Browsing by Author "Sethi, Richa"

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    Enhanced MRI relaxivity of Gd3+-based contrast agents geometrically confined within porous nanoconstructs
    (Wiley, 2012) Sethi, Richa; Ananta, Jeyarama S.; Karmonik, Christof; Zhong, Meng; Fung, Steve H.; Liu, Xuewu; Li, King; Ferrari, Mauro; Wilson, Lon J.; Decuzzi, Paolo; Smalley Institute for Nanoscale Science and Technology; Center for Biological and Environmental Nanotechnology
    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 Gd3+-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)(H2O)]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 Gd3+-chelate compounds into porous structures offers MRI nanoconstructs with enhanced relaxivity (up to 6 times for [Gd(DTPA)(H2O)]2−, and 4 times for [GdTTHA]3−) and, potentially, improved stability, reduced toxicity and tissue specificity.
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    Geometrical confinement of Gd(DOTA) molecules within mesoporous silicon nanoconstructs for MR imaging of cancer
    (Elsevier, 2014) Gizzatov, Ayrat; Stigliano, Cinzia; Ananta, Jeyerama S.; Sethi, Richa; Xu, Rong; Guven, Adem; Ramirez, Maricela; Shen, Haifa; Sood, Anil; Ferrari, Mauro; Wilson, Lon J.; Liu, Xuewu; Decuzzi, Paolo; Smalley Institute for Nanoscale Science and Technology
    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 (1,000 × 400 nm) 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: ~ 5 nm) and huge pore (HP: ~ 40 nm) – and of bulk, non-porous silica beads (1,000 nm 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 (mM·s)−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.
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    Nanosystems: From their design to characterization as advanced MRI contrast agents
    (2013-07-29) Sethi, Richa; Wilson, Lon J.; McDevitt, John T.; Richards-Kortum, Rebecca Rae; Decuzzi, Paolo
    Ultra-short single-walled carbon nanotubes (US-tubes) have been previously shown to be efficient carriers of imaging agents. In particular, gadonanotubes (GNTs) synthesized by loading and nanoscale confinement of Gd3+ ions within US-tubes have been established as high-performance MRI contrast agents (CAs) with efficiencies 40 to 90 times greater than the current clinical CAs. Using nuclear magnetic resonance dispersion (NMRD) and electron spin resonance (ESR) techniques, this work discusses the origin of the magnetic and proton relaxation behavior in MRI of the GNTs and related structures at low magnetic fields. The likely causes for the observed paramagnetism for these materials are explored and their effect on water proton relaxation is discussed. In addition, Gd3+ chelates, which are currently approved for clinical MRI use, provide relaxivities (or contrast enhancement) well below their theoretical limit, and they also lack tissue specificity. In this dissertation, using vascularly injectable mesoporous silicon nanoparticles (SiMPs), general methods for increasing the efficiency of Gd3+-based MRI CAs are described. Two different strategies have been successfully tested where Gd3+ chelates are either geometrically confined within the pores of SiMPs or covalently attached to the surface of SiMPs. For both the approaches, SiMPs with different pore sizes have been used to generate a dominant role in the resulting relaxivity. The nanoconstructs designed using these approaches have been shown to produce relaxivities that are many-fold greater than the free CAs in solution. This enhancement is attributed to the optimization of the molecular parameters that govern relaxivity. Co-loading the pores with a Gd3+-based CA and a fluorescently-labeled antibody has shown the potential of SiMP nanoconstructs as multimodal agents. The strategies outlined in this dissertation are general and can be successfully applied to any imaging agent and porous nanosystem. In summary, this work highlights two key outcomes. First, it provides a better understanding of the magnetic and MRI behavior of the GNTs. Second, it demonstrates that geometrical confinement of CAs and covalent functionalization of nanoparticles are universal strategies for enhancing the performance of Gd3+-based CAs.
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    Surfactant-free Gd3+-ion-containing carbon nanotube MRI contrast agents for stem cell labeling
    (Royal Society of Chemistry, 2015) Gizzatov, Ayrat; Hernández-Rivera, Mayra; Keshishian, Vazrik; Mackeyev, Yuri; Law, Justin J.; Guven, Adem; Sethi, Richa; Qu, Feifei; Muthupillai, Raja; Cabreira-Hansen, Maria da Graça; Willerson, James T.; Perin, Emerson C.; Ma, Qing; Bryant, Robert G.; Wilson, Lon J.; Richard E. Smalley Institute for Nanoscale Science and Technology
    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 Gd3+-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 Gd3+ 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 109 Gd3+ ions per cell.