Contrast Enhanced MRI Assessment of Tumor Blood Volume After Application of Electric Pulses

The effect of application of short, intense electric pulses on tumor blood volume was investigated using albumin-(Gd-DTPA)₃₀ contrast-enhanced magnetic resonance imaging (MRI). One of paired SA-1 fibrosarcoma tumors implanted in each flank of A/J mice was treated with electric pulses. MRI was performed dynamically before and after intravenous administration of albumin-(Gd-DTPA)₃₀ (0.02 mmol Gd/kg), and fractional tumor blood volume was estimated. MRI images of tumors exposed to electric pulses showed no enhancement at 30 min after injection of albu-min-(Gd-DTPA)₃₀. However, marked enhancement was observed in paired tumors of the same mice that were not exposed to electric pulses. A significant difference in blood volume was observed between nontreated tumors and tumors treated with electric pulses. Application of electric pulses to the tumors significantly reduced blood volume in the tumors. Therefore, through a reduction in tumor blood volume, electric pulses may, besides producing electroporation of cells, exert antitumor effectiveness by entrapping drugs within the tumors.     

Synergistic enhancement of iron oxide nanoparticle and gadolinium for dual-contrast MRI

PurposeThe use of MR contrast agents allows accurate diagnosis by exerting an influence on the longitudinal (T₁) or transverse (T₂) relaxation time of the surrounding tissue. In this study, we combined the use of iron oxide (IO) particles and nonspecific extracellular gadolinium chelate (Gd) in order to further improve the sensitivity and specificity of lesion detection.ProceduresWith a 7-Tesla scanner, pre-contrasted, IO-enhanced and dual contrast agent enhanced MRIs were performed in phantom, normal animals, and animal models of lymph node tumor metastases and orthotopic brain tumor. For the dual-contrast (DC) MRI, we focused on the evaluation of T₂ weighted DC MRI with IO administered first, then followed by the injection of a bolus of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA).ResultsBased on the C/N ratios and MRI relaxometry, the synergistic effect of coordinated administration of Gd-DTPA and IO was observed and confirmed in phantom, normal liver and tumor models. At 30 min after administration of Feridex, Gd-DTPA further decreased T₂ relaxation in liver immediately after the injection. Additional administration of Gd-DTPA also immediately increased the signal contrast between tumor and brain parenchyma and maximized the C/N ratio to ?4.12 ± 0.71. Dual contrast MRI also enhanced the delineation of tumor borders and small lesions.ConclusionsDC-MRI will be helpful to improve diagnostic accuracy and decrease the threshold size for lesion detection.     

Dynamic contrast enhanced MRI of mouse fibrosarcoma using small-molecular and novel macromolecular contrast agents

The aim of the study was a comparison of 2 novel macromolecular contrast agents, Gadomer-17 and Polylysine-Gd-DTPA, with commercially available Gd-DTPA in determining the quality of tumor microvasculature by dynamic contrast enhanced MRI. Three groups of 5 mice with SA-1 tumors were studied. To each group of animals one contrast agent was administered; i.e. the first group got Gd-DTPA, the second group Gadomer-17 and the third group Polylysine-Gd-DTPA. To perform dynamic contrast enhanced MRI a standard keyhole approach was used by which consecutive signal intensity change due to contrast agent accumulation in the tumor was measured. From the obtained data, tissue permeability surface area product PS and fractional blood volume BV were calculated on a pixel-by-pixel basis. PS and BV values were calculated for each contrast agent. Based on the values, contrast agents were classified according to their performance in characterizing tumor microvasculature. Results of our study suggest that Gadomer-17 and Polylysine-Gd-DTPA are significantly superior to Gd-DTPA in characterizing tumor microvasculature.     

PEGylation of protein-based MRI contrast agents improves relaxivities and biocompatibilities

Magnetic resonance imaging (MRI) has emerged as a leading diagnostic technique in clinical and preclinical settings. However, the application of MRI to assess specific disease markers for diagnosis and monitoring drug effect has been severely hampered by the lack of desired contrast agents with high relaxivities, and optimized in vivo retention time. We have reported the development of protein-based MRI contrast agents (ProCA1) by rational design of Gd^3 + binding sites into a stable protein resulting in significantly increased longitudinal (r₁) and transverse (r₂) relaxivities compared to Gd-DTPA. Here, we report a further improvement of protein contrast agents ProCA1 for in vivo imaging by protein modification with various sizes of polyethylene glycol (PEG) chain. PEGylation results in significant increases of both r₁ and r₂ relaxivities (up to 200%), and these high relaxivities persist even at field strengths up to 9.4 T. In addition, our experimental results demonstrate that modified contrast agents have significant improvement of in vivo MR imaging and biocompatibilities including dose efficiency, protein solubility, blood retention time and decreased immunogenicity. Such improvement can be important to the animal imaging and pre-clinical research at high or ultra-high field where there is an urgent need for molecular imaging probes and optimized contrast agent.     

Development of Bifunctional Gadolinium-Labeled Superparamagnetic Nanoparticles (Gd-MnMEIO) for In Vivo MR Imaging of the Liver in an Animal Model

Liver tumors are common and imaging methods, particularly magnetic resonance imaging (MRI), play an important role in their non-invasive diagnosis. Previous studies have shown that detection of liver tumors can be improved by injection of two different MR contrast agents. Here, we developed a new contrast agent, Gd-manganese-doped magnetism-engineered iron oxide (Gd-MnMEIO), with enhancement effects on both T1- and T2-weighted MR images of the liver. A 3.0T clinical MR scanner equipped with transmit/receiver coil for mouse was used to obtain both T1-weighted spoiled gradient-echo and T2-weighted fast spin-echo axial images of the liver before and after intravenous contrast agent injection into Balb/c mice with and without tumors. After pre-contrast scanning, six mice per group were intravenously injected with 0.1 mmol/kg Gd-MnMEIO, or the control agents, i.e., Gd-DTPA or SPIO. The scanning time points for T1-weighted images were 0.5, 5, 10, 15, 20, 25, and 30 min after contrast administration. The post-enhanced T2-weighted images were then acquired immediately after T1-weighted acquisition. We found that T1-weighted images were positively enhanced by both Gd-DTPA and Gd-MnMEIO and negatively enhanced by SPIO. The enhancement by both Gd-DTPA and Gd-MnMEIO peaked at 0.5 min and gradually declined thereafter. Gd-MnMEIO (like Gd-DTPA) enhanced T1-weighted images and (like SPIO) T2-weighted images. Marked vascular enhancement was clearly visible on dynamic T1-weighted images with Gd-MnMEIO. In addition, the T2 signal was significantly decreased at 30 min after administration of Gd-MnMEIO. Whereas the effects of Gd-MnMEIO and SPIO on T2-weighted images were similar (p = 0.5824), those of Gd-MnMEIO and Gd-DTPA differed, with Gd-MnMEIO having a significant T2 contrast effect (p = 0.0086). Our study confirms the feasibility of synthesizing an MR contrast agent with both T1 and T2 shortening effects and using such an agent in vivo. This agent enables tumor detection and characterization in single liver MRI sections.     

Can DCEMRI assess the effect of green tea on the angiogenic properties of rodent prostate tumors?

The purpose of this research was to test whether dynamic contrast enhanced MRI could assess the effect of green tea on the angiogenic properties of transplanted rodent tumors. Copenhagen rats bearing AT6.1 prostate tumors inoculated in the hind limbs were randomly assigned to cages in which they were allowed to only drink either plain water (control group) or water containing green tea extract (treated group). Assignments were made after a baseline MRI experiment (week 0) was performed on each rat at 4.7 T. All the rats were subsequently imaged at day 7 (week 1) and day 14 (week 2) to follow tumor growth and vascular development. The two-compartment pharmacokinetic model was used to analyze the dynamic contrast Gd-DTPA enhanced MRI data on a pixel-by-pixel basis over the tumor area to obtain the volume transfer constant (K^trans) and extravascular extracellular space (v_e). An identity Chi-squared test showed that the distributions of averaged histograms (n = 6) of K^trans and v_e were significantly different from week 0 to both weeks 1 and 2 (p < 0.001) in both the control and the treated rats due to increasing areas of tumor necrosis. However, the tumor growth rate was statistically indistinguishable between control and treated rats. There was no significant difference in the distributions of K^trans and v_e between control and treated rats. The results showed that no effects of green tea on tumor micro-vasculature were measurable by dynamic Gd-DTPA enhanced MRI.     

Contrast enhancement of the brain by folate-conjugated gadolinium-diethylenetriaminepentaacetic Acid-human serum albumin nanoparticles by magnetic resonance imaging

AbstractDifferent from regular small molecule contrast agents, nanoparticle-based contrast agents have a longer circulation time and can be modified with ligands to confer tissue-specific contrasting properties. We evaluated the tissue distribution of polymeric nanoparticles (NPs) prepared from human serum albumin (HSA), loaded with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) (Gd-HSA-NP), and coated with folic acid (FA) (Gd-HSA-NP-FA) in mice by magnetic resonance imaging (MRI). FA increases the affinity of the Gd-HSA-NP to FA receptor-expressing cells. Clinical 3 T MRI was used to evaluate the signal intensities in the different organs of mice injected with Gd-DTPA, Gd-HSA-NP, or Gd-HSA-NP-FA. Signal intensities were measured and standardized by calculating the signal to noise ratios. In general, the NP-based contrast agents provided stronger contrasting than Gd-DTPA. Gd-HSA-NP-FA provided a significant contrast enhancement (CE) in the brain (p = .0032), whereas Gd-DTPA or Gd-HSA-NP did not. All studied MRI contrast agents showed significant CE in the blood, kidney, and liver (p < .05). Gd-HSA-NP-FA elicited significantly higher CE in the blood than Gd-HSA-NP (p = .0069); Gd-HSA-NP and Gd-HSA-NP-FA did not show CE in skeletal muscle and gallbladder; Gd-HSA-NP, but not Gd-HSA-NP-FA, showed CE in the cardiac muscle. Gd-HSA-NP-FA has potential as an MRI contrast agent in the brain.     

Macromolecular MRI contrast agents with small dendrimers: pharmacokinetic differences between sizes and cores

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, whole-body 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.     

In Vitro Longitudinal Relaxivity Profile of Gd(ABE-DTTA), an Investigational Magnetic Resonance Imaging Contrast Agent

Purpose

MRI contrast agents (CA) whose contrast enhancement remains relatively high even at the higher end of the magnetic field strength range would be desirable. The purpose of this work was to demonstrate such a desired magnetic field dependency of the longitudinal relaxivity for an experimental MRI CA, Gd(ABE-DTTA).

Materials and Methods

The relaxivity of 0.5mM and 1mM Gd(ABE-DTTA) was measured by Nuclear Magnetic Relaxation Dispersion (NMRD) in the range of 0.0002 to 1T. Two MRI and five NMR instruments were used to cover the range between 1.5 to 20T. Parallel measurement of a Gd-DTPA sample was performed throughout as reference. All measurements were carried out at 37°C and pH 7.4.

Results

The relaxivity values of 0.5mM and 1mM Gd(ABE-DTTA) measured at 1.5, 3, and 7T, within the presently clinically relevant magnetic field range, were 15.3, 11.8, 12.4 s^-1mM^-1 and 18.1, 16.7, and 13.5 s^-1mM^-1, respectively. The control 4 mM Gd-DTPA relaxivities at the same magnetic fields were 3.6, 3.3, and 3.0 s^-1mM^-1, respectively.

Conclusions

The longitudinal relaxivity of Gd(ABE-DTTA) measured within the presently clinically relevant field range is three to five times higher than that of most commercially available agents. Thus, Gd(ABE-DTTA) could be a practical choice at any field strength currently used in clinical imaging including those at the higher end.     

Integrin αvβ3-Targeted Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using a Gadolinium-Loaded Polyethylene Gycol-Dendrimer-Cyclic RGD Conjugate to Evaluate Tumor Angiogenesis and to Assess Early Antiangiogenic Treatment Response in a Mouse Xenograft Tumor Model

AbstractThe purpose of this study was to validate an integrin αvβ3-targeted magnetic resonance contrast agent, PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2, for its ability to detect tumor angiogenesis and assess early response to antiangiogenic therapy using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI). Integrin αvβ3-positive U87 cells and control groups were incubated with fluorescein-labeled cRGD-conjugated dendrimer, and the cellular attachment of the dendrimer was observed. DCE MRI was performed on mice bearing KB xenograft tumors using either PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2 or PEG-G3-(Gd-DTPA)6-(cRAD-DTPA)2. DCE MRI was also performed 2 hours after anti-integrin αvβ3 monoclonal antibody treatment and after bevacizumab treatment on days 3 and 6t. Using DCE MRI, the 30-minute contrast washout percentage was significantly lower in the cRGD-conjugate injection groups. The enhancement patterns were different between the two contrast injection groups. In the antiangiogenic therapy groups, a rapid increase in 30-minute contrast washout percentage was observed in both the LM609 and bevacizumab treatment groups, and this occurred before there was an observable decrease in tumor size. The integrin αvβ3 targeting ability of PEG-G3-(Gd-DTPA)6-(cRGD-DTPA)2 in vitro and in vivo was demonstrated. The 30-minute contrast washout percentage is a useful parameter for examining tumor angiogenesis and for the early assessment of antiangiogenic treatment response.     

Molecular mechanisms for the hepatic uptake of magnetic resonance imaging contrast agents

The mechanisms were investigated for the hepatic transport of 4 different gadolinium complexes used as contrast agents for magnetic resonance imaging (MRI). In basolateral rat hepatocyte plasma membrane vesicles, Gd-DTPA uptake was indistinguishable from non-specific binding to vesicles; Gd-BOPTA and Gd-EOB-DTPA entered plasma membrane vesicles following a linear, concentration-dependent mechanism up to 1.5 mM of substrate. By contrast, Gd-B 20790 uptake followed a saturative kinetic with an apparent Km of 92 +/- 15 microM and a Vmax of 143 +/- 42 pmol/mg prot/15 sec, and it occurred into an osmotic-sensitive space. Sulfobromophthalein ant taurocholate, but not unconjugated bilirubin inhibited the uptake rate of Gd-B 20790 but not that of the other three compounds. Injection into Xenopus laevis oocytes of 5 ng of human OATP cRNA resulted, after 3 days, in a >/=2-fold stimulation (p < 0.001) of transport of Gd-B 20790 but not of Gd-BOPTA or Gd-EOB-DTPA. Collectively, these data indicate that the hepatic uptake of the MRI contrast agent Gd-B 20790 is a carrier-mediated mechanism operated by OATP while MRI compounds with other chemical structures enter the hepatocyte by other mechanisms.     

Differentiation of Breast Cancer from Fibroadenoma with Dual-Echo Dynamic Contrast-Enhanced MRI

Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) of the breast is a routinely used imaging method which is highly sensitive for detecting breast malignancy. Specificity, though, remains suboptimal. Dynamic susceptibility contrast magnetic resonance imaging (DSC MRI), an alternative dynamic contrast imaging technique, evaluates perfusion-related parameters unique from DCE MRI. Previous work has shown that the combination of DSC MRI with DCE MRI can improve diagnostic specificity, though an additional administration of intravenous contrast is required. Dual-echo MRI can measure both T₁W DCE MRI and T₂*W DSC MRI parameters with a single contrast bolus, but has not been previously implemented in breast imaging. We have developed a dual-echo gradient-echo sequence to perform such simultaneous measurements in the breast, and use it to calculate the semi-quantitative T₁W and T₂*W related parameters such as peak enhancement ratio, time of maximal enhancement, regional blood flow, and regional blood volume in 20 malignant lesions and 10 benign fibroadenomas in 38 patients. Imaging parameters were compared to surgical or biopsy obtained tissue samples. Receiver operating characteristic (ROC) curves and area under the ROC curves were calculated for each parameter and combination of parameters. The time of maximal enhancement derived from DCE MRI had a 90% sensitivity and 69% specificity for predicting malignancy. When combined with DSC MRI derived regional blood flow and volume parameters, sensitivity remained unchanged at 90% but specificity increased to 80%. In conclusion, we show that dual-echo MRI with a single administration of contrast agent can simultaneously measure both T₁W and T₂*W related perfusion and kinetic parameters in the breast and the combination of DCE MRI and DSC MRI parameters improves the diagnostic performance of breast MRI to differentiate breast cancer from benign fibroadenomas.     

Quantitative Multi-Parametric Magnetic Resonance Imaging of Tumor Response to Photodynamic Therapy

ObjectiveThe aim of this study was to characterize response to photodynamic therapy (PDT) in a mouse cancer model using a multi-parametric quantitative MRI protocol and to identify MR parameters as potential biomarkers for early assessment of treatment outcome.MethodsCT26.WT colon carcinoma tumors were grown subcutaneously in the hind limb of BALB/c mice. Therapy consisted of intravenous injection of the photosensitizer Bremachlorin, followed by 10 min laser illumination (200 mW/cm²) of the tumor 6 h post injection. MRI at 7 T was performed at baseline, directly after PDT, as well as at 24 h, and 72 h. Tumor relaxation time constants (T₁ and T₂) and apparent diffusion coefficient (ADC) were quantified at each time point. Additionally, Gd-DOTA dynamic contrast-enhanced (DCE) MRI was performed to estimate transfer constants (K^trans) and volume fractions of the extravascular extracellular space (v_e) using standard Tofts-Kermode tracer kinetic modeling. At the end of the experiment, tumor viability was characterized by histology using NADH-diaphorase staining.ResultsThe therapy induced extensive cell death in the tumor and resulted in significant reduction in tumor growth, as compared to untreated controls. Tumor T₁ and T₂ relaxation times remained unchanged up to 24 h, but decreased at 72 h after treatment. Tumor ADC values significantly increased at 24 h and 72 h. DCE-MRI derived tracer kinetic parameters displayed an early response to the treatment. Directly after PDT complete vascular shutdown was observed in large parts of the tumors and reduced uptake (decreased K^trans) in remaining tumor tissue. At 24 h, contrast uptake in most tumors was essentially absent. Out of 5 animals that were monitored for 2 weeks after treatment, 3 had tumor recurrence, in locations that showed strong contrast uptake at 72 h.ConclusionDCE-MRI is an effective tool for visualization of vascular effects directly after PDT. Endogenous contrast parameters T₁, T₂, and ADC, measured at 24 to 72 h after PDT, are also potential biomarkers for evaluation of therapy outcome.     

Synthesis and characterization of poly(L-glutamic acid) gadolinium chelate: a new biodegradable MRI contrast agent

Most currently evaluated macromolecular contrast agents for magnetic resonance imaging (MRI) are not biodegradable. The goal of this study is to synthesize and characterize poly(l-glutamic acid) (PG) gadolinium chelates as biodegradable blood-pool MRI contrast agents. Two PG chelates of gadolinium diethylenetriaminepentaacetic acid (Gd-DTPA) were synthesized through the use of difunctional and monofunctional DTPA precursors. The conjugates were characterized with regard to molecular weight and molecular weight distribution, gadolinium content, relaxivity, and degradability. Distributions of the polymeric MRI contrast agents in various organs were determined by intravenous injection of (111)In-labeled polymers into mice bearing murine breast tumors. MRI scans were performed at 1.5 T in mice after bolus injection of the polymeric chelates. PG-Hex-DTPA-Gd, obtained from aminohexyl-substituted PG and DTPA-dianhydride, was partially cross-linked and was undegradable in the presence of cathepsin B. On the other hand, PG-Bz-DTPA-Gd synthesized directly from PG and monofunctional p-aminobenzyl-DTPA(acetic acid-tert-butyl ester) was a linear polymer and was degradable. The relaxivities of the polymers at 1.5 T were 3-8 times as great as that of Gd-DTPA. Both polymers had high blood concentrations and were primarily accumulated in the kidney. However, PG-Bz-DTPA-Gd was gradually cleared from the body and had significantly less retention in the blood, the spleen, and the kidney. MRI with PG-Bz-DTPA-Gd in mice showed enhanced vascular contrast at up to 2 h after the contrast agent injection. The ability of PG-Bz-DTPA-Gd to be degraded and cleared from the body makes it a favorable macromolecular MRI contrast agent.     

Assessing the Efficacy of Nano- and Micro-Sized Magnetic Particles as Contrast Agents for MRI Cell Tracking

Iron-oxide based contrast agents play an important role in magnetic resonance imaging (MRI) of labelled cells in vivo. Currently, a wide range of such contrast agents is available with sizes varying from several nanometers up to a few micrometers and consisting of single or multiple magnetic cores. Here, we evaluate the effectiveness of these different particles for labelling and imaging stem cells, using a mouse mesenchymal stem cell line to investigate intracellular uptake, retention and processing of nano- and microsized contrast agents. The effect of intracellular confinement on transverse relaxivity was measured by MRI at 7 T and in compliance with the principles of the ‘3Rs’, the suitability of the contrast agents for MR-based cell tracking in vivo was tested using a chick embryo model. We show that for all particles tested, relaxivity was markedly reduced following cellular internalisation, indicating that contrast agent relaxivity in colloidal suspension does not accurately predict performance in MR-based cell tracking studies. Using a bimodal imaging approach comprising fluorescence and MRI, we demonstrate that labelled MSC remain viable following in vivo transplantation and can be tracked effectively using MRI. Importantly, our data suggest that larger particles might confer advantages for longer-term imaging.     

A longitudinal study of radiation-induced changes in tumor vasculature by contrast-enhanced magnetic resonance imaging

Dynamic contrast-enhanced MRI with two different-sized contrast agents, Gd-DTPA and Gadomer-17, was used to study the effects of radiation on the pharmacokinetics of the paramagnetic enhancement of water relaxation in the rat R3230 AC adenocarcinoma tumor model. The kinetics of enhancement was analyzed by a two-compartment pharmacokinetic model to derive parameters related to vascular volume (V(b)) and permeability (K(2)). Rats implanted with tumors were divided into two groups; one received 5 Gy and the other received 20 Gy (137)Cs gamma rays. Sequential dynamic contrast-enhanced MRI studies were performed, one before irradiation, one at day 1 after irradiation, and another at day 3 after irradiation, to investigate the effect of the radiation dose and the changes that occurred over time. The analysis was performed on a pixel-by-pixel basis to study the heterogeneity within the tumor. The pixel distribution profiles of V(b) and K(2) from each tumor were obtained to assess the regional radiation-induced effects on vascular volume and permeability. No significant change in vascular volume was detected with either Gd-DTPA or Gadomer-17 after irradiation of the tumor; however, a small dependence of K(2) on the radiation dose was observed. After low-dose (5 Gy) irradiation, the mean value of K(2) decreased by 46% at day 1 compared to the baseline, presumably due to cell swelling, and decreased further by 67% from the baseline on day 3. When the dose was increased to 20 Gy, the mean value of K(2) measured with Gadomer-17 did not show any significant changes at either day 1 or day 3 after irradiation. The value of K(2) measured with Gd-DTPA did not show any significant changes after either the low or the high radiation dose.     

New vanadium-based magnetic resonance imaging probes: clinical potential for early detection of cancer

We have developed a magnetic resonance imaging (MRI) method for improved detection of cancer with a new class of cancer-specific contrast agents, containing vanadyl (VO²⁺)-chelated organic ligands, specifically bis(acetylacetonato)oxovanadium(IV) [VO(acac)₂]. Vanadyl compounds have been found to accumulate within cells, where they interact with intracellular glycolytic enzymes. Aggressive cancers are metabolically active and highly glycolytic; an MRI contrast agent that enters cells with high glycolytic activity could provide high-resolution functional images of tumor boundaries and internal structure, which cannot be achieved by conventional contrast agents. The present work demonstrates properties of VO(acac)₂ that may give it excellent specificity for cancer detection. A high dose of VO(acac)₂ did not cause any acute or short-term adverse reactions in murine subjects. Calorimetry and spectrofluorometric methods demonstrate that VO(acac)₂ is a blood pool agent that binds to serum albumin with a dissociation constant K _d ~ 2.5 ± 0.7 × 10⁻⁷ M and a binding stoichiometry n = 1.03 ± 0.04. Owing to its prolonged blood half-life and selective leakage from hyperpermeable tumor vasculature, a low dose of VO(acac)₂ (0.15 mmol/kg) selectively enhanced in vivo magnetic resonance images of tumors, providing high-resolution images of their interior structure. The kinetics of uptake and washout are consistent with the hypothesis that VO(acac)₂ preferentially accumulates in cancer cells. Although VO(acac)₂ has a lower relaxivity than gadolinium-based MRI contrast agents, its specificity for highly glycolytic cells may lead to an innovative approach to cancer detection since it has the potential to produce MRI contrast agents that are nontoxic and highly sensitive to cancer metabolism.     

Paramagnetic water-soluble metallofullerenes having the highest relaxivity for MRI contrast agents.

Water-soluble gadolinium (Gd) endohedral metallofullerenes have been synthesized as polyhydroxyl forms (Gd@C(82)(OH)(n)(), Gd-fullerenols) and their paramagnetic properties were evaluated by in vivo as well as in vitro for the novel magnetic resonance imaging (MRI) contrast agents for next generation. The in vitro water proton relaxivity, R(1) (the effect on 1/T(1)), of Gd-fullerenols is significantly higher (20-folds) than that of the commercial MRI contrast agent, Magnevist (gadolinium-diethylenetriaminepentaacetic acid, Gd-DTPA) at 1.0 T close to the common field of clinical MRI. This unusually high proton relaxivity of Gd-fullerenols leads to the highest signal enhancement at extremely lower Gd concentration in MRI studies. The strong signal was confirmed in vivo MRI at lung, liver, spleen, and kidney of CDF1 mice after i.v. administration of Gd-fullerenols at a dose of 5 micromol Gd/kg, which was 1/20 of the typical clinical dose (100 micromol Gd/kg) of Gd-DTPA.     

巨噬细胞膜仿生纳米铁颗粒制备及多形性胶质母细胞瘤MRI成像的初步实验研究

摘要 目的：探讨巨噬细胞膜仿生的纳米铁颗粒（Fe3O4 NCs@MM）对多形性胶质母细胞瘤MRI成像的研究。方法：制备巨噬细胞膜仿生的纳米铁颗粒Fe₃O₄ NCs@MM,利用动态光散射（Dynamic Light Scattering,DLS）和透射电子显微镜（Transmission Electron Microscope,TEM）对其水合动力学粒径、表面电势和形态进行表征。采用SDS-聚丙烯酰胺凝胶电泳（sodium dodecyl sulphate-polyacrylamide gel electrophoresis,SDS-PAGE）评价巨噬细胞膜的完整包覆;紫外可见光谱测定巨噬细胞膜仿生的纳米铁颗粒抗蛋白吸附能力。通过MRI成像系统,分析了含不同浓度的Fe元素（0.1-1.6 mM）的Fe₃O₄ NCs@MM在GSH存在或不存在时的T₁弛豫效应。采用细胞增殖-毒性实验（Cell Counting Kit-8,CCK-8）,测定巨噬细胞膜仿生纳米铁颗粒处理肿瘤细胞24 h后的细胞活性。尾静脉注射巨噬细胞膜仿生纳米铁颗粒至原位胶质母细胞瘤模型中,观察成像效果。结果：巨噬细胞膜仿生的纳米铁颗粒Fe₃O₄ NCs@MM的水合动力学粒径和表面电势分别为 286.5±7.6 nm和-20.7±3.5 mV,且在水溶液中分布均匀,具有较好的单分散性。包覆巨噬细胞膜的纳米铁颗粒具备抗蛋白吸附的能力。MRI成像显示,制备的巨噬细胞膜仿生的纳米铁颗粒Fe₃O₄ NCs@MM为GSH响应型MRI对比剂,具有较好的T₁-加权磁共振成像效果,在尾静脉注射巨噬细胞膜的纳米铁颗粒0.5 h后,肿瘤部位的信号可见增强。结论：巨噬细胞膜仿生的纳米铁颗粒Fe₃O₄ NCs@MM可实现多形性胶质母细胞瘤的MRI成像。