Browsing by Author "Guven, Adem"
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Item Cisplatin@US-tube Carbon Nanocapsules for Enhanced(2014-02-28) Guven, Adem; Wilson, Lon J.; Colvin, Vicki L.; Barrera, Enrique V.; Lewis, Michael T.The use of chemotherapeutic drugs in cancer therapy is often limited by problems with administration such as insolubility, inefficient biodistribution, lack of selectivelty, and inability of the drug to cross cellular barriers. To overcome these limitations, various types of drug delivery systems have been explored, and recently, carbon nanotube (CNT) materials have garnered special attention in the area. This thesis details the preparation, characterization, and in vitro and in vivo testing of a new, ultra-short single-walled carbon nanotube (US-tube)-based drug delivery system for the treatment of cancer. In particular, the encapsulation of cisplatin (CDDP), a widely-used anticancer drug, within US-tubes has been achieved by a loading procedure that is reproducible, and the resulting CDDP@US-tube material characterized by high-resolution transmission electron microscopy (HR-TEM), energy-dispersive spectroscopy (EDS), X-ray photoelectron spectroscopy (XPS), and inductively-coupled optical emission spectroscopy (ICP-OES). Dialysis studies performed in phosphate-buffered saline (PBS) at 37 °C have demonstrated that CDDP release from CDDP@US-tubes can be controlled (retarded) by wrapping the CDDP@US-tubes with Pluronic®-F108 surfactant. The anticancer activity of Pluronic-wrapped CDDP@US-tubes (W-CDDP@US-tubes) has been evaluated against two different breast cancer cell lines, MCF-7 and MDA-MB-231, and found to exhibit enhanced cytotoxicity over free CDDP. Moreover, it has been shown that CDDP release from W-CDDP@US-tubes nanocapsules can be stimulated remotely by a radiofrequency (RF) field which disrupts the Pluronic coating to release CDDP. RF-induced release-dependent cytotoxicity of W-CDDP@US-tubes has been evaluated in vitro against two different liver cancer cell lines, Hep3B and HepG2, and found to exhibit superior cytotoxicity compared to W-CDDP@US-tubes not exposed to RF. Finally, in vivo biodistribution and therapeutic efficacy of the CDDP@US-tube material has been evaluated against three different breast cancer xenograft mouse (SCID/Bg) models, and found to exhibit greater efficacy in suppressing tumor growth than free CDDP for both a MCF-7 cell line xenograft model and a BCM-4272 patient-derived xenograft (PDX) model. The CDDP@US-tubes also demonstrated prolonged circulation time compared to free CDDP which enhances permeability and retention (EPR) effects resulting in significantly more CDDP accumulation in tumors, as determined by Platinum (Pt) analysis via inductively-coupled plasma mass-spectrometry (ICP-MS).Item Enhanced MRI relaxivity of aquated Gd3+ﾠions by carboxyphenylated water-dispersed graphene nanoribbons(Royal Society of Chemistry, 2014) Gizzatov, Ayrat; Keshishian, Vazrik; Guven, Adem; Dimiev, Ayrat M.; Qu, Feifei; Muthupillai, Raja; Decuzzi, Paolo; Bryant, Robert G.; Tour, James M.; Wilson, Lon J.; Richard E. Smalley Institute for Nanoscale Science and TechnologyThe present study demonstrates that highly water-dispersed graphene nanoribbons dispersed by carboxyphenylated substituents and conjugated to aquated Gd3+ﾠions can serve as a high-performance contrast agent (CA) for applications inﾠT1- andﾠT2-weighted magnetic resonance imaging (MRI) with relaxivity (r1,2) values outperforming currently-available clinical CAs by up to 16 times forﾠr1ﾠand 21 times forﾠr2.Item 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 TechnologyPorous 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.Item Hierarchically Structured Magnetic Nanoconstructs with Enhanced Relaxivity and Cooperative Tumor Accumulation(Wiley, 2014) Gizzatov, Ayrat; Key, Jaehong; Aryal, Santosh; Ananta, Jeyarama; Cervadoro, Antonio; Palange, Anna Lisa; Fasano, Matteo; Stigliano, Cinzia; Zhong, Meng; Di Mascolo, Daniele; Guven, Adem; Chiavazzo, Eliodoro; Asinari, Pietro; Liu, Xuewu; Ferrari, Mauro; Wilson, Lon J.; Decuzzi, Paolo; R.E. Smalley Institute for Nanoscale Science and TechnologyIron oxide nanoparticles are formidable multifunctional systems capable of contrast enhancement in magnetic resonance imaging, guidance under remote fields, heat generation, and biodegradation. Yet, this potential is underutilized in that each function manifests at different nanoparticle sizes. Here, sub-micrometer discoidal magnetic nanoconstructs are realized by confining 5 nm ultra-small super-paramagnetic iron oxide nanoparticles (USPIOs) within two different mesoporous structures, made out of silicon and polymers. These nanoconstructs exhibit transversal relaxivities up to ≈10 times (r 2 ≈ 835 mm −1 s−1) higher than conventional USPIOs and, under external magnetic fields, collectively cooperate to amplify tumor accumulation. The boost in r 2 relaxivity arises from the formation of mesoscopic USPIO clusters within the porous matrix, inducing a local reduction in water molecule mobility as demonstrated via molecular dynamics simulations. The cooperative accumulation under static magnetic field derives from the large amount of iron that can be loaded per nanoconstuct (up to ≈65 fg) and the consequential generation of significant inter-particle magnetic dipole interactions. In tumor bearing mice, the silicon-based nanoconstructs provide MRI contrast enhancement at much smaller doses of iron (≈0.5 mg of Fe kg−1 animal) as compared to current practice.Item Relaxivity Enhancement of Aquated Tris(β-diketonate)gadolinium(III) Chelates by Confinement within Ultrashort Single-walled Carbon Nanotubes(John Wiley & Sons, Inc., 2014) Law, Justin J.; Guven, Adem; Wilson, Lon J.; Richard E. Smalley Institute for Nanoscale Science and TechnologyUltrashort single-walled carbon nanotubes loaded with gadolinium ions (gadonanotubes) have been previously shown to exhibit extremely high T1-weighted relaxivities (>100 mM-1s-1). To further examine the effect of nanoconfinement on the relaxivity of gadolinium based contrast agents for magnetic resonance imaging (MRI), a series of ultrashort single-walled carbon nanotube (US-tube) materials internally loaded with gadolinium chelates has been prepared and studied. US-tubes were loaded with Gd(acac)3ﾷ2H2O, Gd(hfac)3ﾷ2H2O, and Gd(thd)3. (acac = acetylacetone, hfac = hexafluoroacetylacetone, thd = tetramethylheptanedione) The longitudinal relaxivities of the prepared materials determined at 25ﾰC in a 1.5 T field were 103 mM-1s-1 for Gd(acac)3ﾷ2H2O@US-tubes, 105 mM-1s-1 for Gd(hfac)3ﾷ2H2O@US-tubes and 26 mM-1s-1 for Gd(thd)3@US-tubes. Compared to the relaxivities obtained for the unloaded chelates (<10 mM-1s-1) as well as accounting for the T1 reduction observed for the empty US-tubes, the boost in relaxivity for chelate-loaded US-tubes is attributed to confinement within the nanotube and depends on the number of coordinated water molecules.Item Remotely triggered cisplatin release from carbon nanocapsules by radiofrequency fields(Elsevier, 2013) Raoof, Mustafa; Cisneros, Brandon T.; Guven, Adem; Corr, Stuart J.; Wilson, Lon J.; Curley, Steven A.; Richard E. Smalley Institute for Nanoscale Science & TechnologyThe efficacy of nanoparticle-mediated drug delivery is limited by its peri-vascular sequestration, thus necessitating a strategy to trigger drug release from such intra-tumoral nanocarrier-drug depots. In our efforts to explore remotely-activated nanocarriers, we have developed carbon nanocapsules comprised of an ultra-short carbon nanotube shell (US-tubes) loaded with cisplatin (CDDP@US-tubes) and covered with a Pluronic surfactant wrapping to minimize passive release. We demonstrate here that non-invasive radiofrequency (RF) field activation of the CDDP@US-tubes produces heat that causes Pluronic disruption which triggers cisplatin release in an RF-dependent manner. Furthermore, release-dependent cytotoxicity is demonstrated in human hepatocellular carcinoma cell lines.Item 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 TechnologyThere 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.