The use of gadolinium-carbon nanostructures to magnetically enhance stem cell retention for cellular cardiomyoplasty.

In this work, the effectiveness of using Gadonanotubes (GNTs) with an external magnetic field to improve retention of transplanted adult mesenchymal stem cells (MSCs) during cellular cardiomyoplasty was evaluated. As a high-performance T1-weighted magnetic resonance imaging (MRI) cell tracking label, the GNTs are gadolinium-loaded carbon nanotube capsules that render MSCs magnetic when internalized. MSCs were internally labeled with either superparamagnetic GNTs or colloidal diamagnetic lutetium (Lu). In vitro cell rolling assays and ex vivo cardiac perfusion experiments qualitatively demonstrated increased magnetic-assisted retention of GNT-labeled MSCs. Subsequent in vivo epicardial cell injections were performed around a 1.3 T NdFeB ring magnet sutured onto the left ventricle of female juvenile pigs (n = 21). Cell dosage, magnet exposure time, and endpoints were varied to evaluate the safety and efficacy of the proposed therapy. Quantification of retained cells in collected tissues by elemental analysis (Gd or Lu) showed that the external magnet helped retain nearly three times more GNT-labeled MSCs than Lu-labeled cells. The sutured magnet was tolerated for up to 168 h; however, an inflammatory response to the magnet was noted after 48 h. These proof-of-concept studies support the feasibility and value of using GNTs as a magnetic nanoparticle facilitator to improve cell retention during cellular cardiomyoplasty.

Bismuth@US-tubes as a Potential Contrast Agent for X-ray Imaging Applications.

The encapsulation of bismuth as BiOCl/Bi2O3 within ultra-short (ca. 50 nm) single-walled carbon nanocapsules (US-tubes) has been achieved. The Bi@US-tubes have been characterized by high-resolution transmission electron microscopy (HR-TEM), energy-dispersive X-ray spectroscopy (EDS), thermogravimetric analysis (TGA), X-ray photoelectron spectroscopy (XPS), and Raman spectroscopy. Bi@US-tubes have been used for intracellular labeling of pig bone marrow-derived mesenchymal stem cells (MSCs) to show high X-ray contrast in computed tomography (CT) cellular imaging for the first time. The relatively high contrast is achieved with low bismuth loading (2.66% by weight) within the US-tubes and without compromising cell viability. X-ray CT imaging of Bi@US-tubes-labeled MSCs showed a nearly two-fold increase in contrast enhancement when compared to unlabeled MSCs in a 100 kV CT clinical scanner. The CT signal enhancement from the Bi@US-tubes is 500 times greater than polymer-coated Bi2S3 nanoparticles and several-fold that of any clinical iodinated contrast agent (CA) at the same concentration. Our findings suggest that the Bi@US-tubes can be used as a potential new class of X-ray CT agent for stem cell labeling and possibly in vivo tracking.

Nanomedicine: making controllable magnetic drug delivery possible for the treatment of breast cancer.

A recent study published in Nano Letters documents the synthesis and performance of porous silica nanocapsules filled with magnetic nanoparticles as a controllable magnetic drug delivery vector. Under a remotely applied radiofrequency magnetic field, these nanocapsules demonstrate on-off switchable release of the internally loaded drug payload. Both in vitro and in vivo studies using MT2 mouse breast cancer cell models demonstrate that the magnetic targeting of these nanocapsules allows for deep tumor penetration and subsequent on-demand release of the drug cargo, significantly reducing tumor cell viability.

In vivo magnetic resonance imaging of the distribution pattern of gadonanotubes released from a degrading poly(lactic-co-glycolic Acid) scaffold.

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.

Gadonanotubes as magnetic nanolabels for stem cell detection.

Stem cell-based therapies have emerged as a promising approach in regenerative medicine. In the development of such therapies, the demand for imaging technologies that permit the noninvasive monitoring of transplanted stem cells in vivo is growing. Here, we report the performance of gadolinium-containing carbon nanocapsules, or gadonanotubes (GNTs), as a new T1-weighted magnetic resonance imaging (MRI) intracellular labeling agent for pig bone marrow-derived mesenchymal stem cells (MSCs). Without the use of a transfection agent, micromolar concentrations of GNTs can deliver up to 109 Gd(3+) ions per cell without compromising cell viability, differentiation potential, proliferation pattern, and phenotype. Imaging 10 × 106 GNT-labeled MSCs demonstrates a nearly two-fold reduction in T1 relaxation time when compared to unlabeled MSCs at 1.5 T in a clinical MRI scanner, which easily permits the discrimination of GNT-labeled MSCs in a T1-weighted MR image. It is anticipated that GNTs will allow in vivo tracking of GNT-labeled MSCs, as well as other mammalian cell types, by T1-weighted imaging with greater efficacy than other current technologies now allow.

Serine-derivatized gadonanotubes as magnetic nanoprobes for intracellular labeling.

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.

Injectable in situ cross-linkable nanocomposites of biodegradable polymers and carbon nanostructures for bone tissue engineering.

This study investigates the effects of nanostructure size and surface area on the rheological properties of un-cross-linked poly(propylene fumarate) (PPF) nanocomposites and the mechanical properties of cross-linked nanocomposites as a function of the nanostructure loading. Three model carbon nanostructures were examined, C(60) fullerenes, ultra-short single-walled carbon nanotubes (US-tubes) and single-walled carbon nanotubes (SWNTs). Rheological measurements showed that C60 and US-tube un-cross-linked nanocomposites exhibited viscous-like characteristics with the complex viscosity independent of frequency for nanostructure concentrations up to 1 wt%. Compressive and flexural mechanical testing demonstrated significant mechanical reinforcement of US-tube and SWNT nanocomposites as compared to cross-linked polymer alone, with an up to twofold increase in the mechanical properties. Scanning electron microscopy examination of the fracture surface of cross-linked US-tube nanocomposite revealed lack of aggregation of US-tubes. Although sol fraction studies did not provide any evidence of additional cross-linking, due to the presence of US-tubes in the nanocomposites, transmission electron microscopy studies suggested the crystallization of PPF on the surface of US-tubes which can contribute to the mechanical reinforcement of the US-tube nanocomposites. These results demonstrate that the rheological properties of un-cross-linked nanocomposites depend mainly on the carbon nanostructure size, whereas the mechanical properties of the cross-linked nanocomposites are dependent on the carbon nanostructure surface area. The data also suggest that US-tube nanocomposites are suitable for further consideration as injectable scaffolds for bone tissue engineering applications.

Gadofullerenes as nanoscale magnetic labels for cellular MRI.

In this study, anionic gadofullerene {Gd@C60[C(COOH)2](10)} was used as an in vitro cellular magnetic resonance imaging label. The cellular uptake characteristics of this gadofullerene were significant and nonspecific, and excellent labeling efficiency (98-100%) was achieved without a transfecting agent. The average uptake was up to 133.6 +/- 5.5 pg Gd per cell or 10(11) Gd3+ ions per cell. The difference in the longitudinal relaxation time T(1) between labeled and unlabeled cells generated good contrast between labeled and unlabeled cells. A clinical magnetic resonance imaging imager at 1.5 T showed that signal intensity on the T(1) weighted magnetic resonance images was 250% greater in labeled cells. Thus, the anionic gadofullerene {Gd@C60[C(COOH)2](10)} is an attractive candidate for ex vivo labeling and noninvasive in vivo tracking of any mammalian cell via magnetic resonance imaging.