Fluorescent dye labeled iron oxide/silica core/shell nanoparticle as a multimodal imaging probe.

PURPOSE: To develop an MRI/optical multimodal imaging probe based on dye-conjugated iron oxide/silica core/shell nanoparticle, and investigate the distance-dependent fluorescence quenching through careful control of the distance between the iron oxide core and fluorescent dyes. METHODS: Different size of core/shell nanoparticles were prepared by varying the silica shell width. PEGylation on the surface of silica shell was followed to improve the stability of particles in the physiological condition. In vitro cytotoxicity was evaluated by the MTT assay on a HeLa cell line and in vivo imaging of subcutaneous SCC7 xenografted mice was performed using MRI/optical imaging modalities. RESULTS: Diameter and ζ-potential of the nanoparticles were measured, and TEM images demonstrated the mono-disperse nature of the particles. Quenching efficiency of the dyes on the surface was nearly 100% in the smallest nanoparticle, while almost no quenching effect was observed for the largest nanoparticle. In vitro cytotoxicity showed nearly 90% cell viability at 0.15 Fe mg/mL, a comparable concentration for clinical use. The tumor area was significantly darkened after the nanoparticle injection due to the high transverse relaxivity value of the nanoparticles. Fluorescence signal was affected by the particle size due to the distance-dependent quenching/dequenching behaviour.

Improved drug targeting to liver tumors after intra-arterial delivery using superparamagnetic iron oxide and iodized oil: preclinical study in a rabbit model.

PURPOSE: The purpose of this study was to evaluate the feasibility and the therapeutic efficacy of a novel drug-delivery system that uses superparamagnetic iron oxide (SPIO) and iodized oil (IO) to improve the selective intra-arterial (IA) drug delivery to an experimentally induced hepatic tumor. MATERIALS AND METHODS: This animal study was approved by our institutional animal care and use committee. Fifteen rabbits with hepatic VX2 carcinomas were treated with IA delivery of 4 different agents: doxorubicin alone (group A, n = 3), doxorubicin/IO (group B, n = 3), a doxorubicin/SPIO complex (group C, n = 4), and a doxorubicin/SPIO/IO complex (group D, n = 5). The infused doxorubicin dose was 1 mg for all groups. The serum doxorubicin concentration was measured at 0, 5, 30, 60, and 120 minutes after the delivery. To assess the distribution of the SPIO, magnetic resonance (MR) scans were performed at day 7 after the delivery, when computed tomographic scans were performed in addition to MR in group B and D to assess the distribution of IO. After the completion of follow-up imaging, all the animals were euthanized to measure the intratumoral doxorubicin concentration and to assess tumor viability through pathologic examination. RESULTS: Groups C and D demonstrated significantly lower MR signal intensities, which inversely corresponded to SPIO deposition, in the tumor areas than did groups A and B. Group D exhibited the lowest serum doxorubicin concentration at all time points up to 180 minutes after the delivery, suggesting minimal passage of doxorubicin into the systemic circulation. The intratumoral doxorubicin concentrations were 72.4 ng/g for group A, 142.0 ng/g for group B, 264.1 ng/g for group C, and 679.6 ng/g for group D. The proportion of viable tumor cells were 65.3% for group A, 1.3% for group B, 17.0% for group C, and 0.1% for group D. CONCLUSIONS: The drug-delivery system developed using SPIO and IO can result in better drug targeting when it is used for IA delivery to liver cancer. The results of this study warrant further investigation of this potential clinical treatment of advanced liver cancer.

Development of MRI/NIRF 'activatable' multimodal imaging probe based on iron oxide nanoparticles.

A fabrication method of Cy5.5-MMP substrate and PEG conjugated iron oxide nanoparticles with thin silica coating (PCM-CS) and its potential as an 'activatable' dual imaging probe for tumor imaging is described in this report. PCM-CS showed an intensity-averaged diameter of 43.1 ± 6.3 nm by dynamic light scattering without any noticeable aggregation over 7 days. Fluorescence of Cy5.5 on the surface of nanoparticles was fully quenched and the quenching efficiency was 97.2%. PCM-CS showed protease specific fluorescence recovery in vitro caused from the specific peptide cleavage by MMP-2 and the probe displayed the sensitivity on 0.5 nM or less enzyme concentration. Tumor was successfully visualized by NIRF and MRI in vivo by intravenously injected PCM-CS. NIRF signal of tumor was gradually increased up to 12h post injection and the intensity of tumor was about 3-4 times higher than normal tissue. NIRF signal at MMP-2 inhibitor treated tumor was clearly lower than tumor without inhibitor due to the insufficient peptide cleavage. NIRF signal at excised tumor was 5-10 times stronger than other organs. Noticeable darkening in magnetic resonance image was observed at the tumor region and the image was gradually darkened at 12h post injection of PCM-CS. The maximum signal difference between tumor region and healthy muscle was 34%.

Stabilized polymeric micelles by electrostatic interactions for drug delivery system.

Methoxy poly(ethylene glycol)-block-oligo(l-aspartic acid)-block-poly(epsilon-caprolactone) with four aspartic acid groups was synthesized with a molecular weight and M(w)/M(n) of 8930 and 1.22. Polymeric micelles were formed by dialysis and stabilized by electrostatic interactions between the carboxylic acid groups and calcium cations. The critical micelle concentration of mPEG-Asp-PCL was determined to be 0.078 mg/mL. At 0.02 mg/mL, the dissociation of micelles without ionic stabilization formed an opaque, phase-separated solution, while the stabilized micelles under the same conditions showed structural stability through ionic stabilization. The paclitaxel-loading and efficiency were 8.7% and 47.6%, respectively, and the drug loading increased the mean diameter from 73.0 nm to 87 nm, which was increased further to 96 nm after ionic fixation. Rapid releases of approximately 65% of the encapsulated paclitaxel from a non-stabilized micelle and 45% from a stabilized micelle were observed in the first 24h at pH 7.4 in a PBS solution containing 0.1 wt% Tween 80. The stabilized micelles then showed a sustained, slow release pattern over a couple of weeks, while the profile from the non-stabilized micelles reached a plateau at approximately 75% after 50h. The enhanced micelle stability independent of concentration through ionic stabilization opens a way for preparing long circulating delivery systems encapsulating water-insoluble drugs.