Surfactant-free Gd³⁺-ion-containing carbon nanotube MRI contrast agents for stem cell labeling

Abstract

There is an ever increasing interest in developing new stem cell therapies. However, imaging and tracking stem cells in vivo after transplantation remains a serious challenge. In this work, we report new, functionalized and high-performance Gd(3+)-ion-containing ultra-short carbon nanotube (US-tube) MRI contrast agent (CA) materials which are highly-water-dispersible (ca. 35 mg ml(-1)) without the need of a surfactant. The new materials have extremely high T1-weighted relaxivities of 90 (mM s)(-1) per Gd(3+) ion at 1.5 T at room temperature and have been used to safely label porcine bone-marrow-derived mesenchymal stem cells for MR imaging. The labeled cells display excellent image contrast in phantom imaging experiments, and TEM images of the labeled cells, in general, reveal small clusters of the CA material located within the cytoplasm with 10(9) Gd(3+) ions per cell.

Stable and non-toxic ultrasmall gadolinium oxide nanoparticle colloids (coating material = polyacrylic acid) as high-performance T1 magnetic resonance imaging contrast agents

“…Both N and q values of the dense Gd 3+ ion cluster are higher than the respective values of the ultrasmall Gd 2 O 3 nanoparticle: q of the Gd 3+ ion in the dense Gd 3+ ion cluster is similar to that of the free Gd 3+ ion and thus higher than that of the nanoparticle, and N of the Gd 3+ ion cluster is also higher than that of the nanoparticle because all the Gd 3+ ions in the Gd 3+ ion clusters can contribute to inducing the longitudinal water proton relaxation whereas in nanoparticles, only the Gd 3+ ions exposed on the nanoparticle surface dominantly contribute to the induction. This explains r 1 values of 70-173 s À1 mM À1 of the dense Gd 3+ ion clusters prepared inside and outside CNTs, [24][25][26] which were 2 to 6 times higher than that of the ultrasmall Gd 2 O 3 nanoparticle in this study. In this way, all the experimental observations of r 1 (Gd 3+ ion cluster) > r 1 (ultrasmall Gd 2 O 3 nanoparticle) > r 1 (free Gd 3+ ) > r 1 (Gd 3+chelate) can be explained using this simple model.…”

“…Theory of water proton relaxation is very complex. 4,5,38 To understand high r 1 values observed in this study and in various Gd-nanosystems, 14,[24][25][26] however, a simple cooperative induction model was empirically proposed here. In this model, several Gd 3+ ions on the nanoparticle surface or in the dense Gd 3+ ion cluster cooperatively induce the longitudinal water proton relaxation of a water molecule.…”

“…Several Gd-nanosystems with very high r 1 values have been reported. 14,[24][25][26] Ultrasmall Gd 2 O 3 nanoplates with a diameter of 2 nm coated with PAA-octylamine (OA) showed an r 1 value of 47.2 s À1 mM À1 (r 2 /r 1 ¼ 1.7) at 1.41 T. 14 Dense Gd 3+ ions conjugated on the surface of carbon nanotubes (CNTs) exhibited an r 1 value of 70 s À1 mM À1 (r 2 /r 1 ¼ 1.5) at 1.41 T and 37 C (ref. 24) and those prepared inside CNTs showed an r 1 value of 94 s À1 mM À1 at 1.41 T and 37 C. 25 Gd 3+ -ion clusters within ultra-short single-walled CNTs exhibited an r 1 value of 164 s À1 mM À1 in an 1% sodium dodecyl benzene sulfate aqueous solution and 173 s À1 mM À1 in a pluronic F98 surfactant aqueous solution at 1.41 T and 40 C. 26 These r 1 values are signicantly higher than those of Gd-chelates.…”

Gadolinium‐containing carbon nanomaterials for magnetic resonance imaging: Trends and challenges

“…Regarding the subcellular internalization, Avti et al and Marangon et al observed that gadonanotubes tended to be compartmentalized within endosomes in the cytoplasm of NIH/3T3 cells and RAW 264.7 mouse macrophages, suggesting an active process of cellular internalization. Nevertheless, Hassan et al, Tran et al and Gizzatov et al reported the formation of gadonanotube aggregates in the cytoplasm, but without encapsulation in vesicles (endosomes). Recently, Holt et al used resonant Raman imaging to determine the subcellular distribution of gadonanotubes, finding them predominantly in a perinuclear location of the cytoplasm (Figure ) and that dispersal agents affected the degree of agglomeration.…”

High-Performance Hybrid Bismuth–Carbon Nanotube Based Contrast Agent for X-ray CT Imaging

“…[14][15][16] Many different nanoparticles are being explored for such application, however, the special interest in CNTs is based on their high aspect ratio, biocompatibility, [17][18][19] and the capability to be chemically functionalized, [20][21][22][23] while remaining relatively inert. 16 CNTs have been previously used as CAs for different clinical imaging modalities 24,25 such as magnetic resonance (MR), [26][27][28][29][30] ultrasound, 31,32 fluorescence imaging in the near infrared (NIR) region, [33][34][35] Raman scattering, 36,37 photoacoustic, 31,[38][39][40] thermoacoustic, 31,41 CT 42,43 , positron emission tomography (PET), 44,45 and single-photon emission computed tomography (SPECT) imaging. 46,47 In previous work, Wilson and coworkers reported the first CNT-based CA material for X-ray CT imaging that contained Bi 3+ ions within the cavities of ultra-short SWCNTs (US-tubes).…”