Ultrasound-triggered imaging and drug delivery using microbubble-self-aggregate complexes.

Co-delivery of microbubbles (MBs) with anticancer drugs is a promising theranostic approach that can enhance both the ultrasound contrast and local extravasation of drugs with the sonoporation effect. The simultaneous administration of MBs and hydrophobic drugs, however, is still challenging due to the limitations in drug loading or undesirable stabilization of MBs. In this research, MB-self-aggregate complexes (MB-SAs) were newly fabricated for the encapsulation of hydrophobic drugs, and their theranostic properties are investigated in vitro and in vivo. Glycol chitosan self-aggregates (GC-SAs) loaded with hydrophobic drugs or dyes were chemically conjugated on the surface MBs. Their conjugation ratio was determined to be 73.9%, and GC-SAs on MBs did not affect the stability of MBs. GC-SA attached MBs (GC@MBs) were successfully visualized with low-intensity insonation and showed enhanced cellular uptake via the sonoporation effect. In vivo biodistribution of GC@MBs was examined with tumor-bearing mice, confirming that their accumulation at the tumor site increased by 1.85 times after ultrasound irradiation. The anticancer drug-loaded GC@MBs also exhibited 10% higher cytotoxicity under ultrasound flash. In conclusion, it was expected that GC@MBs could be used both as an ultrasound contrast agent and a drug carrier even with conventional ultrasonic devices.

Macroporous polymer thin film prepared from temporarily stabilized water-in-oil emulsion.

We report a simple and convenient method for fabricating ordered porous structure in a polymeric thin film. A temporarily stabilized water-in-oil emulsion, where aqueous droplets were dispersed in the medium of polymer-organic solvent solution, was utilized for the preparation of porous structure. The water-in-oil emulsion was simply prepared by sonicating the mixture of water and polymer-organic solvent solution without any colloid stabilizer. The growth of aqueous droplets was profoundly retarded by dissolving a small amount of sucrose, selectively soluble in the dispersed phase. The prepared emulsion was recovered onto a substrate through dip-coating and subsequently air-dried to get a well-ordered porous polymer film. The polymer content in the polymer solution phase and the compositional ratio of the aqueous phase to the polymer solution phase was optimized to fabricate well-ordered structures.

An explanation of dispersion states of single-walled carbon nanotubes in solvents and aqueous surfactant solutions using solubility parameters.

Dispersions of single-walled carbon nanotubes in various solvents and aqueous surfactant emulsions were investigated to correlate the degree of dispersion state with Hansen solubility parameters (deltat2=deltad2+deltap2+deltah2). It was found that the nanotubes were dispersed or suspended very well in the solvents with certain dispersive component (deltad) values. They were precipitated in the solvents with high polar component (deltap) values or hydrogen-bonding component (deltah) values. The solvents in the dispersed group occupied a certain region in a 3-dimensional space of three components. The surfactants with a lipophilic group equal to and longer than decyl, containing 9 methylene groups and 1 methyl group, contributed to the dispersion of nanotubes in water. The surfactants in the dispersed group had a lower limit in the dispersive component (deltad) of the Hansen parameter.

Targeted multimodal imaging modalities.

Molecular imaging non-invasively visualizes and characterizes the biologic functions and mechanisms in living organisms at a molecular level. In recent years, advances in imaging instruments, imaging probes, assay methods, and quantification techniques have enabled more refined and reliable images for more accurate diagnoses. Multimodal imaging combines two or more imaging modalities into one system to produce details in clinical diagnostic imaging that are more precise than conventional imaging. Multimodal imaging offers complementary advantages: high spatial resolution, soft tissue contrast, and biological information on the molecular level with high sensitivity. However, combining all modalities into a single imaging probe involves problems yet to be solved due to the requirement of high dose contrast agents for a component of imaging modality with low sensitivity. The introduction of targeting moieties into the probes enhances the specific binding of targeted multimodal imaging modalities and selective accumulation of the imaging agents at a disease site to provide more accurate diagnoses. An extensive list of prior reports on the targeted multimodal imaging probes categorized by each modality is presented and discussed. In addition to accurate diagnosis, targeted multimodal imaging agents carrying therapeutic medications make it possible to visualize the theranostic effect and the progress of disease. This will facilitate the development of an imaging-guided therapy, which will widen the application of the targeted multimodal imaging field to experiments in vivo.

The intratumoral administration of ferucarbotran conjugated with doxorubicin improved therapeutic effect by magnetic hyperthermia combined with pharmacotherapy in a hepatocellular carcinoma model.

BACKGROUND: Local hyperthermia of tumor in conjunction with chemotherapy is a promising strategy for cancer treatment. The aim of this study was to evaluate the efficacy of intratumoral delivery of clinically approved magnetic nanoparticles (MNPs) conjugated with doxorubicin to simultaneously induce magnetic hyperthermia and drug delivery in a hepatocellular carcinoma (HCC) model. MATERIALS AND METHODS: HCC cells expressing luciferase were implanted into the flank of BALB/c-nu mice (n = 19). When the tumor diameter reached 7-8 mm, the animals were divided into four groups according to the injected agents: group A (normal saline, n = 4), group B (doxorubicin, n = 5), group C (MNP, n = 5), and group D (MNP/doxorubicin complex, n = 5). Animals were exposed to an alternating magnetic field (AMF) to receive magnetic hyperthermia, and intratumoral temperature changes were measured. RESULTS: The rise in temperature of the tumors was 1.88 ± 0.21°C in group A, 0.96 ± 1.05°C in B, 7.93 ± 1.99°C in C, and 8.95 ± 1.31°C in D. The RSI of the tumors at day 14 post-treatment was significantly lower in group D (0.31 ± 0.20) than in group A (2.23 ± 1.14), B (0.94 ± 0.47), and C (1.02 ± 0.21). The apoptosis rates of the tumors were 11.52 ± 3.10% in group A, 23.0 ± 7.68% in B, 25.4 ± 3.36% in C, and 39.0 ± 13.2% in D, respectively. CONCLUSIONS: The intratumoral injection of ferucarbotran conjugated with doxorubicin shows an improved therapeutic effect compared with doxorubicin or ferucarbotran alone when the complex is injected into HCC tissues exposed to AMF for magnetic hyperthermia. This strategy of combining doxorubicin and MNP-induced magnetic hyperthermia exhibits a synergic effect on inhibiting tumor growth in an HCC model.

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.