[Show abstract][Hide abstract] ABSTRACT: The avascular microscopic breast and brain tumors (<1-2 mm diameter) can be noninvasively detected by designing human heavy-chain ferritin (HFn)-based nanoparticles as molecular probes for near-infrared fluorescence (NIRF) and magnetic resonance imaging (MRI). The intravenously injected HFn-based nano-particles (Cy5.5-HFn and M-HFn) can cross the endothelium, epithelium, and blood-brain barriers (BBB) and be internalized into tumor cells.
[Show abstract][Hide abstract] ABSTRACT: A novel biocompatible macromolecule (AG-CM-EDA-DOTA-Gd) was synthesized as a liver magnetic resonance imaging (MRI) contrast agent. AG-CM-EDA-DOTA-Gd consisted of a carboxymethyl-arabinogalactan unit conjugated with gadolinium-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (Gd-DOTA) via ethylenediamine, and was specifically designed to bind to hepatocyte asialoglycoprotein in vivo, in an effort to develop a potential new tool for the diagnosis of liver diseases. The T1-relaxivity (8.87mmol(-1)Ls(-1)) of AG-CM-EDA-DOTA-Gd was 1.86 times than that of Gd-DOTA (4.76mmol(-1)Ls(-1)) in D2O at 9.4 T and 25°C. MRI experiments showed significant enhancement in rat liver following the intravenous administration of AG-CM-EDA-DOTA-Gd (0.094mmol Gd(3+)/kg body weight), which persisted for longer than Gd-DOTA (0.098mmol Gd(3+)/kg body weight). The mean percentage enhancements in the liver parenchyma were 85.2±6.5% and 19.3±3.3% for AG-CM-EDA-DOTA-Gd and Gd-DOTA, respectively. The results of this study therefore indicate that AG-CM-EDA-DOTA-Gd could be used as a potential liver-targeting contrast agent for MRI.
[Show abstract][Hide abstract] ABSTRACT: Objective: In this study, we investigated the dynamic distribution processes of Mn(2+) in rat brain using magnetic resonance imaging (MRI) after an intra-arterial (IA) injection of MnCl2 and following the breaking of the blood-brain barrier (BBB). Methods: Adult male Sprague-Dawley (SD) rats were employed in the study. After the rats were anesthetized with urethane, 25% mannitol was administrated into the right internal carotid artery (ICA) in order to disrupt the BBB, 50 mmol/l (10 mg/kg) of MnCl2 was then injected into ICA prior to the MRI assay. The MRI was performed at 7 T for a continuous 2 hours following the administration of MnCl2. Image reconstruction and analysis were performed using the Statistical Parametric Mapping (SPM) software. Results: As time progressed, the Mn(2+) enhanced signal intensity showed a gradual increase with a maximum increase at 10 minutes following MnCl2 administration, and began to decline after 10 minutes. From 30 minutes to 2 hours, the signal-enhanced region became more homogeneous, and the signal-enhanced range spread to the contralateral area up to 2 hours after MnCl2 administration. Conclusion: These results will help future research to select an appropriate time point to perform functional MRI for different types of activity-induced manganese (AIM) MRI research studies. These findings will allow researchers to discriminate intended, stimulation-specific enhanced signal from unintended, nonspecific enhanced signals.
Neurological Research 12/2013; · 1.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gadolinium (Gd) chelate contrast-enhanced magnetic resonance imaging (MRI) is a preferred method of glioma detection and preoperative localisation because it offers high spatial resolution and non-invasive deep tissue penetration. Gd-based contrast agents, such as Gd-diethyltriaminepentaacetic acid (DTPA-Gd, Magnevist), are widely used clinically for tumor diagnosis. However, the Gd-based MRI approach is limited for patients with glioma who have an uncompromised blood-brain barrier (BBB). Moreover, the rapid renal clearance and non-specificity of such contrast agents further hinders their prevalence. We present a choline derivate (CD)-modified nanoprobe with BBB permeability, glioma specificity and a long blood half-life. Specific accumulation of the nanoprobe in gliomas and subsequent MRI contrast enhancement are demonstrated in vitro in U87 MG cells and in vivo in a xenograft nude model. BBB and glioma dual targeting by this nanoprobe may facilitate precise detection of gliomas with an uncompromised BBB and may offer better preoperative and intraoperative tumor localization.
[Show abstract][Hide abstract] ABSTRACT: In acute vascular events, the endothelium derived tissue factor (TF) is the trigger of the coagulation cascade. In this study, EGFP-EGF1 protein-conjugated PEG-PLGA nanoparticle was employed as a TF targeting vehicle, the NF-κB decoy oligonucleotides (ODNs) was incorporated into it and the resulting EGF1-EGFP-NP-ODNs were evaluated as a vector for therapy of cortex infarction. At 2 h after transfection of TF expressed rat brain capillary endothelial cell, EGF1-EGFP-NP-ODNs was more efficiently internalized and located in the cytoplasm than NP-ODNs. At 4 h and 6 h after administration, ODNs were present in the nuclei and obviously inhibited the TF expression. At 6 h after i.v. administration in vivo, most EGF1-EGFP-NP were accumulated in the embolism vessels, distributed in the damaged endothelial cells and lowered the TF expression. At 24 h after i.v. administration, MR imaging of cortex infarcts were predominantly dwindled.
[Show abstract][Hide abstract] ABSTRACT: Water-soluble malonate multiadducts of paramagnetic gadolinium endohedral metallofullerene, Gd@C82[C(COOH)2]6 and Gd@C82[C(COOH)2]8, were synthesized by Bingel-Hirsch reaction. Gd@C82 was firstly reacted with diethyl bromomalonate in the presence of alkali metal hydride to produce malonic ester multiadducted derivatives, Gd@C82[C(COOCH2CH3)2]x (x = 3-8), by Bingel reaction. They were isolated and purified to obtain Gd@C82[C(COOCH2CH3)2]6 and Gd@C82[C(COOCH2CH3)2]8 by silica-gel column chromatography with a gradient elution method, which were subsequently hydrolyzed to yield water-soluble Gd@C82[C(COOH)2]6 and Gd@C82[C(COOH)2]8 by Hirsch reaction. The structures of the derivatives were characterized by Fourier transform infrared spectrometry and matrix assisted laser desorption ionization time-of-flight mass spectrometry. The longitudinal relaxivities of Gd@C82[C(COOH)2]8 and Gd@C82[C(COOH)2]6, in buffer solution, were found to be 18.20 and 11.08 mM(-1) s(-1) at concentration range between 0.001-0.025 mM Gd, and to be 12.71 and 6.73 mM(-1) s(-1) between 0.050-0.200 mM Gd, respectively. The results showed that the measured relaxivities for malonate derivatives of Gd@C82 were dependent on the concentration of these solutions and the number of hydrophilic carboxyl groups appended on the surface of the Gd@C82 cage.
Journal of Nanoscience and Nanotechnology 02/2013; 13(2):1549-54. · 1.15 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Differently sized NaGdF4 nanocrystals with narrow particle size distributions were synthesized by a high temperature approach. Upon ligand exchange, the as-prepared hydrophobic NaGdF4 nanocrystals were transferred into water by using asymmetric PEGs simultaneously bearing phosphate and maleimide groups. Further investigations demonstrated that the water-soluble NaGdF4 nanocrystals, coated by PEG bearing two phosphate groups on the same side, exhibit not only excellent colloidal stability in water and PBS buffer, but also higher T1 relaxivity than Gd-DTPA (Magnevist®). Through "click" reaction between the maleimide residue on particle surface and thiol group from the partly reduced anti-EGFR monoclonal antibody (mAb), NaGdF4-PEG-mAb nanoprobes were constructed and their biocompatibility and binding specificity were evaluated through in vitro experiments. A series of in vivo experiments were then carried out for detecting intraperitoneal tumor xenografts in nude mice by using magnetic resonance (MR) imaging technique. The results revealed that the NaGdF4-PEG-mAb probes possessed satisfying tumor-specific targeting ability and strong MR contrast enhancement effects.
[Show abstract][Hide abstract] ABSTRACT: Surgical resection is a mainstay of brain tumor treatments. However, the completed excision of malignant brain tumor is challenged by its infiltrative nature. Contrast enhanced magnetic resonance imaging is widely used for defining brain tumor in clinic. However its ability in tumor visualization is hindered by the transient circulation lifetime, nontargeting specificity, and poor blood brain barrier (BBB) permeability of the commercially available MR contrast agents. In this work, we developed a two-order targeted nanoprobe in which MR/optical imaging reporters, tumor vasculature targeted cyclic [RGDyK] peptides, and BBB-permeable Angiopep-2 peptides are labeled on the PAMAM-G5 dendrimer. This nanoprobe is supposed to first target the α(V)β(3) integrin on tumor vasculatures. Increased local concentration of nanoprobe facilitates the association between BBB-permeable peptides and the low-density lipoprotein receptor-related protein (LRP) receptors on the vascular endothelial cells, which further accelerates BBB transverse of the nanoprobe via LRP receptor-mediated endocytosis. The nanoprobes that have penetrated the BBB secondly target the brain tumor because both α(V)β(3) integrin and LRP receptor are highly expressed on the tumor cells. In vivo imaging studies demonstrated that this nanoprobe not only efficiently crossed intact BBB in normal mice, but also precisely delineated the boundary of the orthotropic U87MG human glioblastoma xenograft with high target to background signal ratio. Overall, this two-order targeted nanoprobe holds the promise to noninvasively visualize brain tumors with uncompromised BBB and provides the possibility for real-time optical-image-guided brain tumor resection during surgery.
[Show abstract][Hide abstract] ABSTRACT: This study aims to investigate the retinal metabolic processes in a rat axotomy model. Retinal metabolic changes in optic nerve transection (ONT) rat model were analyzed by (1)H magnetic resonance spectroscopy ((1)H-MRS). Retinal ganglion cells (RGCs) densities were assessed from retinal whole mounts. The retina was stained immunohistochemically with glial fibrillary acidic protein (GFAP). The results showed that the retina in ONT rats had significantly decreased concentrations of γ-aminobutyric acid (GABA), N-acetylaspartate (NAA), taurine (Tau), creatine (Cr) and increased concentrations of alanine (Ala) compared with control. Examination of glutamate (Glu), glutamine (Gln) and Glx (Glu + Gln) concentrations disclosed no significant differences. The mean density of RGCs reduced from 2,249 ± 87 cells/mm(2) in control group to 320 ± 56 cells/mm(2) in ONT group. GFAP immunoreactivity was markedly higher in ONT group than that in control group. The retinal metabolism after ONT was associated with neurotransmitter recycling/production perturbation, as well as other metabolic disequilibrium.
Neurochemical Research 08/2011; 36(12):2427-33. · 2.13 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical diagnosis of cancers using magnetic resonance imaging (MRI) is highly dependent on contrast agents, especially for brain tumors which contain blood-brain barrier (BBB) at the early stage. However, currently mostly used low molecular weight contrast agents such as Gd-DTPA suffer from rapid renal clearance, non-specificity, and low contrast efficiency. The aim of this paper is to investigate the potential of a macromolecular MRI contrast agent based on dendrigraft poly-l-lysines (DGLs), using chlorotoxin (CTX) as a tumor-specific ligand. The contrast agent using CTX-modified conjugate as the main scaffold and Gd-DTPA as the payload was successfully synthesized. The results of fluorescent microscopy showed that the modification of CTX could markedly enhance the cellular uptake in C6 glioma and liver tumor cell lines, but not in normal cell line. Significantly increased accumulation of CTX-modified conjugate within glioma and liver tumor was further demonstrated in tumor-bearing nude mice using in vivo imaging system. The MRI results showed that the signal enhancement of mice treated with CTX-modified contrast reached peak level at 5 min for both glioma and liver tumor, 144.97% ± 19.54% and 158.69% ± 12.41%, respectively, significantly higher than that of unmodified counterpart and commercial control. And most importantly, the signal enhancement of CTX-modified contrast agent maintained much longer compared to that of controls, which might be useful for more exact diagnosis for tumors. CTX-modified dendrimer-based conjugate might be applied as an efficient MRI contrast agent for targeted and accurate tumor diagnosis. This finding is especially important for tumors such as brain glioma which is known hard to be diagnosed due to the presence of BBB.
[Show abstract][Hide abstract] ABSTRACT: A tumor-targeting carrier, peptide HAIYPRH (T7)-conjugated polyethylene glycol-modified polyamidoamine dendrimer (PAMAM-PEG-T7) was explored to deliver magnetic resonance imaging (MRI) contrast agents targeting to the tumor cells specifically. Two different types of tumors, liver cancer and early brain glioma model (involved with the blood-brain barrier), were chosen to evaluate the imaging capacity of this contrast agent. PAMAM-PEG-T7 was synthesized, conjugated with diethylene triamine pentaacetic acid (DTPA) and further chelated gadolinium (Gd), yielding GdDTPA-PAMAM-PEG-T7. The result of ICP-AES showed that about 92 Gd ions could be loaded per PAMAM molecule. The calculated longitudinal relaxivity R1 of the GdDTPA-PAMAM-PEG-T7 was 10.7 mm(-1) S(-1) per Gd (984.4 mm(-1) S(-1) per PAMAM), while that of GdDTPA was only 4.8 mm(-1) S(-1). PAMAM-PEG-T7 had better targeting capacity to the liver cancer cells in vitro and in vivo, compared with PAMAM-PEG. The accumulation of PAMAM-PEG-T7 was 162.5% times that of PAMAM-PEG. But for glioma cells, PAMAM-PEG-T7 did not show its specificity. Furthermore, GdDTPA-PAMAM-PEG-T7 could improve the diagnostic efficiency of liver cancer with the enhanced signal (187%), compared to 130% for PAMAM-PEG and 121% for GdDTPA. GdDTPA-PAMAM-PEG-T7 could selectively identify liver cancer but not early glioma. This nanoscaled MRI contrast agent GdDTPA-PAMAM-PEG-T7 might allow for selective and efficient diagnosis of tumors without the natural barrier including liver cancer.
[Show abstract][Hide abstract] ABSTRACT: Age-related metabolic changes in the hippocampus of APP(Swe)/PS1(dE9) mice were measured with long echo-time in vivo (1)H-magnetic resonance spectroscopy ((1)H-MRS). Thioflavine S staining and Nissl staining were used to characterize deposition of Aβ aggregates and neuronal degeneration in the transgenic animals, respectively. The results showed that the APP(Swe)/PS1(dE9) mice had significantly decreased hippocampal N-acetyl aspartate (NAA)/total creatine (tCr) level at 16 months of age, which was associated with degeneration of and intracellular deposition of thioflavine S-positive materials in hippocampal CA3 pyramidal neurons. The results of this study provide direct evidence showing association among Aβ pathology (intracellular deposition of thioflavine S-positive materials), neuronal degeneration, and metabolic changes observable with in vivo (1)H-MRS in the hippocampus of APP(Swe)/PS1(dE9) mice.
Journal of Neuroscience Research 11/2010; 88(14):3155-60. · 2.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Antiangiogenesis is an effective strategy for cancer treatment because uncontrolled tumor growth depends on tumor angiogenesis and sufficient blood supply. Great progress has been made in developing a "molecular" form of angiogenesis inhibitors; however, the narrow inhibition spectrum limits anticancer efficacy as those inhibitors that usually target a few or even a single angiogenic factor among many angiogenic factors might initially be effective but ultimately lead to the failure of the treatment due to the induction of expression of other angiogenic factors. In this work, we report that with a multiple hydroxyl groups functionalized surface, the Gd@C(82)(OH)(22) fullerenic nanoparticles (f-NPs) are capable of simultaneously downregulating more than 10 angiogenic factors in the mRNA level that is further confirmed at the protein level. After studying this antiangiogenesis activity of the f-NPs by cellular experiment, we further investigated its anticancer efficacy in vivo. A two-week treatment with the f-NPs decreased >40% tumor microvessels density and efficiently lowered the speed of blood supply to tumor tissues by approximately 40%. Efficacy of the treatment using f-NPs in nude mice was comparable to the clinic anticancer drug paclitaxel, while no pronounced side effects were found. These findings indicate that the f-NPs with multiple hydroxyl groups serve as a potent antiangiogenesis inhibitor that can simultaneously target multiple angiogenic factors. We propose that using nanoscale "particulate" itself as a new form of medicine (particulate medicine) may be superior to the traditional "molecular" form of medicine (molecular medicine) in cancer treatment.
[Show abstract][Hide abstract] ABSTRACT: Manganese-enhanced magnetic resonance imaging (MEMRI) has been widely applied to trace neuronal tracts and to monitor morphological and functional responses of specific brain circuits to changes in physiological and/or environmental conditions. In this study, we traced the efferent axonal projections from ventral tegmental area (VTA) to forebrain structures, an integrating part of the reward circuit implicated in drug addiction, in rats using MEMRI. Urethane- and chloral hydrate-anesthetized rats received injection of 100 nl of 200 mM MnCl(2) solution into the right VTA. Mn(2+)-induced signal enhancements were monitored 24 h after injection. The dose of MnCl(2) injection was shown, by histological evaluation, to have minor toxic effects to the neurons in/near the injection site. Dynamic Mn(2+)-induced signal intensity changes in urethane-anesthetized rats during a 24-h period were fit to a sigmoidal function to obtain parameters slope and t(50), which describe the dynamics of apparent Mn(2+)accumulation. The results showed that most of the forebrain structures known to receive neuronal projections from the VTA, including prefrontal cortex, nucleus accumbens, globus pallidus and caudate putaman, were enhanced at 24 h after injection of MnCl(2) into the ipsilateral VTA, and anesthesia seemed have little effects on the amount of Mn(2+)being transported from the VTA to these structures.
Magnetic Resonance Imaging 10/2008; 27(3):293-9. · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Arabinogalactan derivatives conjugated with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA) by ethylenediamine (Gd-DTPA-CMAG-A2) or hexylamine (Gd-DTPA-CMAG-A6) have been synthesized and characterized by means of Fourier transform infrared spectra (FTIR), 13C nuclear magnetic resonance (13C NMR), size exclusion chromatography (SEC), and inductively coupled plasma atomic emission spectrometry (ICP-AES). Relaxivity studies showed that arabinogalactan-bound complexes possessed higher relaxation effectiveness compared with the clinically used Gd-DTPA, and the influence of the spacer arm lengths on the T1 relaxivities was studied. Their stability was investigated by competition study with Ca2+, EDTA, and DTPA. MR imaging of Wistar rats showed remarkable enhancement in rat liver and kidney after i.v. injection of Gd-DTPA-CMAG-A2 (0.079+/-0.002 mmol/kg Gd3+): The mean percentage enhancement of the liver parenchyma and kidney was 38.7+/-6.4% and 69.4+/-4.4% at 10-30 min. Our preliminary in vivo and in vitro study indicates that the arabinogalactan-bound complexes are potential liver-specific contrast agents for MRI.
Carbohydrate Research 04/2008; 343(4):685-94. · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Two mono-substituted manganese polyoxometalates, K(6)MnSiW(11)O(39) (MnSiW(11)) and K(8)MnP(2)W(17)O(61) (MnP(2)W(17)), have been evaluated by in vivo and in vitro experiments as the candidates of potential tissue-specific contrast agents for magnetic resonance imaging (MRI). T1-relaxivities of 12.1mM(-1)s(-1) for MnSiW(11) and 4.7 mM(-1)s(-1) for MnP(2)W(17) (400 MHz, 25 degrees C) were higher than or similar to that of the commercial MRI contrast agent (GdDTPA). Their relaxivities in BSA and hTf solutions were also reported. After administration of MnSiW(11) and MnP(2)W(17) to Wistar rats, MR imaging showed longer and remarkable enhancement in rat liver and favorable renal excretion capability. The signal intensity increased by 74.0+/-4.9% for the liver during the whole imaging period (90 min) and by 67.2+/-5.3% for kidney within 20-70 min after injection at 40+/-3 micromol kg(-1) dose for MnSiW(11). MnP(2)W(17) induced 71.5+/-15.1% enhancement for the liver in 10-45 min range and 73.1+/-3.2% enhancement for kidney within 5-40 min after injection at 39+/-3 micromol kg(-1) dose. In vitro and in vivo study showed MnSiW(11) and MnP(2)W(17) being favorable candidates as the tissue-specific contrast agents for MRI.
Journal of Inorganic Biochemistry 08/2007; 101(7):1036-42. · 3.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this work, elemental distributions in the rat olfactory bulbs (OB) were measured by synchrotron radiation X-ray fluorescence
(SRXRF) 9 hours after unilateral intranaris application of MnCl2 solution. The effects of deposition of exogenous Mn in the OB on the distributions of other elements, particularly calcium,
were also investigated. The results show that the application of MnCl2 solution in the nasal cavity resulted in inhomogeneous deposition of Mn in the OB, with the highest Mn content found in the
ipsilateral glomerular layer (GL). Locations in the ipsilateral hemisphere of the OB with higher Mn content were found to
be associated with significantly higher calcium and zinc contents, suggesting the presence of excess exogenous Mn may affect
the homeostasis of other trace elements such as calcium and zinc.
Journal of Radioanalytical and Nuclear Chemistry 01/2007; 272(3):589-593. · 1.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Previous studies have found that rats subjected to 15-min transient middle cerebral artery occlusion (MCAO) show neurodegeneration in the dorsolateral striatum only, and the resulting striatal lesion is associated with increased T1-weighted (T1W) signal intensity (SI) and decreased T2-weighted (T2W) SI at 2-8 weeks after the initial ischemia. It has been shown that the delayed increase in T1W SI in the ischemic region is associated with deposition of paramagnetic manganese ions. However, it has been suggested that other mechanisms, such as tissue calcification and lipid accumulation, also contribute to the relaxation time changes. To clarify this issue, we measured changes in relaxation times, lipid accumulation, and elemental distributions in the brain of rats subjected to 15-min MCAO using MRI, in vivo 1H MR spectroscopy (MRS), and synchrotron radiation X-ray fluorescence (SRXRF). The results show that a delayed (2 weeks after ischemia) increase in T1W SI in the ischemic striatum is associated with significant increases in manganese, calcium, and iron, but without evident accumulation of MRS-visible lipids or hydroxyapatite precipitation. It was also found that 15-min MCAO results in acutely reduced N-acetylaspartate (NAA)/creatine (Cr) ratio in the ipsilateral striatum, which recovers to the control level at 2 weeks after ischemia.
Magnetic Resonance in Medicine 10/2006; 56(3):474-80. · 3.27 Impact Factor