. 75 MHz, which is close to the frequencies used in clinics. The good performances of Gd-BAC-EDDS as a contrast agent were also confirmed through in vitro magnetic resonance imaging experiments with a 0.2 T magnetic field.

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A liposomal Gd contrast agent does not cross the mouse placental barrier.

Publications

A liposomal Gd contrast agent does not cross the mouse placental barrier.

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