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The objectives of this study were to describe the pharmacokinetics and tissue distribution of superparamagnetic iron oxide nanoparticle (SPIO) stabilized with alginate (SPIO-alginate), and investigate its potential in detecting liver cancers as a newly developed magnetic resonance (MR) contrast agent. Pharmacokinetics and tissue distribution of SPIO-alginate were investigated in Sprague-Dawley rats. The results showed that SPIO-alginate was eliminated rapidly from serum with the half-life of 0.27 h at 109.5 micromol Fe/kg and accumulated dominantly in liver and spleen with a total percentage of more than 90% of dose after intravenous injection. The studies of pharmacokinetics and distribution of SPIO-alginate in rats indicated the MR contrast agent, based on SPIO, mainly accumulating in targeting organs that contain phagocytosing cells, i.e. liver and spleen. The efficacies in detecting hepatocellular carcinoma (HCC) of rat with primary liver cancer and xenograft liver cancers of rabbit were investigated before and after injection of SPIO-alginate. The signal intensity of liver parenchyma in rabbit with VX2 tumor after injection of SPIO-alginate was reduced sharply resulting in a significant contrast between liver parenchyma and tumor. Detection of the HCC in rat model was also demonstrated. The present study provides evidence that SPIO-alginate might have the ability to improve the detection of liver tumors as an MR contrast agent, and the efficacy is associated with the SPIO specifically located in Kupffer cells in hepatic sinusoid.

SPION with appropriate surface chemistry have been widely used experimentally for numerous in vivo applications. In this study, SPION stabilized by alginate (SPION-alginate) were prepared by a modified coprecipitation method. The structure, size, morphology, magnetic property and relaxivity of the SPION-alginate were characterized systematically by means of XRD, TEM, ESEM, AFM, DLS, SQUID magnetometer and MRI, respectively, and the interaction between alginate and iron oxide (Fe(3)O(4)) was characterized by FT-IR and AFM. The results revealed that typical iron oxide nanoparticles were Fe(3)O(4) with a core diameter of 5-10 nm and SPION-alginate had a hydrodynamic diameter of 193.8-483.2 nm. From the magnetization curve, the Ms of a suspension of SPION-alginate was 40 emu/g, corresponding to 73% of that of solid SPION-alginate. This high Ms may be due to the binding of Fe(3)O(4) nanoparticles to alginate macromolecule strands as visually confirmed by AFM. SPION-alginate of several hundred nanometers was stable in size for 12 months at 4 degrees C. Moreover, T1 relaxivity and T2 relaxivity of SPION-alginate in saline (1.5 T, 20 degrees C) were 7.86+/-0.20 s(-1) mM(-1) and 281.2+/-26.4 s(-1) mM(-1), respectively.

Formulations of ultra-deformable liposomes containing bleomycin (Bleosome) have previously been described and proposed for topical treatment of skin cancer [Lau, K.G., Chopra, S., Maitani, Y., 2003. Entrapment of bleomycin in ultra-deformable liposomes. S. T. P. Pharm. Sci. 13, 237-239]. In this study, the stability of various Bleosome formulations was characterised and a purification process was established to isolate Bleosome for testing on cultures of either human cutaneous keratinocytes (NEB-1) immortalised by human papilloma virus (HPV)-type 16, or a spontaneously immortalised human squamous cell carcinoma (SCC) from a primary tumour. Bleosome facilitated entrapment of high concentrations of active bleomycin and samples purified by gel-filtration chromatography remained stable during 7 days of storage at 4 degrees C or at room temperature. Serially-diluted samples of this purified, high-strength product, 'high dose' were applied onto keratinocyte cell cultures to elucidate Bleosome LD50 profiles. In vitro data revealed that the LD50 of bleomycin encapsulated in Bleosome was approximately three-fold higher than free bleomycin solution for SCC cells, and nearly 30 times higher for NEB-1 cells. However, Bleosome containing 30 microg/ml of active bleomycin killed more than twice as many SCC cells than NEB-1 cells. At that concentration, the potency of liposomal bleomycin on causing cell death of SCC cells was found to be similar to that of free bleomycin solution. This effect was not seen on NEB-1 cells. It seems that SCC cells were particularly susceptible to Bleosome containing high levels of bleomycin. Results from these experiments promote the development of a novel product for the topical treatment of skin cancer.

In the present study, cholesteryl hemisuccinate (CHEMS) was evaluated for use as a membrane stabilizer in dipalmitoylphosphatidylcholine (DPPC) liposomes. Differential scanning calorimetry (DSC) and a calcein release study showed that CHEMS was more effective than cholesterol (CHOL) in increasing DPPC membrane stability. The findings of Fourier transform infrared spectroscopy (FT-IR) also suggested that CHEMS interacts with DPPC via both hydrogen bonding and electrostatic interaction. More importantly, CHEMS did not interact with saikosaponin-d (SSD), a triterpene saponin from Bupleurum species, unlike CHOL. SSD-containing liposomes with DPPC, CHEMS and DSPE-PEG could greatly decrease the hemolytic activity of SSD. This study demonstrated that CHEMS has more stabilization ability than CHOL since CHEMS may exhibit both hydrogen bond interaction and electrostatic interaction with DPPC membrane while CHOL only has hydrogen bond interaction, resulting in stable and low-hemolytic SSD-liposomes.

The purpose of this work was to improve the oral bioavailability of cyclosporine A (CyA) by preparation the CyA-pH sensitive nanoparticles. The CyA-pH sensitive nanoparticles were prepared by using poly(methacrylic acid and methacrylate) copolymer. The characterization and the dispersion state of CyA at the surface or inside the polymeric matrices of the nanoparticles were investigated. The in vitro release studies were conducted by ultracentrifuge method. The bioavailability of CyA from nanoparticles and Neoral microemulsion was assessed in Sprague-Dawley (SD) rats at a dose of 15 mg/kg. The particle size of the nanoparticles was within the range from 37.4 +/- 5.6 to 106.7 +/- 14.8 nm. The drug entrapped efficiency was very high (from 90.9 to 99.9%) and in all cases the drug was amorphous or molecularly dispersed within the nanoparticles polymeric matrices. In vitro release experiments revealed that the nanoparticles exhibited perfect pH-dependant release profiles. The relative bioavailability of CyA was markedly increased by 32.5% for CyA-S100 nanoparticles (P < 0.05), and by 15.2% and 13.6% for CyA-L100-55 and CyA-L100 nanoparticles respectively, while it was decreased by 5.2% from CyA-E100 nanoparticles when compared with the Neoral microemulsion. With these results, the potential of pH-sensitive nanoparticles for the oral delivery of CyA was confirmed.

The effects of 1-O-ethyl-3-butylcyclohexanol (OEBC) on the in vitro skin permeation of ten model drugs with different physicochemical properties across excised rat skin were evaluated. The results showed that the addition of OEBC significantly improved the in vitro skin permeation of the model drugs compared with the control (without OEBC). To clarify the promoting mechanism of OEBC, a multiple regression analysis was employed. When the permeation study was performed without OEBC, the permeability coefficient was quantitatively predicted as a linear function of molecular weight (log MW) and their lipophilicity (partition coefficient of drugs between octanol and water (log K(o/w)) with a sufficiently high correlation coefficient (r=0.842). It was suggested that skin permeation of drugs without OEBC was explained as a function of diffusion of drugs through the skin and partitioning of drugs to the skin. Although OEBC was administered, the permeability coefficient of drugs cannot be predicted as a linear function of log MW and log K(o/w) (r=0.572).