In Chan Song

Multifunctional Uniform Nanoparticles Composed of a Magnetite Nanocrystal Core and a Mesoporous Silica Shell for Magnetic Resonance and Fluorescence Imaging and for Drug Delivery

During the past two decades, extensive research has been carried out on the biomedical applications of nanostructured materials. Among these various nanomaterials, mesoporous silica materials have been intensively investigated for their potential application as delivery vehicles for small-molecule drugs, DNA, and proteins, owing to their uniform pore size, large surface area, and high accessible pore volume. However, to date, there are only a few reports on the in vivo application of mesoporous silica materials administrated by intravenous injection, because it is difficult to synthesize discrete and monodisperse mesoporous silica particles smaller than around 100 nm that possess high colloidal stability in a physiological environment and small enough size to allow a long blood circulation. In general, bigger nanoparticles (NPs) result in more rapid uptake by the reticuloendothelial system (RES), such as liver and spleen, but smaller NPs can escape from phagocytes in RES and circulate through blood vessels with a long blood half-life. Although there have been several reports on the synthesis of uniform mesoporous silica particles smaller than 200 nm observed in TEM, the particles are not discrete but aggregated. Consequently, it is still a challenge to synthesize discrete, monodisperse, and size-controllable mesoporous silica NPs for in vivo applications. Recently, multifunctional nanostructured materials have been applied to multimodal imaging and simultaneous diagnosis and therapy. In this context, the integration of mesoporous silica with superparamagnetic monodisperse nanocrystals to form uniform core–shell composite particles has great potential for simultaneous bioimaging and drug delivery. Although there have been several reports on composite materials of magnetic nanocrystals and mesoporous silica materials, these materials have not been used for in vivo applications because of their size and aggregation. Herein, we present discrete, monodisperse, and precisely sizecontrollable core–shell mesoporous silica NPs smaller than 100 nm by using single Fe3O4 nanocrystals as cores (designated as Fe3O4@mSiO2). We also demonstrate the multifunctional bioapplications of the core–shell NPs for simultaneous magnetic resonance (MR) and fluorescence imaging, and for drug delivery. The synthetic protocol is represented in Scheme 1. Cetyltrimethylammonium bromide (CTAB) serves not only as the stabilizing surfactant for the transfer of hydrophobic Fe3O4 nanocrystals [10] to the aqueous phase but also as the organic template for the formation of mesopores in the sol– gel reaction. After removing the CTAB templates from the as-synthesized materials by heating them at reflux in acidic ethanol solution (pH 1.4), we collected the Fe3O4@mSiO2 particles. When we decreased the pH value of the extraction solution below 1.0, Fe3O4 nanocrystals as well as CTAB were fully removed from the as-synthesized Fe3O4@mSiO2, resulting in hollow mesoporous silica NPs (designated as H-mSiO2). Finally, for biomedical applications, the surface of the NPs was modified with PEG to render them biocompatible by

Uniform mesoporous dye-doped silica nanoparticles decorated with multiple magnetite nanocrystals for simultaneous enhanced magnetic resonance imaging, fluorescence imaging, and drug delivery.

Highly versatile nanocomposite nanoparticles were synthesized by decorating the surface of mesoporous dye-doped silica nanoparticles with multiple magnetite nanocrystals. The superparamagnetic property of the magnetite nanocrystals enabled the nanoparticles to be used as a contrast agent in magnetic resonance (MR) imaging, and the dye molecule in the silica framework imparted optical imaging modality. Integrating a multitude of magnetite nanocrystals on the silica surface resulted in remarkable enhancement of MR signal due to the synergistic magnetism. An anticancer drug, doxorubicin (DOX), could be loaded in the pores and induced efficient cell death. In vivo passive targeting and accumulation of the nanoparticles at the tumor sites was confirmed by both T2 MR and fluorescence imaging. Furthermore, apoptotic morphology was clearly detected in tumor tissues of mice treated with DOX loaded nanocomposite nanoparticles, demonstrating that DOX was successfully delivered to the tumor sites and its anticancer activity was retained.

Diffusion-weighted MR Imaging: Pretreatment Prediction of Response to Neoadjuvant Chemotherapy in Patients with Breast Cancer

PURPOSE To evaluate the potential of diffusion-weighted (DW) magnetic resonance (MR) imaging with an apparent diffusion coefficient (ADC) map in the prediction of response to neoadjuvant chemotherapy in patients with breast cancer. MATERIALS AND METHODS This retrospective study was approved by the institutional review board, which waived the informed consent requirement. Fifty-three consecutive women (mean age, 43.7 years; median age, 42.0 years; age range, 24-65 years) with 53 invasive breast cancers (mean diameter, 5.0 cm; median diameter, 4.2 cm; diameter range, 2.0-13.3 cm) who had undergone chemotherapy were included. Both DW MR imaging (b values, 0 and 750 sec/mm(2)) and dynamic contrast material-enhanced (DCE) MR imaging were performed at 1.5 T before and after chemotherapy prior to surgery. Mean time from initiation of chemotherapy to posttreatment ADC measurement was 54 days (range, 48-62 days). Average ADC for three regions of interest per tumor on ADC maps was calculated. Patients with a reduction in tumor diameter of at least 30% after chemotherapy at DCE MR imaging were defined as responders. Pretreatment ADCs and percentage increases in ADC after chemotherapy in responders and nonresponders were compared. The best pretreatment ADC cutoff with which to differentiate between responders and nonresponders was calculated with receiver operating characteristic curve analysis. RESULTS After chemotherapy, 36 (68%) patients were classified as responders, and 17 (32%) were classified as nonresponders. Pretreatment mean ADC ([1.036 ± 0.015] × 10(-3) mm(2)/sec [standard error]) of responders was significantly lower than that of nonresponders ([1.299 ± 0.079] × 10(-3) mm(2)/sec) (P = .004). Furthermore, mean percentage ADC increase of responders (47.9% ± 4.8) was higher than that of nonresponders (18.1% ± 4.5) (P < .001). The best pretreatment ADC cutoff with which to differentiate between responders and nonresponders was 1.17 × 10(-3) mm(2)/sec, which yielded a sensitivity of 94% (95% confidence interval [CI]: 81%, 99%) and a specificity of 71% (95% CI: 44%, 90%). CONCLUSION Patients with breast cancer and a low pretreatment ADC tended to respond better to chemotherapy. Prediction of response to neoadjuvant chemotherapy with DW MR imaging might help physicians individualize treatments and avoid ineffective chemotherapy.

Synthesis of Uniform Hollow Oxide Nanoparticles through Nanoscale Acid Etching

We synthesized various hollow oxide nanoparticles from as-prepared MnO and iron oxide nanocrystals. Heating metal oxide nanocrystals dispersed in technical grade trioctylphosphine oxide (TOPO) at 300 degrees C for hours yielded hollow nanoparticles retaining the size and shape uniformity of the original nanocrystals. The method was highly reproducible and could be generalized to synthesize hollow oxide nanoparticles of various sizes, shapes, and compositions. Control experiments revealed that the impurities in technical grade TOPO, especially alkylphosphonic acid, were responsible for the etching of metal oxide nanocrystals to the hollow structures. Elemental mapping analysis revealed that the inward diffusion of phosphorus and the outward diffusion of metal took place in the intermediate stages during the etching process. The elemental analysis using XPS, EELS, and EDX showed that the hollow nanoparticles were amorphous metal oxides containing significant amount of phosphorus. The hollow nanoparticles synthesized from MnO and iron oxide nanocrystals were paramagnetic at room temperature and when dispersed in water showed spin relaxation enhancement effect for magnetic resonance imaging (MRI). Because of their morphology and magnetic property, the hollow nanoparticles would be utilized for multifunctional biomedical applications such as the drug delivery vehicles and the MRI contrast agents.

Simple and Generalized Synthesis of Oxide−Metal Heterostructured Nanoparticles and their Applications in Multimodal Biomedical Probes

Heterostructured nanoparticles composed of metals and Fe3O4 or MnO were synthesized by thermal decomposition of mixtures of metal-oleate complexes (for the oxide component) and metal-oleylamine complexes (for the metal component). The products included flowerlike-shaped nanoparticles of Pt-Fe3O4 and Ni-Fe3O4 and snowmanlike-shaped nanoparticles of Ag-MnO and Au-MnO. Powder X-ray diffraction patterns showed that these nanoparticles were composed of face-centered cubic (fcc)-structured Fe3O4 or MnO and fcc-structured metals. The relaxivity values of the Au-MnO and Au-Fe3O4 nanoparticles were similar to those of the MnO and Fe3O4 nanoparticles, respectively. Au-Fe3O4 heterostructured nanoparticles conjugated with two kinds of 12-base oligonucleotide sequences were able to sense a complementary 24-mer sequence, causing nanoparticle aggregation. This hybridization-mediated aggregation was detected by the overall size increase indicated by dynamic light scattering data, the red shift of the surface plasmon band of the Au component, and the enhancement of the signal intensity of the Fe3O4 component in T2-weighted magnetic resonance imaging.

Tumor Targeting Chitosan Nanoparticles for Dual-Modality Optical/MR Cancer Imaging

We report tumor targeting nanoparticles for optical/MR dual imaging based on self-assembled glycol chitosan to be a potential multimodal imaging probe. To develop an optical/MR dual imaging probe, biocompatible and water-soluble glycol chitosan (M(w) = 50 kDa) were chemically modified with 5beta-cholanic acid (CA), resulting in amphiphilic glycol chitosan-5beta-cholanic acid conjugates (GC-CA). For optical imaging near-infrared fluorescence (NIRF) dye, Cy5.5, was conjugated to GC-CA resulting in Cy5-labeled GC-CA conjugates (Cy5.5-GC-CA). Moreover, in order to chelate gadolinium (Gd(III)) in the Cy5.5-GC-CA conjugates, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was directly conjugated in Cy5.5-GC-CA. Finally, the excess GdCl(3) was added to DOTA modified Cy5.5-GC-CA conjugates in distilled water (pH 5.5). The freshly prepared Gd(III) encapsulated Cy5.5-GC-CA conjugates were spontaneously self-assembled into stable Cy5.5 labeled and Gd(III) encapsulated chitosan nanoparticles (Cy5.5-CNP-Gd(III)). The Cy5.5-CNP-Gd(III) was spherical in shape and approximately 350 nm in size. From the cellular experiment, it was demonstrated that Cy5.5-CNP-Gd(III) were efficiently taken up and distributed in cytoplasm (NIRF filter; red). When the Cy5.5-GC-Gd(III) were systemically administrated into the tail vein of tumor-bearing mice, large amounts of nanoparticles were successfully localized within the tumor, which was confirmed by noninvasive near-infrared fluorescence and MR imaging system simultaneously. These results revealed that the dual-modal imaging probe of Cy5.5-CNP-Gd(III) has the potential to be used as an optical/MR dual imaging agent for cancer treatment.

Diffusion-weighted MRI in cystic or necrotic intracranial lesions.

Abstract Our purpose was to investigate the signal intensities of cystic or necrotic intracranial lesions on diffusion-weighted MRI (DWI) and measure their apparent diffusion coefficients (ADC). We examined 39 cystic or necrotic intracranial lesions in 33 consecutive patients: five malignant gliomas, seven metastases, two other necrotic tumours, a haemangioblastoma, three epidermoids, an arachnoid cyst, seven pyogenic abscesses, 12 cases of cysticercosis and one of radiation necrosis. DWI was performed on a 1.5 T unit using a single-shot echo-planar spin-echo pulse sequence with b 1000 s/mm2. The signal intensity of the cystic or necrotic portion on DWI was classified by visual assessment as markedly low (as low as cerebrospinal fluid), slightly lower than, isointense with, and slightly or markedly higher than normal brain parenchyma. ADC were calculated in 31 lesions using a linear estimation method with measurements from b of 0 and 1000 s/mm2. The cystic or necrotic portions of all neoplasms (other than two metastases) gave slightly or markedly low signal, with ADC of more than 2.60 × 10−3 mm2/s. Two metastases in two patients showed marked high signal, with ADC of 0.50 × 10−3 mm2/s and 1.23 × 10−3 mm2/s, respectively. Epidermoids showed slight or marked high signal, with ADC of less than 1.03 × 10−3 mm2/s. The arachnoid cyst gave markedly low signal, with ADC of 3.00 × 10−3 mm2/s. All abscesses showed marked high signal, with ADC below 0.95 × 10−3 mm2/s. The cases of cysticercosis showed variable signal intensity; markedly low in five, slightly low in three and markedly high in four.

In Vivo Proton Magnetic Resonance Spectroscopy of Central Neurocytomas

OBJECTIVE The authors report on the metabolic features of central neurocytomas observed during in vivo single-voxel proton magnetic resonance spectroscopy. METHODS Volume-selective single-voxel proton magnetic resonance spectroscopy was performed with a 1.5-T unit using a point-resolved spectroscopy sequence (TR/TE = 2000 ms/135 and 270 ms) to obtain spectra of a single 8-cc voxel. The subjects were five patients in the Department of Neurosurgery of Seoul National University Hospital whose central neurocytomas had been diagnosed histologically. The peak intensities of compounds containing choline (Cho), N-acetylaspartate, creatine/phosphocreatine, and lactate were analyzed. RESULTS The ratios of Cho to creatine/phosphocreatine and Cho to N-acetylaspartate were significantly higher than ratios in normal brains. A lactate signal was present, and an unidentified signal was also observed at 3.55 ppm, which might have been produced by inositol or glycine. CONCLUSION A combination of the signal at 3.55 ppm and a prominent Cho peak seems to be a characteristic feature of central neurocytomas. Volume-selective single-voxel proton magnetic resonance spectroscopy could provide additional information to aid in diagnosing this condition.

Labeling efficacy of superparamagnetic iron oxide nanoparticles to human neural stem cells: comparison of ferumoxides, monocrystalline iron oxide, cross-linked iron oxide (CLIO)-NH2 and tat-CLIO.

Objective We wanted to compare the human neural stem cell (hNSC) labeling efficacy of different superparamagnetic iron oxide nanoparticles (SPIONs), namely, ferumoxides, monocrystalline iron oxide (MION), cross-linked iron oxide (CLIO)-NH2 and tat-CLIO. Materials and Methods The hNSCs (5 × 105 HB1F3 cells/ml) were incubated for 24 hr in cell culture media that contained 25 µg/ml of ferumoxides, MION or CLIO-NH2, and with or without poly-L-lysine (PLL) and tat-CLIO. The cellular iron uptake was analyzed qualitatively with using a light microscope and this was quantified via atomic absorption spectrophotometry. The visibility of the labeled cells was assessed with MR imaging. Results The incorporation of SPIONs into the hNSCs did not affect the cellular proliferations and viabilities. The hNSCs labeled with tat-CLIO showed the longest retention, up to 72 hr, and they contained 2.15 ± 0.3 pg iron/cell, which are 59 fold, 430 fold and six fold more incorporated iron than that of the hNSCs labeled with ferumoxides, MION or CLIO-NH2, respectively. However, when PLL was added, the incorporation of ferumoxides, MION or CLIO-NH2 into the hNSCs was comparable to that of tat-CLIO. Conclusion For MR imaging, hNSCs can be efficiently labeled with tat-CLIO alone or with a combination of ferumoxides, MION, CLIO-NH2 and the transfection agent PLL.

Diffusion-tensor imaging for glioma grading at 3-T magnetic resonance imaging: Analysis of fractional anisotropy and mean diffusivity

Purpose: To retrospectively determine whether fractional anisotropy (FA) or mean diffusivity (MD) value at 3-T diffusion-tensor imaging is different between low- and high-grade gliomas and may be useful for glioma grading. Methods: Review board approval was obtained, and informed consent was waived. Diffusion-tensor imaging was performed in 27 patients with surgically proved gliomas (19 high-grade and 8 low-grade gliomas). Fractional anisotropy and MD values were measured in 3 regions; peritumoral edema, and enhancing and nonenhancing tumor regions. We compared mean FA and MD values of nonenhancing tumor regions between low- and high-grade gliomas and compared the FA and MD values among the 3 mentioned regions in high-grade gliomas. The relationship between FA and MD values of tumors was also investigated. Statistical analysis was performed using the Student t test and Pearson correlation coefficients. Results: In the nonenhancing regions of tumors, FA ratios were not significantly different between low- and high-grade gliomas (0.472 and 0.701, P = 0.075), but MD ratios were significantly lower in high-grade gliomas (1.899 and 1.23, P < 0.001). In high-grade gliomas, enhancing tumors showed a tendency toward a lower FA ratio than nonenhancing tumors (P = 0.034), but FA values or ratios of peritumoral edema were not significantly different from those of enhancing or nonenhancing tumor. No strong relationship was found between FA and MD values. Conclusions: Fractional anisotropy values of low- and high-grade gliomas were not significantly different. However, MD values of nonenhancing low-grade gliomas were significantly higher than those of nonenhancing high-grade gliomas, which will be useful for the grading of nonenhancing infiltrative gliomas.