Encapsulation of alpha-Particle-Emitting Ac-225(3+) Ions Within Carbon Nanotubes
JOURNAL OF NUCLEAR MEDICINE
2015; 56 (6): 897-900
Gadolinium oxide nanoplates with high longitudinal relaxivity for magnetic resonance imaging
2014; 6 (22): 13637-13645
(225)Ac(3+) is a generator of α-particle-emitting radionuclides with 4 net α-particle decays that can be used therapeutically. Targeting (225)Ac(3+) by use of ligands conjugated to traditional bifunctional chelates limits the amount of (225)Ac(3+) that can be delivered. Ultrashort, single-walled carbon nanotubes (US-tubes), previously demonstrated as sequestering agents of trivalent lanthanide ions and small molecules, also successfully incorporate (225)Ac(3+).Aqueous loading of both (225)Ac(3+) ions and Gd(3+) ions via bath sonication was used to construct (225)Ac@gadonanotubes ((225)Ac@GNTs). The (225)Ac@GNTs were subsequently challenged with heat, time, and human serum.US-tubes internally loaded with both (225)Ac(3+) ions and Gd(3+) ions show 2 distinct populations of (225)Ac(3+) ions: one rapidly lost in human serum and one that remains bound to the US-tubes despite additional challenge with heat, time, and serum. The presence of the latter population depended on cosequestration of Gd(3+) and (225)Ac(3+) ions.US-tubes successfully sequester (225)Ac(3+) ions in the presence of Gd(3+) ions and retain them after a human serum challenge, rendering (225)Ac@GNTs candidates for radioimmunotherapy for delivery of (225)Ac(3+) ions at higher concentrations than is currently possible for traditional ligand carriers.
View details for DOI 10.2967/jnumed.115.158311
View details for Web of Science ID 000355570300019
View details for PubMedID 25931476
Geometrical confinement of Gd(DOTA) molecules within mesoporous silicon nanoconstructs for MR imaging of cancer
2014; 352 (1): 97-101
Molecular-based contrast agents for magnetic resonance imaging (MRI) are often characterized by insufficient relaxivity, thus requiring the systemic injection of high doses to induce sufficient contrast enhancement at the target site. In this work, gadolinium oxide (Gd2O3) nanoplates are produced via a thermal decomposition method. The nanoplates have a core diameter varying from 2 to 22 nm, a thickness of 1 to 2 nm and are coated with either an oleic acid bilayer or an octylamine modified poly(acrylic acid) (PAA-OA) polymer layer. For the smaller nanoplates, longitudinal relaxivities (r1) of 7.96 and 47.2 (mM s)(-1) were measured at 1.41 T for the oleic acid bilayer and PAA-OA coating, respectively. These values moderately reduce as the size of the Gd2O3 nanoplates increases, and are always larger for the PAA-OA coating. Cytotoxicity studies on human dermal fibroblast cells documented no significant toxicity, with 100% cell viability preserved up to 250 μM for the PAA-OA coated Gd2O3 nanoplates. Given the 10 times increase in longitudinal relaxivity over the commercially available Gd-based molecular agents and the favorable toxicity profile, the 2 nm PAA-OA coated Gd2O3 nanoplates could represent a new class of highly effective T1 MRI contrast agents.
View details for DOI 10.1039/c4nr03505d
View details for Web of Science ID 000344836800044
View details for PubMedID 25273814
Hierarchically Structured Magnetic Nanoconstructs with Enhanced Relaxivity and Cooperative Tumor Accumulation
ADVANCED FUNCTIONAL MATERIALS
2014; 24 (29): 4584-4594
Gadolinium-Conjugated Gold Nanoshells for Multimodal Diagnostic Imaging and Photothermal Cancer Therapy
2014; 10 (3): 556-565
Porous silicon has been used for the delivery of therapeutic and imaging agents in several biomedical applications. Here, mesoporous silicon nanoconstructs (SiMPs) with a discoidal shape and a sub-micrometer size (1000×400nm) have been conjugated with gadolinium-tetraazacyclododecane tetraacetic acid Gd(DOTA) molecules and proposed as contrast agents for Magnetic Resonance Imaging. The surface of the SiMPs with different porosities - small pore (SP: ∼5nm) and huge pore (HP: ∼40nm) - and of bulk, non-porous silica beads (1000nm in diameter) have been modified with covalently attached (3-aminopropyl)triethoxysilane (APTES) groups, conjugated with DOTA molecules, and reacted with an aqueous solution of GdCl3. The resulting Gd(DOTA) molecules confined within the small pores of the Gd-SiMPs achieve longitudinal relaxivities r1 of ∼17 (mMs)(-)(1), which is 4 times greater than for free Gd(DOTA). This enhancement is ascribed to the confinement and stable chelation of Gd(DOTA) molecules within the SiMP mesoporous matrix. The resulting nanoconstructs possess no cytotoxicity and accumulate in ovarian tumors up to 2% of the injected dose per gram tissue, upon tail vein injection. All together this data suggests that Gd-SiMPs could be efficiently used for MR vascular imaging in cancer and other diseases.
View details for DOI 10.1016/j.canlet.2014.06.001
View details for Web of Science ID 000341481800013
View details for PubMedID 24931336
Engineered magnetic hybrid nanoparticles with enhanced relaxivity for tumor imaging
2013; 34 (31): 7725-7732
Multimodal imaging offers the potential to improve diagnosis and enhance the specificity of photothermal cancer therapy. Toward this goal, gadolinium-conjugated gold nanoshells are engineered and it is demonstrated that they enhance contrast for magnetic resonance imaging, X-ray, optical coherence tomography, reflectance confocal microscopy, and two-photon luminescence. Additionally, these particles effectively convert near-infrared light to heat, which can be used to ablate cancer cells. Ultimately, these studies demonstrate the potential of gadolinium-nanoshells for image-guided photothermal ablation.
View details for DOI 10.1002/smll.201302217
View details for Web of Science ID 000331944300017
View details for PubMedID 24115690
Engineering discoidal polymeric nanoconstructs with enhanced magneto-optical properties for tumor imaging
2013; 34 (21): 5402-5410
Clinically used contrast agents for magnetic resonance imaging (MRI) suffer by the lack of specificity; short circulation time; and insufficient relaxivity. Here, a one-step combinatorial approach is described for the synthesis of magnetic lipid-polymer (hybrid) nanoparticles (MHNPs) encapsulating 5 nm ultra-small super-paramagnetic iron oxide particles (USPIOs) and decorated with Gd(3+) ions. The MHNPs comprise a hydrophobic poly(lactic acid-co-glycolic acid) (PLGA) core, containing up to ~5% USPIOs (w/w), stabilized by lipid and polyethylene glycol (PEG). Gd(3+) ions are directly chelated to the external lipid monolayer. Three different nanoparticle configurations are presented including Gd(3+) chelates only (Gd-MHNPs); USPIOs only (Fe-MHNPs); and the combination thereof (MHNPs). All three MHNPs exhibit a hydrodynamic diameter of about 150 nm. The Gd-MHNPs present a longitudinal relaxivity (r1 = 12.95 ± 0.53 (mM s)(-1)) about four times larger than conventional Gd-based contrast agents (r1 = 3.4 (mM s)(-1)); MHNPs have a transversal relaxivity of r2 = 164.07 ± 7.0 (mM s)(-1), which is three to four times larger than most conventional systems (r2 ~ 50 (mM s)(-1)). In melanoma bearing mice, elemental analysis for Gd shows about 3% of the injected MHNPs accumulating in the tumor and 2% still circulating in the blood, at 24 h post-injection. In a clinical 3T MRI scanner, MHNPs provide significant contrast confirming the observed tumor deposition. This approach can also accommodate the co-loading of hydrophobic therapeutic compounds in the MHNP core, paving the way for theranostic systems.
View details for DOI 10.1016/j.biomaterials.2013.07.003
View details for Web of Science ID 000323459100017
View details for PubMedID 23871540
Enhanced MRI relaxivity of Gd3+-based contrast agents geometrically confined within porous nanoconstructs
CONTRAST MEDIA & MOLECULAR IMAGING
2012; 7 (6): 501-508
The in vivo performance of nanoparticles is affected by their size, shape and surface properties. Fabrication methods based on emulsification and nano-precipitation cannot control these features precisely and independently over multiple scales. Herein, discoidal polymeric nanoconstructs (DPNs) with a diameter of 1000 nm and a height of 500 nm are demonstrated via a modified hydrogel-template strategy. The DPNs are obtained by mixing in one synthesis step the constituent polymers - poly(lactic acid-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) dimethacrylate - and the payload with magneto-optical properties - 5 nm ultra-small super-paramagnetic iron oxide nanoparticles (SPIOs) and Rhodamine B dye (RhB). The DPN geometrical features are characterized by multiple microscopy techniques. The release of the Rhodamine B dye is pH dependent and increases under acidic conditions by the enhanced hydrolysis of the polymeric matrix. Each DPN is loaded with ~100 fg of iron and can be efficiently dragged by static and external magnetic fields. Moreover, the USPIO confinement within the DPN porous structure is responsible for a significant enhancement in MRI relaxivity (r2 ~ 500 (mMs)(-1)), up to ~5 times larger than commercially available systems. These nanoconstructs suggest a general strategy to engineer theranostic systems for anti-angiogenic treatment and vascular imaging.
View details for DOI 10.1016/j.biomaterials.2013.03.078
View details for Web of Science ID 000319630000049
View details for PubMedID 23611451
Cellular uptake and imaging studies of gadolinium-loaded single-walled carbon nanotubes as MRI contrast agents
CONTRAST MEDIA & MOLECULAR IMAGING
2011; 6 (2): 93-99
Gadolinium chelates, which are currently approved for clinical MRI use, provide relaxivities well below their theoretical limit, and they also lack tissue specificity. Recently, the geometrical confinement of Gd(3+) -based contrast agents (CAs) within porous structures has been proposed as a novel, alternative strategy to improve relaxivity without chemical modification of the CA. Here, we have characterized and optimized the performance of MRI nanoconstructs obtained by loading [Gd(DTPA)(H(2) O)](2-) (Magnevist®) into the pores of injectable mesoporous silicon particles. Nanoconstructs with three different pore sizes were studied, and at 60 MHz, they exhibited longitudinal relaxivities of ~24 m m(-1) s(-1) for 5-10 nm pores and ~10 m m(-1) s(-1) for 30 - 40 nm pores. No enhancement in relaxivity was observed for larger pores sizes. Using an outer-sphere compound, [GdTTHA](3-) , and mathematical modeling, it was demonstrated that the relaxivity enhancement is due to the increase in rotational correlation times (CA adsorbed on the pore walls) and diffusion correlation times (reduced mobility of the water molecules), as the pore sizes decreases. It was also observed that extensive CA adsorption on the outer surface of the silicon particles negates the advantages offered by nanoscale confinement. Upon incubation with HeLa cells, the nanoconstructs did not demonstrate significant cytotoxicity for up to 3 days post incubation, at different particle/cell ratios. In addition, the nanoconstructs showed complete degradation after 24 h of continuous agitation in phosphate-buffered saline. These data support and confirm the hypothesis that the geometrical confinement of Gd(3+) -chelate compounds into porous structures offers MRI nanoconstructs with enhanced relaxivity (up to 6 times for [Gd(DTPA)(H(2) O)](2-) , and 4 times for [GdTTHA](3-) ) and, potentially, improved stability, reduced toxicity and tissue specificity.
View details for DOI 10.1002/cmmi.1480
View details for Web of Science ID 000308940900004
View details for PubMedID 22991316
In Vivo Magnetic Resonance Imaging of the Distribution Pattern of Gadonanotubes Released from a Degrading Poly(Lactic-Co-Glycolic Acid) Scaffold
TISSUE ENGINEERING PART C-METHODS
2011; 17 (1): 19-26
We quantify here, for the first time, the intracellular uptake (J774A.1 murine macrophage cells) of gadolinium-loaded ultra-short single-walled carbon nanotubes (gadonanotubes or GNTs) in a 3 T MRI scanner using R(2) and R(2)* mapping in vitro. GNT-labeled cells exhibited high and linear changes in net transverse relaxations (ΔR(2) and ΔR 2*) with increasing cell concentration. The measured ΔR(2)* were about three to four times greater than the respective ΔR(2) for each cell concentration. The intracellular uptake of GNTs was validated with inductively coupled plasma optical emission spectrometry (ICP-OES), indicating an average cellular uptake of 0.44 ± 0.09 pg Gd per cell or 1.69 × 10(9) Gd(3+) ions per cell. Cell proliferation MTS assays demonstrated that the cells were effectively labeled, without cytotoxicity, for GNTs concentrations ≤28 µM Gd. In vivo relaxometry of a subcutaneously-injected GNT-labeled cell pellet in a mouse was also demonstrated at 3 T. Finally, the pronounced R(2)* effect of GNT-labeled cells enabled successful in vitro visualization of labeled cells at 9.4 T.
View details for DOI 10.1002/cmmi.410
View details for Web of Science ID 000289942600005
View details for PubMedID 21504063
Geometrical confinement of gadolinium-based contrast agents in nanoporous particles enhances T-1 contrast
2010; 5 (11): 815-821
To improve the mechanical properties of polymers used in bone repair, it has been suggested to incorporate single-walled carbon nanotubes (CNTs). However, concern exists about the biosafety of the CNTs in vivo. Therefore, the aim of this study was to develop a magnetic resonance imaging technique to examine the distribution pattern of CNTs after release from a degrading poly(lactic-co-glycolic acid) (PLGA) scaffold in vivo. Five rats received a PLGA scaffold with incorporated gadolinium-labeled single-walled CNTs ("gadonanotubes") subcutaneously. The rats were analyzed up to 5 weeks, subsequently euthanized, followed by histological evaluation of the explanted scaffolds with their surrounding tissue. A significant increase in intensity of the scaffold surrounding tissue was shown in the time period around 3 weeks, as compared to internal control areas. The intensity declined soon thereafter. This is suggested to be caused by the release of gadonanotubes from the degrading scaffold into the surrounding tissue. Histological imaging showed encapsulation by connective fibrous tissue and some mild inflammation around the scaffolds. In conclusion, magnetic resonance imaging is an excellent technique to study the biological fate of gadonanotubes. However, to formulate solid conclusions on the distribution pattern of gadonanotubes in vivo the experimental setup requires further optimization.
View details for DOI 10.1089/ten.tec.2010.0089
View details for Web of Science ID 000285874700003
View details for PubMedID 20666611
Magnetic resonance imaging studies on gadonanotube-reinforced biodegradable polymer nanocomposites.
Journal of biomedical materials research. Part A
2010; 93 (4): 1454-1462
Magnetic resonance imaging contrast agents are currently designed by modifying their structural and physiochemical properties to improve relaxivity and to enhance image contrast. Here, we show a general method for increasing relaxivity by confining contrast agents inside the nanoporous structure of silicon particles. Magnevist, gadofullerenes and gadonanotubes were loaded inside the pores of quasi-hemispherical and discoidal particles. For all combinations of nanoconstructs, a boost in longitudinal proton relaxivity r(1) was observed: Magnevist, r(1) ≈ 14 mM(-1) s(-1)/Gd(3+) ion (∼ 8.15 × 10(+7) mM(-1) s(-1)/construct); gadofullerenes, r(1) ≈ 200 mM(-1) s(-1)/Gd(3+) ion (∼ 7 × 10(+9) mM(-1) s(-1)/construct); gadonanotubes, r(1) ≈ 150 mM(-1) s(-1)/Gd(3+) ion (∼ 2 × 10(+9) mM(-1) s(-1)/construct). These relaxivity values are about 4 to 50 times larger than those of clinically available gadolinium-based agents (∼ 4 mM(-1) s(-1)/Gd(3+) ion). The enhancement in contrast is attributed to the geometrical confinement of the agents, which influences the paramagnetic behaviour of the Gd(3+) ions. Thus, nanoscale confinement offers a new and general strategy for enhancing the contrast of gadolinium-based contrast agents.
View details for DOI 10.1038/NNANO.2010.203
View details for Web of Science ID 000283847800018
View details for PubMedID 20972435
Three-dimensional tissue culture based on magnetic cell levitation
2010; 5 (4): 291-296
We report about the in vitro cytotoxicity and MRI studies of Gd(3+)ions-doped ultra-short single-walled carbon nanotube (gadonanotubes), gadonanotubes- reinforced poly(lactic-co-glycolic acid) (PLGA) polymer nanocomposites and in vivo small animal MRI studies using the gadonanotubes. These studies were performed to explore the suitability of gadonanotubes-reinforced PLGA polymer nanocomposite as a model scaffold for noninvasive magnetic resonance imaging (MRI) to evaluate nanotube release during the degradation process of the scaffold and their biodistribution upon release from the polymer matrix in vivo. The gadonanotubes at 1-100 ppm and the gadonanotubes/PLGA nanocomposites (2 wt % gadonanotubes) did not show any cytotoxicity in vitro as demonstrated using the LIVE/DEAD viability assay. For the first time, r(2) relaxivity measurements were obtained for the superparamagnetic gadonanotubes. In vitro 7T MRI of the superparamagnetic gadonanotubes ([Gd] = 0.15 mM) suspended in a biocompatible 1% Pluronic F127 solution, gave a r(2) value of 578 mM(-1) s(-1). Upon subcutaneous injection of the gadonanotubes suspension into the dorsal region of rats, the high r(2) value translated into excellent and prolonged negative contrast enhancement of in vivo T(2)weighted proton MRI images. The in vitro characterization of the nanocomposite discs and their degradation process by MRI, showed strong influence of the gadonanotube on water proton relaxations. These results indicate that the gadonanotubes/PLGA nanocomposites are suitable for further in vivo studies to track by MRI the biodegradation release and biodistribution of gadonanotubes.
View details for DOI 10.1002/jbm.a.32650
View details for PubMedID 19927368
In Vivo Behavior of Large Doses of Ultrashort and Full-Length Single-Walled Carbon Nanotubes after Oral and Intraperitoneal Administration to Swiss Mice
2010; 4 (3): 1481-1492
Cell culture is an essential tool in drug discovery, tissue engineering and stem cell research. Conventional tissue culture produces two-dimensional cell growth with gene expression, signalling and morphology that can be different from those found in vivo, and this compromises its clinical relevance. Here, we report a three-dimensional tissue culture based on magnetic levitation of cells in the presence of a hydrogel consisting of gold, magnetic iron oxide nanoparticles and filamentous bacteriophage. By spatially controlling the magnetic field, the geometry of the cell mass can be manipulated, and multicellular clustering of different cell types in co-culture can be achieved. Magnetically levitated human glioblastoma cells showed similar protein expression profiles to those observed in human tumour xenografts. Taken together, these results indicate that levitated three-dimensional culture with magnetized phage-based hydrogels more closely recapitulates in vivo protein expression and may be more feasible for long-term multicellular studies.
View details for DOI 10.1038/nnano.2010.23
View details for Web of Science ID 000276460600017
View details for PubMedID 20228788
Serine-derivatized gadonanotubes as magnetic nanoprobes for intracellular labeling
CONTRAST MEDIA & MOLECULAR IMAGING
2010; 5 (1): 34-38
Carbon nanotube (CNT) materials are of special interest as potential tools for biomedical applications. However, available toxicological data concerning single-walled carbon nanotubes (SWNTs) and multiwalled carbon nanotubes (MWNTs) remain contradictory. Here, we compared the effects of SWNTs as a function of dose, length, and surface chemistry in Swiss mice. Transmission electron microscopy (TEM), Raman, near-infrared (NIR), and X-ray photoelectron spectroscopies have been used to characterize the tested materials. The dose of SWNT materials used in this study is considerably higher than that proposed for most biomedical applications, but it was deemed necessary to administer such large doses to accurately assess the toxicological impact of the materials. In an acute toxicity test, SWNTs were administered orally at a dose level of 1000 mg/kg bodyweight (b.w.). Neither death nor growth or behavioral troubles were observed. After intraperitoneal administration, SWNTs, irrespective of their length or dose (50-1000 mg/kg b.w.), can coalesce inside the body to form fiberlike structures. When structure lengths exceeded 10 mum, they irremediably induced granuloma formation. Smaller aggregates did not induce granuloma formation, but they persisted inside cells for up to 5 months after administration. Short (<300 nm) well-individualized SWNTs can escape the reticuloendothelial system to be excreted through the kidneys and bile ducts. These findings suggest that if the potential of SWNTs for medical applications is to be realized, they should be engineered into discrete, individual "molecule-like" species.
View details for DOI 10.1021/nn901573w
View details for Web of Science ID 000275858200030
View details for PubMedID 20175510
Single-Walled Carbon Nanotube Materials as T-2-Weighted MRI Contrast Agents
JOURNAL OF PHYSICAL CHEMISTRY C
2009; 113 (45): 19369-19372
Catalytic Synthesis of Amino Acid and Peptide Derivatized Gadonanotubes
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
2009; 131 (24): 8342-?
Gadonanotubes (GNTs), which are powerful new T(1)-weighted MRI contrast agents, were derivatized with serine amino acid substituents to produce water-soluble (2 mg ml(-1)) ser-gadonanotubes (ser-GNs) as magnetic nanoprobes for intracellular labeling. The ser-GNTs were used to efficiently label MCF-7 human breast cancer cells (1.5 x 10(9) Gd(3+) ions/cell) with no observable cytotoxicity. Cell pellets derived from the ser-GNT labeled cells give bright T(1)-weighted MR images, confirming that the ser-GNTs are a promising new nanoprobe technology for magnetic cell labeling and possibly for in vivo cellular trafficking.
View details for DOI 10.1002/cmmi.293
View details for Web of Science ID 000275945500005
View details for PubMedID 20101755
Assessing transneuronal dysfunction utilizing manganese-enhanced MRI (MEMRI)
MAGNETIC RESONANCE IN MEDICINE
2008; 60 (1): 169-175
A new Rh(6)(CO)(16)-catalyzed functionalization of gadonanotube MRI probes offers the opportunity to prepare a number of amino acid and peptide derivatized gadonanotubes under RT conditions, containing, for example, the cyclic RGD peptide for the biological targeting of cancer.
View details for DOI 10.1021/ja900918x
View details for Web of Science ID 000267630000003
View details for PubMedID 19492838
In this study we utilized manganese-enhanced MRI (MEMRI) to evaluate the in vivo transneuronal efficiency of manganese ion (Mn(2+)) movement as a means to assess overall changes in neuronal function. We designated this extension the manganese transfer index (MTI) value. To evaluate the MTI value as an index of transneuronal physiology we examined both pharmacological agents and different mouse models of neuronal dysfunction. We found that treatment with isoflurane, which attenuates synaptic vesicle release, or memantine, which attenuates postsynaptic uptake of Ca(2+) as well as Mn(2+), resulted in a decrease in the MTI value. Furthermore, we evaluated if changes in the MTI value can be detected in three knockout mice with altered brain function accompanied either with or without neurodegeneration. Our data demonstrate that the MTI values either decreased or increased in response to different functional as well as anatomical changes. These results demonstrate the potential utility of the MTI value as an in vivo index for the detection of changes in neuronal function in animal models of human disease.
View details for DOI 10.1002/mrm.21648
View details for Web of Science ID 000257267700020
View details for PubMedID 18581360