42 research outputs found
Magnetic resonance imaging of dense and light non-aqueous phase liquid in a rock fracture,
[1] Magnetic resonance (MR) imaging was used to observe the flow of dense (FC-75) and light (dodecane) non-aqueous phase liquids (NAPLs) through a water saturated dolomite fracture. Dynamic two-phase behavior was influenced by (1) buoyancy of the NAPL relative to the aqueous phase, (2) fracture aperture distribution, and (3) alteration of wettability by long-term presence of NAPL phase. MR imaging was capable of characterizing the fracture geometry and the fluid flow, but was limited by outlet flow conditions in the sample and acquisition times. This method permits observation of two-phase flow under natural wettability and matrix porosity, providing significant advantages over plastic or glass replicas. INDEX TERMS: 1829 Hydrology: Groundwater hydrology; 5194 Physical Properties of Rocks: Instruments and techniques; 1831 Hydrology: Groundwater quality. Citation: Becker, M. W., M. Pelc, R. V. Mazurchuk, and J. Spernyak, Magnetic resonance imaging of dense and light non-aqueous phase liquid in a rock fracture, Geophys
Self-assembled Tetrahedral Iron(III) Cage for MRI Guided Delivery of a Gold Drug
A T1 MRI probe based on a self-assembled tetrahedral iron(III) cage acts as a host for a gold(I) anticancer drug, which is added as Au(PEt3)Cl. 1H NMR characterization of the gold complex within the Ga(III) analog of the tetrahedral cage is consistent with loss of chloride to give a mixture of Au(PEt3)(OH2) and Au(PEt3)(OH) within the cage. This aqua species may be converted to encapsulated Au(PEt3)CN by treatment with KCN. The binding constant of the gold aqua complex is estimated as ā 103 M-1 by displacement experiments with various ammonium cations. Studies show that the iron cage with encapsulated gold complex binds tightly to serum albumin and that there is little dissociation of iron or gold complexes over 24 hours. The iron-gold host-guest complex shows enhanced contrast of the vasculature, consistent with strong binding of the cage to serum proteins. Uptake of the iron cage into C26 tumors as shown by MRI corresponds to the deposition of gold as measured by ICP-MS. These data suggest that the tetrahedral iron cage may serve as a host and carrier for gold drugs towards applications as theragnostic agents
Encapsulated or amphiphilic liposomal Fe(III) coordination complexes for MRI studies of tumor uptake and clearance
Liposomes containing high-spin Fe(III) coordination complexes were prepared towards the production of MRI probes with improved relaxivity and rapid pharmacokinetic clearance in mice. The amphiphilic Fe(III) complexes were anchored into the liposome with two alkyl chains to give a coordination sphere containing mixed amide hydroxypropyl pendant groups. Three types of MRI probes were prepared including those with intraliposomal Fe(III) complex (LipoA) alone, amphiphilic Fe(III) complex (LipoB) or both intraliposomal and amphiphilic complex (LipoC). Water proton relaxivities r1 and r2 were measured and compared to a small molecule macrocyclic Fe(III) complex containing similar donor groups. Liposomes with amphiphilic Fe(III) complex (LipoB) have a per particle relaxivity of 37,000 and a per iron relaxivity of 2.6 mM-1s-1 in solutions with pH 7.2, 34 C at 1.4 T. Liposomes containing both amphiphilic and intraliposomal Fe(III) complexes (lipoC) have reduced per iron relaxivity of 0.8 mM-1s-1 in solution consistent with quenching of the interior Fe(III) complex relaxivity and per particle relaxivity of 42 ,000 mM-1s-1. Liposomes containing only encapsulated Fe(III) complex have a lower relaxivity of 0.46 mM-1s-1 per iron complex. Studies show that lipoB and lipoC produce enhanced signal in the CT26 tumors of BALB/c mice. However, the biodistribution and clearance of the liposomal nanoparticles differs greatly. LipoB is a blood pool agent with a long circulation time whereas lipoC is cleared more rapidly through both renal and hepatobiliary pathways
Long-circulating magnetoliposomes as surrogates for assessing pancreatic tumour permeability and nanoparticle deposition
Nanocarriers are candidates for cancer chemotherapy delivery, with growing numbers of clinically-approved nano-liposomal formulations such as DoxilĀ® and OnivydeĀ® (liposomal doxorubicin and irinotecan) providing proof-of-concept. However, their complex biodistribution and the varying susceptibility of individual patient tumours to nanoparticle deposition remains a clinical challenge. Here we describe the preparation, characterisation, and biological evaluation of phospholipidic structures containing solid magnetic cores (SMLs) as an MRI-trackable surrogate that could aid in the clinical development and deployment of nano-liposomal formulations. Through the sequential assembly of size-defined iron oxide nanoparticle clusters with a stabilizing anionic phospholipid inner monolayer and an outer monolayer of independently-selectable composition, SMLs can mimic physiologically a wide range of nano-liposomal carrier compositions. In patient-derived xenograft models of pancreatic adenocarcinoma, similar tumour deposition of SML and their nano-liposomal counterparts of identical bilayer composition was observed in vivo, both at the tissue level (fluorescence intensities of 1.5 Ć 108 Ā± 1.8 Ć 107 and 1.2 Ć 108 Ā± 6.3 Ć 107, respectively; ns, 99% confidence interval) and non-invasively using MR imaging. We observed superior capabilities of SML as a surrogate for nano-liposomal formulations as compared to other clinically-approved iron oxide nano-formulations (ferumoxytol). In combination with diagnostic and therapeutic imaging tools, SMLs have high clinical translational potential to predict nano-liposomal drug carrier deposition and could assist in stratifying patients into treatment regimens that promote optimal tumour deposition of nanoparticulate chemotherapy carriers. Statement of significance: Solid magnetoliposomes (SMLs) with compositions resembling that of FDA-approved agents such as DoxilĀ® and OnivydeĀ® offer potential application as non-invasive MRI stratification agents to assess extent of tumour deposition of nano-liposomal therapeutics prior to administration. In animals with pancreatic adenocarcinoma (PDAC), SML-PEG exhibited (i) tumour deposition comparable to liposomes of the same composition; (ii) extended circulation times, with continued tumour deposition up to 24 hours post-injection; and (iii) MRI capabilities to determine tumour deposition up to 1 week post-injection, and confirmation of patient-to-patient variation in nanoparticulate deposition in tumours. Hence SMLs with controlled formulation are a step towards non-invasive MRI stratification approaches for patients, enabled by evaluation of the extent of deposition in tumours prior to administration of nano-liposomal therapeutics.Science Foundation IrelandIrish Research CouncilNational Cancer InstituteU.S. National Inst. of Health/NCIFulbright Commission of Ireland Student AwardEuropean Association for Cancer ResearchRoyal Society of Chemistr
Activity of the Vascular-Disrupting Agent 5,6-Dimethylxanthenone-4-Acetic Acid against Human Head and Neck Carcinoma Xenografts
Head and neck squamous cell carcinomas (HNSCC) constitute a majority of the tumors of the upper aerodigestive tract and continue to present a significant therapeutic challenge. To explore the potential of vascular-targeted therapy in HNSCC, we investigated the antivascular, antitumor activity of the potent vascular-disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against two HNSCC xenografts with markedly different morphologic and vascular characteristics. Athymic nude mice bearing subcutaneous FaDu (human pharyngeal squamous cell carcinoma) and A253 (human submaxillary gland epidermoid carcinoma) tumors were administered a single dose of DMXAA (30 mg/kg, i.p). Changes in vascular function were evaluated 24 hours after treatment using contrast-enhanced magnetic resonance imaging (MRI) and immunohistochemistry (CD31). Signal enhancement (E) and change in longitudinal relaxation rates (ĪR(1)) were calculated to measure alterations in vascular perfusion. MRI showed a 78% and 49% reduction in vascular perfusion in FaDu and A253 xenografts, respectively. CD31-immunostaining of tumor sections revealed three-fold (FaDu) and two-fold (A253) reductions in microvessel density (MVD) 24 hours after treatment. DMXAA was equally effective against both xenografts, with significant tumor growth inhibition observed 30 days after treatment. These results indicate that DMXAA may be beneficial in the management of HNSCC, alone or in combination with other treatments
Visualizing the Acute Effects of Vascular-Targeted Therapy In Vivo Using Intravital Microscopy and Magnetic Resonance Imaging: Correlation with Endothelial Apoptosis, Cytokine Induction, and Treatment Outcome
The acute effects of the vascular-disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) were investigated in vivo using intravital microscopy (IVM) and magnetic resonance imaging (MRI). Changes in vascular permeability and blood flow of syngeneic CT-26 murine colon adenocarcinomas were assessed at 4 and 24 hours after DMXAA treatment (30 mg/kg, i.p.) and correlated with induction of tumor necrosis factor-Ī± (TNF-Ī±), endothelial damage [CD31/terminal deoxynucleotidyl transferase (TdT)], and treatment outcome. Intravital imaging revealed a marked increase in vascular permeability 4 hours after treatment, consistent with increases in intratumoral mRNA and protein levels of TNF-Ī±. Parallel contrast-enhanced MRI studies showed a ā¼ 4-fold increase in longitudinal relaxation rates (ĪR(1)), indicative of increased contrast agent accumulation within the tumor. Dual immunostained tumor sections (CD31/TdT) revealed evidence of endothelial apoptosis at this time point. Twenty-four hours after treatment, extensive hemorrhage and complete disruption of vascular architecture were observed with IVM, along with a significant reduction in ĪR(1); and virtual absence of CD31 immunostaining. DMXAA-induced tumor vascular damage resulted in significant long-term (60-day) cures compared to untreated controls. Multimodality imaging approaches are useful in visualizing the effects of antivascular therapy in vivo. Such approaches allow cross validation and correlation of findings with underlying molecular changes contributing to treatment outcome
Saccharomyces cerevisiae and Candida albicans Yeast Cells Labeled with Fe(III) Complexes as MRI Probes
The development of MRI probes is of interest for labeling antibiotic-resistant fungal infections based on yeast. Our work showed that yeast cells can be labeled with high-spin Fe(III) complexes to produce enhanced T2 water proton relaxation. These Fe(III)-based macrocyclic complexes contained a 1,4,7-triazacyclononane framework, two pendant alcohol groups, and either a non-coordinating ancillary group and a bound water molecule or a third coordinating pendant. The Fe(III) complexes that had an open coordination site associated strongly with Saccharomyces cerevisiae upon incubation, as shown by screening using Z-spectra analysis. The incubation of one Fe(III) complex with either Saccharomyces cerevisiae or Candida albicans yeast led to an interaction with the β-glucan-based cell wall, as shown by the ready retrieval of the complex by the bidentate chelator called maltol. Other conditions, such as a heat shock treatment of the complexes, produced Fe(III) complex uptake that could not be reversed by the addition of maltol. Appending a fluorescence dye to Fe(TOB) led to uptake through secretory pathways, as shown by confocal fluorescence microscopy and by the incomplete retrieval of the Fe(III) complex by the maltol treatment. Yeast cells that were labeled with these Fe(III) complexes displayed enhanced water proton T2 relaxation, both for S. cerevisiae and for yeast and hyphal forms of C. albicans
Gear Up for a pH Shift: A Responsive Iron(II) 2āAmino-6-picolyl-Appended Macrocyclic paraCEST Agent That Protonates at a Pendent Group
Two
high-spin FeĀ(II) and CoĀ(II) complexes of 1,4,7,10-tetraazacyclododecane
(CYCLEN) appended with four 2-amino-6-picolyl groups, denoted as [FeĀ(TAPC)]<sup>2+</sup> and [CoĀ(TAPC)]<sup>2+</sup>, are reported. These complexes
demonstrate <i>C</i><sub>2</sub>-symmetrical geometry from
coordination of two pendents, and they are present in a single diastereomeric
form in aqueous solution as shown by <sup>1</sup>H NMR spectroscopy
and by a single-crystal X-ray structure for the CoĀ(II) complex. A
highly shifted but low-intensity CEST (chemical exchange saturation
transfer) signal from NH groups is observed at ā118 ppm for
[CoĀ(TAPC)]<sup>2+</sup> at pH 6.0 and 37 Ā°C. A higher intensity
CEST peak is observed for [FeĀ(TAPC)]<sup>2+</sup>, which demonstrates
a pH-dependent frequency shift from ā72 to ā79 ppm at
pH 7.7 to 4.8, respectively, at 37 Ā°C. This shift in the CEST
peak correlates with the protonation of the unbound 2-amino-6-picolyl
pendents, as suggested by UVāvis and <sup>1</sup>H NMR spectroscopy
studies at different pH values. Phantom imaging demonstrates the challenges
and feasibility of using the [FeĀ(TAPC)]<sup>2+</sup> agent on a low-field
MRI scanner. The [FeĀ(TAPC)]<sup>2+</sup> complex is the first transition-metal-based
paraCEST agent that produces a pH-induced CEST frequency change toward
the development of probes for concentration-independent imaging of
pH