Magnetic resonance (MR) imaging contrast agents are widely used in medical diagnostic imaging due to their ability to improve tissue contrast and provide pathological correlates for a wide range of diseases. While various compounds have been evaluated as MR contrast agents, gadolinium (Gd) complexes continue to be the most widely used, and account for essentially all of the agents being used in the clinic today. Currently, all of the clinically-approved Gd complexes consist of individual Gd ions chelated with a low molecular weight acyclic or cyclic ligand (). Due to their small size, many of these agents (e.g. Magnevist, Dotarem, DO3A) distribute throughout the intravascular and interstitial space and are rapidly cleared via renal filtration.
Clinally-approved and clinically-tested Gd-based contrast agents. All relaxivity values were acquired at 20 MHz, 310K.
The pharmacokinetics and route of excretion of several Gd complexes have been altered by modifying the chemical properties of the Gd-chelate. For example, the presence of the lipophilic moiety on Multienhance (Gd-BOPTA) helps drive hepatic excretion, while a small ligand on Vasovist (MS-325, Ablavar) allows this complex to reversibly bind human albumin in plasma, leading to a plasma half-life of 2–3h[1
]. This is markedly longer than Magnevist (t1/2
of only 0.2±0.13hrs) (http://berlex.bayerhealthcare.com/html/products/pi/Magnevist_PI.pdf
) and other clinical agents. Recent reports of other small molecules that can promote tissue or molecular-specific targeting[2
] suggest that there is tremendous room for future developments in chelation chemistry; however, despite this promise, it is generally accepted that small Gd complexes cannot be used to differentiate between healthy and disease pathologies through binding of specific cell surface biomarkers. This is simply due to the inability of individual chelates to provide sufficient contrast via this targeting mechanism. For example, if it is estimated that a cancer cell has a volume of 1 pL (i.e. ~12.4 um diameter) and if it is assumed that each cancer cell has 1 million target receptors, the receptor concentration will only be 1.66 nM. Therefore, even if a tumor consisted entirely of cancer cells and all receptors were bound by Gd complexes, the concentration of Gd within the tumor would be ~5 orders of magnitude below the detection limit - the lower detection limit of most small Gd complexes (e.g. Magnevist) on a 1.5 T MR imaging system is considered to be ~100 µM[3
]. Similarly, even if 10’s of Gd complexes were attached to antibodies, to confer molecular specificity, and even if there was a 10-fold improvement in relaxivity owing to the slower rotational correlation time that results from attaching Gd to larger macromolecules[4
], the signal amplification would still be ~3 orders of magnitude too low. This limitation has led to emerging interest in the development and use of Gd-based nanoparticles and macromolecules as MR molecular imaging contrast agents.
Numerous nanoparticles and macromolecules have already been explored as platforms for Gd-labeling and/or encapsulation, including polymers, proteins, dendrimers, micelles, and vesicles[5
]. The value in preparing nanoparticles/macromolecules for molecular imaging applications stems from their ability to carry a large payload of Gd, the ease in which their physicochemical properties can be finely tuned, which can influence their pharmacokinetic and pharmacodynamic profiles, and the ability to readily functionalize their surface with molecularly specific targeting agents.
Despite their promise, early work with Gd-labeled macromolecules has revealed that translation of these agents to the clinic can be hampered by the slow, and in some cases, incomplete excretion of these larger agents[6
]. Moreover, while Gd-complexes are generally considered safe when used in clinically recommended doses, there has been an expanding body of literature linking Gd to nephrotoxicity and Nephrogenic Systemic Fibrosis (NSF) in patients with kidney disease. It is hypothesized that prolonged tissue exposure to chelated Gd occurs in patients with reduced renal clearance, which may allow Gd to be released from its chelate and deposit in tissues. In response to concerns over NSF, it is now recommended that patients with acute kidney injury (AKI) and stage 4/5 chronic kidney disease (CKD) do not undergo Gd-enhanced MR imaging. The apparent relationship between poor Gd excretion and NSF is particularly concerning when developing Gd-based nanoparticles, because nanoparticles generally exhibit a much longer circulation and retention time in patients compared with small Gd complexes. Therefore, it is anticipated that in order to develop effective and safe Gd-based nanoparticles as MR contrast agents for molecule imaging, it will be necessary to strike a delicate balance between adequate circulation times for effective targeting and rapid excretion to minimize the likelihood of toxic side effects.
In this review, we will showcase Gd-based macromolecules and nanoparticles that have been developed for molecular imaging applications. Although a wide range of approaches will be discussed, particular emphasis will be placed on nanoparticles that exhibit a high relaxivity per nanoparticle, i.e. (relaxivity of Gd)×(Gd per nanoparticle), and a high “relaxivity density”, which we define as (relaxivity per nanoparticle)/(nanoparticle volume or molecular weight). To date, most Gd-based contrast agents are compared in terms of Gd relaxivity. While this parameter is important for perfusion and blood pool applications, where a higher relaxivity can mean a lower injected dose or higher contrast, it can be argued that it is not an appropriate yardstick for molecular imaging contrast agents. For example, if a tumor cell has a fixed number of receptors on its surface, the binding of nanoparticles with 100,000 Gd/nanoparticle will certainly provide more contrast than binding of an individual Gd complex to each receptor, even if the Gd complex has a higher ion relaxivity. Moreover, since simply increasing the overall size of the nanoparticle will lead to a corresponding increase in the relaxivity per nanoparticle, in some instances it also makes sense to normalize to the nanoparticle volume or molecular weight to remove this potential bias and create a fair measure for comparison. A summary of the physical and magnetic properties of various macromolecule and nanoparticle-based MR contrast agents reported in this review are provided in .
Physical and magnetic properties of selected Gd-based nanoparticles and macromolecules
In addition to providing an overview of various Gd-based nanoparticles, we will begin with a brief discussion on recent advances in the development of Gd ligands. Although individual chelated Gd complexes cannot be used for molecular imaging applications on their own, advances in this field are sure to benefit Gd-based nanoparticles since the relaxivity of individual Gd complexes directly contribute to the overall relaxivity per nanoparticle and relaxivity density.