Shiping Yang

Targeted dual-contrast T1- and T2-weighted magnetic resonance imaging of tumors using multifunctional gadolinium-labeled superparamagnetic iron oxide nanoparticles

Development of a multifunctional nanoparticle (NP) system allowing for dual-contrast T(1)- and T(2)-weighted targeted magnetic resonance (MR) imaging of tumors could significantly improve the diagnosis accuracy. In this study, superparamagnetic silica-coated iron oxide core-shell nanoparticles (Fe(3)O(4)@SiO(2) NPs) with a diameter of approximately 21 nm were synthesized via a thermal decomposition approach and were aminated through silanization. The amine-functionalized Fe(3)O(4)@SiO(2) NPs enabled the covalent conjugation of a paramagnetic gadolinium complex (Gd-DTPA, DTPA: diethylenetriamine pentaacetic acid) and an arginine-glycine-aspartic acid (RGD) peptide as a targeting ligand onto their surface. The formed Fe(3)O(4)@SiO(2)(Gd-DTPA)-RGD NPs are water-dispersible, stable, and biocompatible as confirmed by MTT cell viability assay. Relaxivity measurements show that they have a T(1) relaxivity (r(1)) of 4.2 mM(-1) s(-1) and T(2) relaxivity (r(2)) of 17.4 mM(-1) s(-1) at the Gd/Fe molar ratio of 0.3:1, suggesting a possibility to use them as both T(1) positive and T(2) negative contrast agents. In vitro and in vivo MR imaging experiments show that the developed multifunctional Fe(3)O(4)@SiO(2)(Gd-DTPA)-RGD NPs enable targeted dual-contrast T(1)- and T(2)-weighted MR imaging of tumor cells over-expressing high-affinity α(v)β(3) integrin in vitro and in vivo. Our results clearly indicate that the approach to forming multifunctional Fe(3)O(4)@SiO(2)(Gd-DTPA)-RGD NPs could be extended for fabricating other biologically active NPs for T(1)- and T(2)-weighted MR imaging of other biological systems with high accuracy.

Water-soluble superparamagnetic manganese ferrite nanoparticles for magnetic resonance imaging.

We report here a thermal decomposition approach to the synthesis of water-soluble superparamagnetic manganese ferrite (MnFe(2)O(4)) nanoparticles (NPs) for magnetic resonance (MR) imaging applications. In this approach, tetraethylene glycol was utilized as a coordination and stabilization agent, rendering the NPs water-soluble and stable. The formed NPs had a diameter of 7 nm with a narrow size distribution, and were superparamagnetic with a saturated magnetization (Ms) of 39 emu/g. In vitro cytotoxicity test revealed that the MnFe(2)O(4) NPs were biocompatible at a particle concentration below 200 microg/mL. The transverse relaxivity of MnFe(2)O(4) NPs in water and cells after incubation were determined to be 189.3mm(-1)s(-1) and 36.8mm(-1)s(-1) based on iron concentration, respectively. In vivo MR imaging studies in conjunction with inductively coupled plasma-atomic emission spectroscopy showed that the MnFe(2)O(4) NPs were preferentially accumulated in liver after intravenous injection for 4h. This suggests that the developed MnFe(2)O(4) NPs can serve as a sensitive MR imaging contrast agent for liver imaging. By appropriately modifying or functionalizing the surface of the NPs, these particles may be used for MR detection of other diseases.

Solvothermal synthesis of cobalt ferrite nanoparticles loaded on multiwalled carbon nanotubes for magnetic resonance imaging and drug delivery.

Multiwalled carbon nanotube (MWCNT)/cobalt ferrite (CoFe(2)O(4)) magnetic hybrids were synthesized by a solvothermal method. The reaction temperature significantly affected the structure of the resultant MWCNT/CoFe(2)O(4) hybrids, which varied from 6nm CoFe(2)O(4) nanoparticles uniformly coated on the nanotubes at 180°C to agglomerated CoFe(2)O(4) spherical particles threaded by MWCNTs and forming necklace-like nanostructures at 240°C. Based on the superparamagnetic property at room temperature and high hydrophilicity, the MWCNT/CoFe(2)O(4) hybrids prepared at 180°C (MWCNT/CoFe(2)O(4)-180) were further investigated for biomedical applications, which showed a high T(2) relaxivity of 152.8 Fe mM(-1)s(-1) in aqueous solutions, a significant negative contrast enhancement effect on cancer cells and, more importantly, low cytotoxicity and negligible hemolytic activity. The anticancer drug doxorubicin (DOX) can be loaded onto the hybrids and subsequently released in a sustained and pH-responsive way. The DOX-loaded hybrids exhibited notable cytotoxicity to HeLa cancer cells due to the intracellular release of DOX. These results suggest that MWCNT/CoFe(2)O(4)-180 hybrids may be used as both effective magnetic resonance imaging contrast agents and anticancer drug delivery systems for simultaneous cancer diagnosis and chemotherapy.

Paramagnetic hollow silica nanospheres for in vivo targeted ultrasound and magnetic resonance imaging

A series of hollow silica nanospheres (HSNSs) with sizes ranging from 100 to 400 nm were synthesized and used for primary ultrasound imaging (US) efficiency assessment. The 400 nm HSNSs were chosen as platform for conjugation with Gd-DTPA and cyclo-arginine-glycine-aspartic acid c(RGD) peptide to construct US and magnetic resonance imaging (MRI) dual-modal contrast agents (CAs): [HSNSs@(DTPA-Gd)-RGD]. The obtained CAs displayed good physiological stability, low cytotoxicity and negligible hemolytic activity in vitro. Furthermore, the passive accumulation and active-targeting of the HSNSs in the tumor site of mice was demonstrated by US and MR imaging, respectively. The qualitative and quantitative biodistribution of the HSNSs showed that they mainly accumulated in the tissues of liver, lung, tumor after intravenous administration and then be excreted from feces. In addition, histological, hematological, blood and biochemical analysis were used to further study toxicity of the HSNSs, and all results indicated that there were no covert toxicity of HSNSs in mice after long exposure times. Findings from this study indicated that the silica-based paramagnetic HSNSs can be used as a platform for long-term targeted imaging and therapy studies safely in vivo.

Biocompatiable hollow silica microspheres as novel ultrasound contrast agents for in vivo imaging

Surface PEGylated hollow silica microspheres (PEG–HSS) of ∼1250 nm in diameter were prepared by coating a thin layer of amino functionalized silica on the template of positive charged polystyrene, removing the template in THF solution, and further coupling the HSS with methoxy polyethylene glycol propionic acid (mPEG–COOH). Cytotoxicity tests, hemolysis assays, and confocal fluorescent imaging proved that the PEG–HSS have low cytotoxicity, good blood compatibility and cell permeability. Further in vitro ultrasound imaging of the as-prepared PEG–HSS in both physiological saline solution and human blood was investigated under different imaging conditions, including different ultrasound frequencies, mechanical indexes (MIs), and different PEG–HSS concentrations, which demonstrated obvious signal enhancement. In vivo ultrasound imaging was conducted on male rats after intra-testicle injection of the PEG–HSS. These results indicate that the PEG–HSS have great potential in application as a novel ultrasound contrast agent.

Facile synthesis of amino-functionalized hollow silica microspheres and their potential application for ultrasound imaging

By using the positive charged polystyrene (PS) microsphere as template, mono-disperse amino-(-NH(2)) functionalized hollow silica microspheres (HSMS-NH(2)) with ~1310 nm in diameter and uniform shells were successfully prepared with a modified sol-gel process. The amino functionalized silica were coated on the PS microspheres via ammonia catalysis, co-hydrolysis and condensation of TEOS and APTES, and then the PS templates were selectively dissolved in THF solution to form the functional hollow microspheres. The controllable thickness (35-85 nm) and amino density (2.46×10(-5)-6.18×10(-5) mol/g) of the shells could be facilely tuned by changing the amount of TEOS and APTES. In vitro ultrasound images of as-prepared HSMS-NH(2) with different concentrations in the physiological saline solution were further investigated. The obvious signal enhancement indicates that as-prepared HSMS-NH(2) has a great potential application for ultrasound imaging.

A d-f heteronuclear complex for dual-mode phosphorescence and magnetic resonance imaging

A d-f heteronuclear complex (Ir-Gd) by coupling an iridium(III) complex to a macrocycle-based gadolinium complex has been developed as as a dual-mode bioimaging probe for luminescence imaging and magnetic resonance imaging (MRI). The cyclometalated iridium complex showed an intense visible metal-to-ligand charge transfer (MLCT) absorption and strong yellow phosphorescent luminescence. It has specificity of staining in murine mitochondria confirmed by confocal laser scanning microscopy. The macrocycle-based gadolinium complex provides the longitudinal relaxivity of 3.36 mm(-1)s(-1) on a 3 T system, which has been applied to MRI for liver in mice. Furthermore, the biodistribution of Ir-Gd has been investigated using inductively coupled plasma-atomic emission spectroscopy (ICP-AES) analyses. Such platform should be extended to further applications in the identification and diagnosis of liver diseases.

Enhanced decoloration efficacy of electrospun polymer nanofibers immobilized with Fe/Ni bimetallic nanoparticles

Colloidal Fe/Ni bimetallic nanoparticles (NPs) have been applied as important materials for environmental remediation applications; however, the reusability of the colloidal Fe/Ni NPs still remains a great issue that limits their environmental applications. In this paper, we developed two different routes to synthesize and immobilize Fe/Ni bimetallic NPs using electrospun polyacrylic acid/polyvinyl alcohol nanofibers as nanoreactors: (1) synthesis of Fe NPs followed by post-coating Ni on Fe NPs (referred to post-coated Fe/Ni NPs) and (2) co-reduction of nickel and iron precursors within the nanofibers (referred to co-reduced Ni/Fe NPs). The formed electrospun nanofibrous mats containing Fe/Ni bimetallic NPs were characterized via different techniques. The decoloration efficiency of the two kinds of Fe/Ni NP-containing nanofibrous mats was compared with that of single metal zero-valent iron NP-containing nanofibrous mats. We show that the co-reduced Fe/Ni NP-containing nanofibrous mats have much higher decoloration efficiency than the single iron NP-immobilized polymer mats; whereas the mats containing post-coated Fe/Ni NPs have lower decoloration efficiency than the single iron NP-containing mats. The formed co-reduced Fe/Ni NP-containing polymer nanofibers can be reused for at least 4 times with high decoloration efficiency. With the easiness of formation and convenient reusability and recyclability, the bimetallic NP-containing polymer nanofibers could be applied in different potential applications including environmental remediation, fuel cells, and electrochemical sensors.

Surfactant-controlled morphology and magnetic property of manganese ferrite nanocrystal contrast agent

MnFe(2)O(4) nanocrystals (NCs) coated with three different surfactants (oleic acid, oleylamine or 1,2-hexadecanediol) and their mixtures, with sizes in range 6-12 nm, were synthesized by high-temperature decomposition of organometallic precursors. The effects of morphology and surface chemistry of MnFe(2)O(4) NCs on the magnetic properties were systematically investigated by comparing their saturation magnetization values and their capability to improve the negative contrast for magnetic resonance imaging (MRI) after converting the hydrophobic NCs to hydrophilic ones by a ligand exchange protocol. An important finding is that the magnetization values and proton relaxivity rates of MnFe(2)O(4) NCs are strongly dependent on the size and surface state of the particles that covalently bonded with different hydrophobic ligands before ligand exchange. In particular, monodisperse cubic MnFe(2)O(4) NCs could be obtained when oleylamine and 1,2-hexadecanediol were used as mixed stabilizers, and showed excellent morphology and magnetic properties. Furthermore, the low cytotoxicity and good cell uptake MR imaging of the dopamine capped MnFe(2)O(4) NCs make them promising candidates for use as bio-imaging probes.

General protocol for the synthesis of functionalized magnetic nanoparticles for magnetic resonance imaging from protected metal-organic precursors.

The development of magnetic nanoparticles (MNPs) with functional groups has been intensively pursued in recent years. Herein, a simple, versatile, and cost-effective strategy to synthesize water-soluble and amino-functionalized MNPs, based on the thermal decomposition of phthalimide-protected metal-organic precursors followed by deprotection, was developed. The resulting amino-functionalized Fe3O4, MnFe2O4, and Mn3O4 MNPs with particle sizes of about 14.3, 7.5, and 6.6 nm, respectively, had narrow size distributions and good dispersibility in water. These MNPs also exhibited high magnetism and relaxivities of r2 = 107.25 mM(-1)  s(-1) for Fe3O4, r2 = 245.75 mM(-1)  s(-1) for MnFe2O4, and r1 = 2.74 mM(-1)  s(-1) for Mn3O4. The amino-functionalized MNPs were further conjugated with a fluorescent dye (rhodamine B) and a targeting ligand (folic acid: FA) and used as multifunctional probes. Magnetic resonance imaging and flow-cytometric studies showed that these probes could specifically target cancer cells overexpressing FA receptors. This new protocol opens a new way for the synthesis and design of water-soluble and amino-functionalized MNPs by an easy and versatile route.