New macromolecular polymeric MRI contrast agents for application in the differentiation of cancer from benign soft tissues (original) (raw)
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Biomacromolecules, 2007
Diagnostic contrast media for magnetic resonance imaging (MRI) are often applied to enhance the signal of blood allowing for quantitative definition of vascular functional characteristics including tissue blood volume, flow, and leakiness. Well-tolerated and safe macromolecular formulations are currently being sought that remain in the blood for a relatively long period and that leak selectively from diseased vessels, particularly cancer vessels. We synthesized a new class of macromolecular, water-soluble MRI contrast media by introducing two diverging polylysine cascade amplifiers at each end of a poly(ethylene glycol) (PEG) backbone, followed by substitution of terminal lysine amino groups with Gd-DTPA chelates. Four candidate PEG cascade conjugates are reported here, PEG3400-Gen4-(Gd-DTPA) 8 , PEG6000-Gen4-(Gd-DTPA) 8 , PEG12000-Gen4-(Gd-DTPA) 8 , and PEG3400-Gen5-(Gd-DTPA) 13 with descriptions of their basic physical, biological, and kinetic properties, including real and effective molecular sizes, proton T1 relaxivities in water and plasma, partition coefficients, osmolalities, chelate stability, stability in plasma, stability to autoclaving, certain in vivo pharmacokinetics (blood half-life, blood clearance, volume of distribution), and whole body elimination profiles in normal rodents. These candidate PEG-core cascade MRI contrast media showed a range of effective molecular sizes similar to proteins weighing 74-132 kDa, although their actual molecular weights were much smaller, 12-20 kDa. All compounds exhibited a narrow range of size dispersity and relatively high T1 relaxivities (approximately 3 times the value for unconjugated Gd-DTPA at 2 T and 37°C). Representative compounds also showed a high degree of hydrophilicity, stability in solution buffer and plasma, and lack of binding to proteins. The two candidate compounds with the largest effective molecular sizes, PEG12000-Gen4-(Gd-DTPA) 8 and PEG3400-Gen5-(Gd-DTPA) 13 , had longer blood half-lives, 36 and 73 min, respectively (monoexponential kinetics for both), and showed strong, prolonged MRI enhancement of vessels. Results also indicate that in vivo pharmacokinetics and bodily elimination profiles can be adjusted by the selection of molecular size for the PEG core and the selection of the amplification degree of the cascade polylysine clusters. The initially evaluated compounds from this new class of contrast media show acceptable, desirable characteristics in many, but not all, respects. Further efforts are directed toward candidate macromolecules having higher thermodynamic stability, higher degree of substitution by gadolinium chelates, and more rapid bodily elimination.
Despite the great efforts in the areas of early diagnosis and treatment of cancer, this disease continues to grow and is still a global killer. Cancer treatment efficiency is relatively high in the early stages of the disease. Therefore, early diagnosis is a key factor in cancer treatment. Among the various diagnostic methods, molecular imaging is one of the fastest and safest ones. Because of its unique characteristics,magnetic resonance imaging has a special position inmost researches. To increase the contrast ofMR images, many pharmaceuticals have been known and used so far. Gadopentetate (with commercial name Magnevist) is the first magnetic resonance imaging contrast media that has been approved by the US Food and Drug Administration. In this study, gadopentetate was first synthesized and then attached to a tree-like polymer called dendrimer which is formed by polyethylene glycol core and surrounding citric acid groups. Stability studies of the drug were carried out to ensure proper synthesis.Then, the uptake of the drug into liver hepatocellular cell line and the drug cytotoxicity were evaluated. Finally, in vitro and in vivo MR imaging were performed with the new synthetic drug. Based on the findings of this research, connecting gadopentetate to dendrimer surface produces a stronger, safer, and more efficient contrast media. Gd(III)-diethylenetriamine pentaacetate-meglumine-dendrimer drug has the ability to enter cells and does not produce significant cytotoxicity. It also increases the relaxivity of tissue and enhances the MR images contrast.The obtained results confirm the hypothesis that the binding of gadopentetate to citric acid dendrimer produces a new, biodegradable, stable, and strong version of the old contrast media.
Journal of Inorganic Biochemistry, 2011
We report in vivo and in vitro MRI properties of six gadolinium-dendrimer and gadoliniumalbumin conjugates of derivatized acyclic diethylenetriamine-N,N',N',N'', N''-pentaacetic acid (1B4M) and macrocyclic 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (C-DOTA). The three albumin-based agents have comparable protein to chelate ratios (1:16-18) as well as molar relaxivity (8.8-10.4 mM −1 s −1 ). The three dendrimer based agents have blood clearance half-lives ranging from 17 to 66 min while that of the three albumin-based agents are comparable to one another (40-47 min). The dynamic image obtained from use of the albumin conjugate based on the macrocycle (C-DOTA) showed a higher contrast compared to the remaining two albumin based agents. Our conclusion from all of the results is that the macrocyclic-based (DOTA) agents are more suitable than the acyclic-based (1B4M) agent for in vivo use based on their MRI properties combined with the kinetic inertness property associated with the more stable Gd(III) DOTA complex.
Magnetic Resonance in Medicine, 1998
Dynamic contrast-enhanced MR imaging was used to measure the kinetics of enhancement in three different animal tumor models (Walker 256, R3230 AC, MCF7) using three different Gd complexes (Gd-DTPA, Gd-DTPA-24-cascade-polymer 30 kD, and polylysine-Gd-DTPA 50 kD). The three tumor models varied in growth rate, with the most rapid growth demonstrated by Walker 256 cells and the slowest growth occurring in the MCF7 cells. For each tumor, the kinetics of enhancement using polylysine-Gd-DTPA was analyzed using a pharmacokinetic model to estimate the vascular volume of the tumor. The rate of entry of the contrast agent into the interstitial space served as the measure of vascular permeability. The smallest molecular-weight agent, Gd-DTPA, could not provide information about vascular permeability. The intermediate and the largest agents both demonstrated that the faster-growing Walker 256 tumor had greater vascular permeability than did the slower-growing R3230 AC tumor. The degree of vascular permeability in the MCF7 tumor could not be assessed fairly due to insufficient statistics. The current study provides evidence supporting the hypothesis that more rapidly growing tumors have higher vascular permeability than do tumors that grow more slowly.
Magnetic Resonance in Medicine, 2001
As MRI contrast agents, more hydrophobic molecules reportedly accumulate in the liver and thus are potentially useful as liver MRI contrast agents. In this study, a generation-4 polypropylenimine diaminobutane dendrimer (DAB-Am64), which is expected to be more hydrophobic than the generation-4 polyamidoamine dendrimer (PAMAM-G4D), was used to synthesize a conjugate with 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M) [DAB-Am64-(1B4M-Gd)64] for complexing Gd(III) ions. This DAB conjugate quickly accumulated in the liver and its characteristics were studied and compared with those of a PAMAM conjugate [PAMAM-G4D-(1B4M-Gd)64], which is known to be a useful vascular MRI contrast agent, in regard to its availability as a liver MRI contrast agent. DAB-Am64-(1B4M-Gd)64 accumulated significantly more in the liver and less in blood than PAMAM-G4D-(1B4M-Gd)64 (P < 0.001). Contrast-enhanced MRI with DAB-Am64-(1B4M-Gd)64 was able to homogeneously enhance liver parenchyma and visualize both portal and hepatic veins of 0.5 mm diameter in mice. In conclusion, DAB-Am64-(1B4M-Gd)64 is a good candidate for a liver MRI contrast agent. Magn Reson Med 46:795–802, 2001. © 2001 Wiley-Liss, Inc.
Bioconjugate Chemistry, 2003
Large macromolecular MRI contrast agents with albumin or dendrimer cores are useful for imaging blood vessels. However, their prolonged retention is a major limitation for clinical use. Although smaller dendrimer-based MRI contrast agents are more quickly excreted by the kidneys, they are also able to visualize vascular structures better than Gd-DTPA due to less extravasation. Additionally, unlike Gd-DTPA, they transiently accumulate in renal tubules and thus also can be used to visualize renal structural and functional damage. However, these dendrimer agents are retained in the body for a prolonged time. The purpose of this study was to obtain information from which a macromolecular dendrimer-based MRI contrast agents feasible for use in further clinical studies could be chosen. Six small dendrimer-based MRI contrast agents were synthesized, and their pharmacokinetics, wholebody retention, and dynamic MRI were evaluated in mice to determine an optimal agent in comparison to Gd-[DTPA]-dimeglumine. Diaminobutane (DAB) dendrimer-based agents cleared more rapidly from the body than polyamidoamine (PAMAM) dendrimer-based agents with the same numbers of branches. Smaller dendrimer conjugates were more rapidly excreted from the body than the larger dendrimer conjugates. Since PAMAM-G2, DAB-G3, and DAB-G2 dendrimer-based contrast agents showed relatively rapid excretion, these three conjugates might be acceptable for use in further clinical applications.
MRI macromolecular contrast agents as indicators of changed tumor blood flow
Background. A rapid mapping technique derived from dynamic contrast enhanced MRI data was used to identify and characterize reduction of blood flow in fibrosarcoma SA-1 tumors treated either by application of electric pulses or vinblastine. Materials and methods. Tissue permeability surface area product (PS) and fractional blood volume (BV) were calculated on a pixel-by-pixel basis using dynamic MRI intensity data after administration of gadomer-17 or polylysine-Gd-DTPA; prototypic macromolecular contrast agents designed for blood pool enhance-ment. PS and BV values of untreated tumors were compared to those of tumors treated by local application of 8 electric pulses (amplitude/distance ratio, 1300 V/cm; duration, 100 ms, frequency, 1 Hz) percutaneo-usly to the tumor or by systemic administration of vinblastine (2.5 mg/kg). Results. Both treatments transiently, but significantly reduced tumor blood flow, application of electric pul-ses to the tumors being by 40% more effective in re...
Contrast Media & Molecular Imaging, 2015
Macromolecular gadolinium (Gd)-based contrast agents are in development as blood pool markers for MRI. HPG-GdF is a 583 kDa hyperbranched polyglycerol doubly tagged with Gd and Alexa 647 nm dye, making it both MR and histologically visible. In this study we examined the location of HPG-GdF in whole-tumor xenograft sections matched to in vivo DCE-MR images of both HPG-GdF and Gadovist. Despite its large size, we have shown that HPG-GdF extravasates from some tumor vessels and accumulates over time, but does not distribute beyond a few cell diameters from vessels. Fractional plasma volume (fPV) and apparent permeability-surface area product (aPS) parameters were derived from the MR concentration-time curves of HPG-GdF. Non-viable necrotic tumor tissue was excluded from the analysis by applying a novel bolus arrival time (BAT) algorithm to all voxels. aPS derived from HPG-GdF was the only MR parameter to identify a difference in vascular function between HCT116 and HT29 colorectal tumors. This study is the first to relate low and high molecular weight contrast agents with matched whole-tumor histological sections. These detailed comparisons identified tumor regions that appear distinct from each other using the HPG-GdF biomarkers related to perfusion and vessel leakiness, while Gadovist-imaged parameter measures in the same regions were unable to detect variation in vascular function. We have established HPG-GdF as a biocompatible multi-modal high molecular weight contrast agent with application for examining vascular function in both MR and histological modalities.