Macromolecular Magnetic Resonance Imaging Contrast Research Articles

A Gd(III)-labelled self-assembling peptide as a potential pH-responsive MRI contrast agent.

A marine-derived peptide labelled with a Gd(III)-chelate was found to self-assemble depending on the solution pH, accompanied by changes in T1-relaxivity (r1) values when in the dispersed or self-assembled form. Such pH-responsive behavior can be advantageous in the development of macromolecular magnetic resonance imaging (MRI) contrast agents which monitor the tissue physiology.

A novel manganese chelated macromolecular MRI contrast agent based on O-carboxymethyl chitosan derivatives

Currently used Gd-based and Mn-based small molecular MRI contrast agents fail to meet the requirements for the long-term monitoring, and the potential safety risk under high administration dose or repeat dosing needs to be considered. In the present study, a biocompatible macromolecular magnetic resonance imaging (MRI) contrast agents based on O-carboxymethyl chitosan (CMCS), CMCS-(Mn-DTPA)n was designed and synthesized. The relaxivity of CMCS-(Mn-DTPA)n is approximately 3.5 and 5.5 times higher than that of Gd-DTPA and Mn-DPDP in aqueous solution, respectively. The MRI signal intensity in the kidney and liver of Sprague Dawley (SD) rats is significantly increased at a dose of 0.03 mM Mn/kg b.w. CMCS-(Mn-DTPA)n accompanied by a long effective imaging window. According to in vitro studies, CMCS-(Mn-DTPA)n exhibits good cellular and blood biocompatibility at the dose necessary for MRI imaging. Based on the results from in vivo studies, manganese (Mn) is completely excreted from SD rats within ten days after administration and does not exert a pathological effect on the liver. CMCS-(Mn-DTPA)n represents a potentially novel MRI contrast agent due to its excellent relaxivity, long effective imaging window and good biocompatibility.

Recent advances on stimuli-responsive macromolecular magnetic resonance imaging (MRI) contrast agents

Magnetic resonance imaging (MRI) has been extensively used in clinical diagnosis and currently over 30% MRI runs are performed in the presence of contrast agents. However, commercially available contrast agents originated from small molecules typically exhibit relatively low relaxivities and insufficient circulation time. Therefore, there is a long pursuit to develop new contrast agents with high relaxivities to discriminate pathological tissues from normal ones. Compared with small molecule MRI contrast agents, the incorporation of small molecule contrast agents into macromolecular scaffolds allows for constructing macromolecular MRI contrast agents, remarkably elevating the relaxivities due in part to increased rotational correlation time (τR). Moreover, if the macromolecular scaffolds are responsive to external stimuli, the MRI signals could be selectively switched on at the desired sites (e.g., pathological tissues), further intensifying the imaging contrast. In this feature article, we outline the recent achievements in the fabrication of stimuli-responsive macromolecular MRI contrast agents. Specifically, macromolecular contrast agents being responsive to acidic pH, redox potentials, and other stimuli including photoirradiation, pathogens, and salt concentration are discussed. These smart contrast agents could affect either longitudinal (T1) or transverse (T2) relaxation times of water protons or other nuclei (e.g., 19F), exhibiting enhanced signals in pathological tissues yet suppressed signals in normal ones and displaying promising potentials in in vitro and in vivo MRI applications.

Biodegradable Nanoglobular Magnetic Resonance Imaging Contrast Agent Constructed with Host-Guest Self-Assembly for Tumor-Targeted Imaging.

Gadolinium-based macromolecular magnetic resonance imaging (MRI) contrast agents (CAs) have attracted increasing interest in tumor diagnosis. However, their practical application is potentially limited because the long-term retention of gadolinium ion in vivo will induce toxicity. Here, a nanoglobular MRI contrast agent (CA) PAMAM-PG- g-s-s-DOTA(Gd) + FA was designed and synthesized on the basis of the facile host-guest interaction between β-cyclodextrin and adamantane, which initiated the self-assembly of poly(glycerol) (PG) separately conjugated with gadolinium chelates by disulfide bonds and folic acid (FA) molecule onto the surface of poly(amidoamine) (PAMAM) dendrimer, finally realizing the biodegradability and targeting specificity. The nanoglobular CA has a higher longitudinal relaxivity ( r1) than commercial gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), showing a value of 8.39 mM-1 s-1 at 0.5 T, and presents favorable biocompatibility on the observations of cytotoxicity and tissue toxicity. Furthermore, MRI on cells and tumor-bearing mice both demonstrate the obvious targeting specificity, on the basis of which the effective contrast enhancement at tumor location was obtained. In addition, this CA exhibits the ability of cleavage to form free small-molecule gadolinium chelates and can realize minimal gadolinium retention in main organs and tissues after tumor detection. These results suggest that the biodegradable nanoglobular PAMAM-PG- g-s-s-DOTA(Gd) + FA can be a safe and efficient MRI CA for tumor diagnosis.

Oligoethylenimine-grafted chitosan as enhanced T1 contrast agent for in vivo targeted tumor MRI.

To synthesize and characterize an effective macromolecular magnetic resonance imaging (MRI) contrast agent based on oligoethylenimine-grafted chitosan with targeting capability. In this study we synthesized and characterized oligoethylenimine-grafted chitosan copolymers, followed by conjugating with Gd-DTPA and folic acid. The toxicity was evaluated by WST assay, and in vitro MRI studies were performed in comparison with Gd-DTPA. Finally, the contrast enhancement of the new macromolecular MRI contrast agent was then evaluated in the mice bearing KB xenografts. Compared to Gd-DTPA (4.3 mM(-1) s(-1) ), this macromolecular contrast agent (mCA) exhibited much higher T1 relaxivity (14.4 mM(-1) s(-1) ), up to 3.3 times higher. Meanwhile, the WST assay illustrated that the viability of KB cells remained at 90% even when the Gd concentration was 1 mM. During the in vivo study, the image contrast produced by FA-mCA was higher than one produced by mCA, up to 2.5 times higher. Our results showed this macromolecular contrast agent has potential for developing sensitive and biocompatible MRI probe with targeting capability. J. Magn. Reson. Imaging 2016;44:23-29.

Manganese(III) porphyrins complexed with P22 virus-like particles as T 1-enhanced contrast agents for magnetic resonance imaging

Virus-like particles are powerful platforms for the development of functional hybrid materials. Here, we have grown a cross-linked polymer (cross-linked aminoethyl methacrylate) within the confines of the bacteriophage P22 capsid (P22-xAEMA) and functionalized the polymer with various loadings of paramagnetic manganese(III) protoporphyrin IX (MnPP) complexes for evaluation as a macromolecular magnetic resonance imaging contrast agent. The resulting construct (P22-xAEMA-MnPP) has r1,particle = 7,098 mM(-1) s(-1) at 298 K and 2.1 T (90 MHz) for a loading of 3,646 MnPP molecules per capsid. The Solomon-Bloembergen-Morgan theory for paramagnetic relaxivity predicts conjugating MnPP to P22, a supramolecular structure, would result in an enhancement in ionic relaxivity; however, all loadings experienced low ionic relaxivities, r 1,ionic, ranging from 1.45 to 3.66 mM(-1) s(-1), similar to the ionic relaxivity of free MnPP. We hypothesize that intermolecular interactions between neighboring MnPP molecules block access of water to the metal site, resulting in low r 1,ionic relaxivities. We investigated the effect of MnPP interactions on relaxivity further by either blocking or exposing water binding sites on MnPP. On the basis of these results, future design strategies for enhanced r 1,ionic relaxivity are suggested. The measured r 2,ionic relaxivities demonstrated an inverse relationship between loading and relaxivity. This results in a loading-dependent r 2/r 1 behavior of these materials indicating synthetic control over the relaxivity properties, making them interesting alternatives to current magnetic resonance imaging contrast agents.

Gadolinium‐conjugated folate–poly(ethylene glycol)–polyamidoamine dendrimer–carboxyl nanoparticles as potential tumor‐targeted, circulation‐prolonged macromolecular magnetic resonance imaging contrast agents. II

AbstractA new macromolecular gadolinium‐based magnetic resonance imaging (MRI) contrast agent, folic acid (FA)–poly(ethylene glycol) (PEG)–polyamidoamine dendrimer (PAMAM)–Gd, was synthesized with a core of PAMAM, which was modified with conjugates of FA and PEG and then chelated by gadolinium ions. The final products, with FA as the targeting moiety, were evaluated for their tumor‐targeting MRI contrast‐agent potential. The concentration detection limits in vitro; contrast‐enhanced MRI in the heart, kidney, and liver of mice; and metabolism of FA–PEG–PAMAM–Gd were measured by a Siemens Tim Trio human MRI scanner at 3 T. Transmission electron microscopy was used to determine the targeting of FA–PEG–PAMAM–Gd to human epidermoid carcinomas cell lines (KB) or murine aneuploid fibrosarcoma cell lines (L929). The toxicity was also assayed to evaluate the biocompatibility of this contrast agent. The minimum detectable concentration of FA–PEG4K–PAMAM–Gd (where the subscript 4K indicates a molecular weight of 4000 Da) was 15‐fold lower than that of the commercially available contrast agent gadopentetate dimeglumine. The MRI images displayed a gradual persistent signal enhancement on tumors, and millimeter‐sized (∼ 3 mm) tumors were well visualized with FA–PEG4K–PAMAM–Gd. In conclusion, the dendritic complexes were well suited for use as an FA‐mediated targeting contrast agent for early diagnosis of tumors in mice. The dendritic contrast agents displayed lower concentration detection limits, which suggests their future use in molecular imaging. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011

Pharmacokinetics and magnetic resonance imaging of biodegradable macromolecular blood‐pool contrast agent PG–Gd in non‐human primates: a pilot study

The purpose of this study was to evaluate poly(L-glutamic acid)-benzyl-DTPA-Gd (PG-Gd), a new biodegradable macromolecular magnetic resonance imaging contrast agent, for its pharmacokinetics and MRI enhancement in nonhuman primates. Studies were performed in rhesus monkeys at intravenous doses of 0.01, 0.02 and 0.08 mmol Gd/kg. T(1)-weighted MR images were acquired at 1.5 T using fast spoiled gradient recalled echo and fast spin echo imaging protocols. The small-molecule contrast agent Magnevist was used as a control. PG-Gd in the monkey showed a bi-exponential disposition. The initial blood concentrations within 2 h of PG-Gd administration were much higher than those for Magnevist. The high blood concentration of PG-Gd was consistent with the MR imaging data, which showed prolonged circulation of PG-Gd in the blood pool. Enhancement of blood vessels and organs with a high blood perfusion (heart, liver, and kidney) was clearly visualized at 2 h after contrast injection at the three doses used. A greater than proportional increase of the area under the blood concentration-time curve was observed when the administered single dose was increased from 0.01 to 0.08 mmol/kg. By 2 days after PG-Gd injection, the contrast agent was mostly cleared from all major organs, including kidney. The mean residence time was 15 h at the 0.08 mmol/kg dose. A similar pharmacokinetic profile was observed in mice, with a mean residence time of 5.4 h and a volume of distribution at steady-state of 85.5 ml/kg, indicating that the drug was mainly distributed in the blood compartment. Based on this pilot study, further investigations on the potential systemic toxicity of PG-Gd in both rodents and large animals are warranted before testing this agent in humans.

Strategies for the covalent conjugation of a bifunctional chelating agent to albumin: Synthesis and characterization of potential MRI contrast agents

With the purpose to develop macromolecular magnetic resonance imaging contrast agents, we herein report three different synthetic approaches to the covalent attachment of bifunctional chelating agents to human serum albumin followed by coordination to contrast enhancing gadolinium(III). Applied methods cover active ester-mediated conjugation, linkage through glutaryl spacer, as well as the connection by the employment of glutaraldehyde. The content of gadolinium(III) was evaluated by inductively-coupled-plasma mass-spectrometry (ICP-MS) measurements and indicated reproducible amounts of conjugated contrast enhancing material. Small angle X-ray scattering (SAXS) experiments provided the size and altered shape of the gadolinium loaded proteins in comparison to unmodified albumin. Finally, the magnetic resonance properties of the protein conjugates were evaluated. The results indicated suitability of the gadolinium(III) loaded protein conjugates for use as macromolecular contrast agents in magnetic resonance imaging (MRI).

Polyion complex micelle MRI contrast agents from poly(ethylene glycol)- b-poly( l-lysine) block copolymers having Gd-DOTA; preparations and their control of T1-relaxivities and blood circulation characteristics

The current study synthesized macromolecular magnetic resonance imaging (MRI) contrast agents constituted of the poly(ethylene glycol)-b-poly( l-lysine) block copolymer (PEG-P(Lys)). A chelate group, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), was attached to the primary amino group of the block copolymer in desired contents. Gd-DOTA-based macromolecular contrast agents were prepared from PEG-P(Lys) having DOTA (PEG-P(Lys-DOTA) and Gd(III) ions. All of the PEG-P(Lys) block copolymers having gadolinium ions (PEG-P(Lys-DOTA-Gd)) showed higher T 1 relaxivity (per gadolinium), r 1 = 5.6–7.3 mM − 1 s − 1 , than that of a low-molecular-weight gadolinium-chelate, diethylenetriaminepentaacetic acid-gadolinium(III) (Gd-DTPA) at 9.4 T. The study prepared the polyion complex (PIC) micelles from the amino groups of the lysine units and an oppositely charged polyanion, poly(methacrylic acid) or dextran sulfate, in an aqueous medium. In contrast, the fully DOTA-attached PEG-P(Lys-DOTA-Gd) formed a PIC with a polycation. Compared with partially DOTA-attached cationic PEG-P(Lys-DOTA-Gd), this PIC micelle yielded a forty percent decrease of r 1. This r 1 decrease was considered to result from a change in the accessibility of water molecules to gadolinium ions in the micelles' inner core. The r 1 was decreased upon formation of the PIC micelle, and this change proved that our concept worked in vitro. Blood-circulation characteristics of PIC micelles were controlled by means of changing the molecular weight of the counter anion. The PIC micelles accumulated in tumor tissues, and MRI study showed T1W image of axial slice of tumor area was significantly enhanced at 24 h after the injection.

Gadolinium‐conjugated FA‐PEG‐PAMAM‐COOH nanoparticles as potential tumor‐targeted circulation‐prolonged macromolecular MRI contrast agents

AbstractThe aim of research is to develop potential tumor‐targeted circulation‐prolonged macromolecular magnetic resonance imaging (MRI) contrast agents without the use of low molecular gadolinium (Gd) ligands. The contrast agents were based on polymer–metal complex nanoparticles with controllable particle size to achieve the active and passive tumor‐targeted potential. In particular, poly (amidoamine) (PAMAM) dendrimer with 32 carboxylic groups was modified with folate‐conjugated poly (ethyleneglycol) amine (FA‐PEG‐NH2, Mw: 2 k and 4 kDa). FA‐PEG‐PAMAM‐Gd macromolecular MRI contrast agents were prepared by the complex reaction between the carboxylic groups in PAMAM and GdCl3. The structure of FA‐PEG‐PAMAM‐COOH was confirmed by nuclear magnetic resonance (1H‐NMR), Fourier transform infrared (FTIR) spectra, and electrospray ionization mass spectra (ESI‐MS). The mass percentage content of Gd (III) in FA‐PEG‐PAMAM‐Gd was measured by inductively coupled plasma‐atomic emission spectrometer (ICP‐AES). The sizes of these nanoparticles were about 70 nm measured by transmission electron microscopy, suggestion of their passive targeting potential to tumor tissue. In comparison with clinically available small molecular Gadopentetate dimeglumine, FA‐PEG‐PAMAM‐Gd showed comparable cytotoxicity and higher relaxation rate, suggestion of their great potential as tumor‐targeted nanosized macromolecular MRI contrast agents due to the overexpressed FA receptor in human tumor cell surfaces. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2010

Polydisulfide Based Biodegradable Macromolecular Magnetic Resonance Imaging Contrast Agents.

Macromolecular Gd(III) complexes are advantageous over small molecular Gd(III) complexes in contrast enhanced magnetic resonance imaging (MRI) because of their prolonged blood circulation and preferential tumor accumulation. However, macromolecular contrast agents have not been approved for clinical applications because of the safety concerns related to their slow body excretion. Polydisulfide Gd(III) complexes have been designed and developed as biodegradable macromolecular MRI contrast agents to alleviate the concerns by facilitating the clearance of Gd(III) complexes from the body. These agents initially behave as macromolecular agents and result in superior contrast enhancement in the vasculature and tumor tissues. They can then be readily degraded in vivo into small molecular chelates that can rapidly excrete from the body via renal filtration after the MRI examinations. Various polydisulfide Gd(III) complexes have been prepared as biodegradable macromolecular MRI contrast agents. These agents have resulted in strong contrast enhancement in the vasculature and tumor tissue in animal models with minimal long-term tissue accumulation comparable to small molecular contrast agents. Polydisulfide Gd(III) complexes are promising for further clinical development as safe and effective biodegradable macromolecular MRI contrast agents for cardiovascular and cancer imaging. The review summarizes the chemistry and properties of polydisulfide Gd(III) complexes.

Abstract LB-383: In vitro and in vivo MRI evaluation of a novel metallofullerene nanoparticle

Abstract Some disadvantages of conventional small molecule contrast agents, such as Magnevist® (Gd - DTPA), are that they extravasate rapidly and are quickly eliminated from blood, limiting the viable MRI time. Macromolecular magnetic resonance imaging (MRI) contrast agents, on the other hand, are useful blood-pool agents and have found application in monitoring tumor vasculature and angiogenesis. There is an urgent need for new MRI contrast agents with higher relaxivity and longer blood half-life. Here, we report in vitro and in vivo characterization of a water-soluble derivatized fullerene nanoparticle contrast agent (NCL124) in comparison to the market standard, Magnevist. In comparison to Magnevist, NCL124 had higher R1and R2 relaxivities in human plasma at 22° C and 37°C. In vivo MRI imaging was performed on a LS174T dual-flank xenografts following a single intravenous injection of NCL 124 or Magnevist contrast agent (0.2 mmol Gd/Kg) using a 3.0 Tesla clinical whole-body MRI. Based on the relaxivity-time profiles, the Vss for NCL124 was similar to that of albumin (∼ 100 mL/Kg), suggesting high protein binding, while the Vss of Magnevist was similar to that of extracellular tissue water (∼200 mL/Kg), as expected for an extracellular diffusible tracer. NCL124 also had a longer blood half-life (∼ 100 min) than Magnevist (19 min). Taken together, the higher concentration (Cmax) and exposure (AUCall) of NCL124 in the blood, coupled with slow elimination, supports the use of NCL124 as a blood-pool contrast agent. Intriguingly, the half-life of NCL124 varied by tumor size, while Magnevist showed similar half-life in both tumors. This suggests NCL124 may have significant utility in predicting differences in tumor vascular and lymphatic permeability, and potentially be useful as a marker for antiangiogenic therapy. Funded by NCI contract # HHSN261200800001E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-383.

Structural effect on degradability and in vivo contrast enhancement of polydisulfide Gd(III) complexes as biodegradable macromolecular MRI contrast agents

The structural effect of biodegradable macromolecular magnetic resonance imaging (MRI) contrast agents, polydisulfide gadolinium (Gd)(III) chelates, on their in vitro degradability, and cardiovascular and tumor imaging were evaluated in mice. Polydisulfide Gd(III) chelates, Gd-DTPA cystamine copolymers (GDCC), Gd-DTPA l-cystine copolymers (GDCP), Gd-DTPA d-cystine copolymers (dGDCP) and Gd-DTPA glutathione (oxidized) copolymers (GDGP), with different sizes and narrow molecular weight distribution were prepared and evaluated both in vitro and in vivo in mice bearing MDA-MB-231 tumor xenografts. GDGP with large steric hindrance around the disulfide bonds had greater T(1) and T(2) relaxivities than GDCC, GDCP and dGDCP. The degradability of the polydisulfide by the endogenous thiols decreased with increasing steric effects around the disulfide bonds in the order of GDCC>GDCP, dGDCP>GDGP. The size and degradability of the contrast agents had a significant impact on vascular contrast enhancement kinetics. The agents with a large size and low degradability resulted in more prolonged vascular enhancement than the agents with a small size and high degradability. It seems that the size and degradability of the agents did not significantly affect tumor enhancement. All agents resulted in significant contrast enhancement in tumor tissue. This study has demonstrated that the vascular enhancement kinetics of the polydisulfide MRI contrast agents can be controlled by their sizes and structures. The polydisulfide Gd(III) chelates are promising biodegradable macromolecular MRI contrast agents for magnetic resonance angiography and cancer imaging.

Polydisulfide Gd(III) chelates as biodegradable macromolecular magnetic resonance imaging contrast agents

Macromolecular gadolinium (Gd)(III) complexes have a prolonged blood circulation time and can preferentially accumulate in solid tumors, depending on the tumor blood vessel hyperpermeability, resulting in superior contrast enhancement in magnetic resonance (MR) cardiovascular imaging and cancer imaging as shown in animal models. Unfortunately, safety concerns related to these agents' slow elimination from the body impede their clinical development. Polydisulfide Gd(III) complexes have been designed and developed as biodegradable macromolecular magnetic resonance imaging (MRI) contrast agents to facilitate the clearance of Gd(III) complexes from the body after MRI examinations. These novel agents can act as macromolecular contrast agents for in vivo imaging and excrete rapidly as low-molecular-weight agents. The rationale and recent development of the novel biodegradable contrast agents are reviewed here. Polydisulfide Gd(III) complexes have relatively long blood circulation time and gradually degrade into small Gd(III) complexes, which are rapidly excreted via renal filtration. These agents result in effective and prolonged in vivo contrast enhancement in the blood pool and tumor tissue in animal models, yet demonstrate minimal Gd(III) tissue retention as the clinically used low-molecular-weight agents. Structural modification of the agents can readily alter the contrast-enhancement kinetics. Polydisulfide Gd(III) complexes are promising for further clinical development as safe, effective, biodegradable macromolecular MRI contrast agents for cardiovascular and cancer imaging, and for evaluation of therapeutic response.

Pharmacokinetics and Tissue Retention of (Gd-DTPA)-Cystamine Copolymers, a Biodegradable Macromolecular Magnetic Resonance Imaging Contrast Agent

To investigate the pharmacokinetics, long-term tissue retention of Gd(III) ions, and magnetic resonance imaging (MRI) contrast enhancement of extracellular biodegradable macromolecular Gd(III) complexes, (Gd-DTPA)-cystamine copolymers (GDCC), of different molecular weights. The pharmacokinetics of blood clearance and long-term Gd(III) retention of GDCC were investigated in Sprague-Dawley rats. Pharmacokinetic parameters were calculated by using a two-compartment model. The blood pool contrast enhancement of GDCC was evaluated in Sprague-Dawley rats on a Siemens Trio 3T MR scanner. Gd-(DTPA-BMA) was used as a control. The alpha phase half-life of Gd-(DTPA-BMA) and GDCC with molecular weights of 18,000 (GDCC-18) and 60,000 Da (GDCC-60) was 0.48 +/- 0.16 min, 1.08 +/- 0.24 min, and 1.74 +/- 0.57 min, and the beta phase half-life was 21.2 +/- 5.5 min, 26.5 +/- 5.9 min, and 53.7 +/- 15.9 min, respectively. GDCC had minimal long-term Gd tissue retention comparable to that of Gd-(DTPA-BMA). GDCC resulted in more significant contrast enhancement in the blood pool than Gd-(DTPA-BMA). GDCC provides a prolonged blood pool retention time for effective MRI contrast enhancement and then clears rapidly with minimal accumulation of Gd (III) ions. It is promising for further development as a blood pool MRI contrast agent.

Gadolinium(III) DO3A macrocycles and polyethylene glycol coupled to dendrimers Effect of molecular weight on physical and biological properties of macromolecular magnetic resonance imaging contrast agents

The macrocycle 1-(4-isothiocyanatobenzyl)amido-4,7,10-triacetic acid-tetraazacyclododecane (DO3A-bz-NCS) was synthesized and coupled to the terminal amine sites of a series of different generations (Gn) of polyamidoamine or starburst dendrimers (n-SBDs) creating macromolecular polychelates. Gadolinium ion was added to the dendrimer polychelates for evaluating the parameters needed to create magnetic resonance imaging (MRI) contrast agents that have long blood circulation times. The resulting water soluble n-SBD-GdDO3As were mono-disperse and ranged from 11 Gd3+ ions per G3 dendrimer (MW 18.4 kDalton (kDa)) to 57 Gd3+ ions per G5 dendrimer (MW 61.8 kDa). Nuclear Magnetic Resonance Dispersion (NMRD) profiles revealed peak relaxivities up to 18.8 mM−1 s−1 at 25 MHz, with the magnitude increasing linearly as a function of molecular weight. Blood elimination half-life in rats increased with molecular weight ranging from 11(±5) min for 3-SBD-(GdDO3A)24 (22 kDa) to 115(±8) min for the 5-SBD-(GdDO3A)57 (61.8 kDa). Seven-day liver retention increased from 1 to over 40% over the same molecular weight range. The effects of grafting polyethylene glycol (PEG) onto n-SBD-GdDO3A polychelates were also studied. Relaxivities ranged from 11 to 14.9 mM−1 s−1, blood elimination half-lives increased significantly (range 33–1219 min) and the seven-day liver uptake dropped to 1–8% of the injected dose. However, no correlations between these measurements and molecular weight were found over the range studied (20.5–69.3 kDa). These results suggest that both the molecular weight and type of terminal group on the n-SBD-GdDO3A polychelates control the pharmacokinetics and biodistribution of the macromolecular contrast agent. The addition of covalently bound PEG to the n-SBD-GdDO3A surface significantly improved the biological performance of the contrast agents.

Synthesis and Relaxivity of Polyamide Paramagnetic Metal Complexes for Magnetic Resonance Imaging

A new class of paramagnetic macromolecular magnetic resonance imaging contrast agents has been developed. Eight new polyamide ligands were synthesized by copolymerization of ethylenediaminetetraacetic acid dianhydride or diethylenetriaminepentaacetic acid dianhydride and diamine monomers. Their gadolinium(III), manganese(II) and iron(III) complexes were also synthesized. All polyamide ligands and metal complexes were characterized by 1H nuclear magnetic resonance, infrared spectra and elemental analyses. Relaxivity studies showed that the polyamide paramagnetic metal complexes had obviously higher relaxation effectiveness as compared to corresponding simple monomeric paramagnetic metal complexes.

Quantification of capillary permeability to macromolecular magnetic resonance imaging contrast media in experimental mammary adenocarcinomas.

Quantification of capillary permeability to macromolecular magnetic resonance imaging contrast media in experimental mammary adenocarcinomas.

Macromolecular Magnetic Resonance Imaging Contrast Media Accumulated Experience

BRASCH, ROBERT C. MD; MOSELEY, MICHAEL E. PHD; DUPON, JEAN PHD; WANG, SHIH-CHANG MD; AICHER, KLAUS P. MD; WIKSTROM, MATS MD; SCHMIEDL, UDO MD, PHD; WOLFE, CHRISTOPHER L. MD; OGAN, MARC D. PHD; GROOD, WOLFGANG MD; PAAJANEN, HANNU MD, PHD; WHITE, DAVID MD Author Information