Biomedical subjects

Soo-Jeong Lim

Publications and source records attributed to Soo-Jeong Lim.

26 records · Page 2Linked to original sources

PubMed2002

Cyclosporin A enhances the apoptotic effects of N-(4-hydroxyphenyl)retinamide in breast cancer cells.

4HPR, an analogue of ATRA, effectively induces growth inhibition and apoptosis in breast cancer cell lines and animal models but is ineffective against advanced human breast tumors. Different compounds, including tamoxifen, are currently being tested to increase 4HPR efficacy in the clinic. Here, we report that cyclosporin A selectively increases the ability of 4HPR, but not ATRA, to induce growth inhibition and apoptosis in ER(+) and ER(-) breast cancer cell lines. Increased apoptosis by the 4HPR and cyclosporin A combination was correlated with increased production of the free radical nitric oxide. Thus, the 4HPR and cyclosporin A combination may potentially be a novel therapeutic modality against breast tumors.

Antineoplastic Agents↗

PubMed2002

Formulation parameters determining the physicochemical characteristics of solid lipid nanoparticles loaded with all-trans retinoic acid.

Solid lipid nanoparticles (SLNs) have gained attention as a colloidal drug carrier, particularly for drugs with limited solubility. The poor aqueous solubility of all-trans retinoic acid (ATRA) has been a limiting factor in its clinical use. This study was undertaken to overcome the solubility limitation of ATRA by loading in SLNs. The physicochemical characteristics of ATRA-loaded SLNs were investigated by particle size analysis, zeta potential measurement, thermal analysis and HPLC determination of ATRA content. The mean particle size of ATRA-loaded SLNs could be reduced (1) by mixing EggPC and Tween 80 as a surfactant and (2) by increasing the total surfactant amount. The smallest mean particle size of SLNs was obtained with 50 mg/g surfactant mixture composed of 54:46% (w/w) EggPC:Tween 80 (154.9 nm). The zeta potential of SLNs could be increased by mixing EggPC, Tween 80 and DSPE-PEG in the surfactant mixture. The zeta potential of SLNs prepared with 50 mg/g surfactant mixture composed of 48:6:46% (w/w) of EggPC:DSPE-PEG:Tween 80 was -38.18 mV. ATRA could be loaded at 2.4% (percentage of lipid matrix) on these SLNs without impairing their physical stability. After freeze-drying, the mean particle size and polydispersity index of ATRA-loaded SLNs were only slightly increased (181.8 vs. 265.2 nm, 0.173 vs. 0.200). Furthermore, no significant change was observed in the SLN-loaded concentration of ATRA and the zeta potential of SLNs after freeze-drying. Taken together, SLN formulation of ATRA with similar characteristics to those of parenteral emulsions could be obtained even after freeze-drying.

Antineoplastic Agents↗

PubMed2002

Her2/neu induces all-trans retinoic acid (ATRA) resistance in breast cancer cells.

We observed that all-trans retinoic acid (ATRA) inhibited the growth of MCF-7 breast cancer cells, but not those transfected with HER2/NEU or its transactivating ligand HEREGULIN. This suggests that Her2/neu causes breast cancer cells to be resistant to the growth inhibitory effects of ATRA. To confirm this observation, MDA-MB-453 and BT-474 cells, which have high levels of Her2/neu and are resistant to ATRA, were incubated with the trastuzumab (Herceptin) antibody so that we could determine whether inhibition of the expression and function of Her2/neu would resensitize these cells to ATRA. Indeed, we found that MDA-MB-453 and BT-474 cells treated with trastuzumab were growth inhibitory by ATRA. We then determined whether Her2/neu uses Grb2 and Akt proteins to induce ATRA resistance. Liposome-incorporated Grb2 antisense oligonucleotides (L-Grb2) and a dominant negative (DN) AKT mutant were used to down-regulate Grb2 expression and inhibit Akt activity, respectively. When incubated with L-Grb2 or transfected with the DN AKT mutant, ATRA-resistant, Her2/neu-overexpressing cells became sensitive to ATRA. Our results indicate that Her2/neu utilizes Grb2 and Akt proteins to induce ATRA resistance in breast cancer cells. ATRA sensitivity was also correlated with RARalpha protein levels since higher RARalpha protein levels were observed in cells in which the Her2/neu pathway was inhibited.

Antineoplastic Agents↗

PubMed2002

Recent progress in drug delivery systems for anticancer agents.

Recent progress in understanding the molecular basis of cancer brought out new materials such as oligonucleotides, genes, peptides and proteins as a source of new anticancer agents. Due to their macromolecular properties, however, new strategies of delivery for them are required to achieve their full therapeutic efficacy in clinical setting. Development of improved dosage forms of currently marketed anticancer drugs can also enhance their therapeutic values. Currently developed delivery systems for anticancer agents include colloidal systems (liposomes, emulsions, nanoparticles and micelles), polymer implants and polymer conjugates. These delivery systems have been able to provide enhanced therapeutic activity and reduced toxicity of anticancer agents mainly by altering their pharmacokinetics and biodistribution. Furthermore, the identification of cell-specific receptor/antigens on cancer cells have brought the development of ligand- or antibody-bearing delivery systems which can be targeted to cancer cells by specific binding to receptors or antigens. They have exhibited specific and selective delivery of anticancer agents to cancer. As a consequence of extensive research, clinical development of anticancer agents utilizing various delivery systems is undergoing worldwide. New technologies and multidisciplinary expertise to develop advanced drug delivery systems, applicable to a wide range of anticancer agents, may eventually lead to an effective cancer therapy in the future.

Antineoplastic Agents↗

PubMed2002

Microemulsion formulation of clonixic acid: solubility enhancement and pain reduction.

Clonixic acid is currently marketed as a salt form because of its poor water-solubility. However, the commercial dosage form causes severe pain after intramuscular or intravenous injection. To improve the solubility of clonixic acid and to reduce pain on injection, clonixic acid was incorporated into oil-in-water microemulsions prepared from pre-microemulsion concentrate composed of varying ratios of oil and surfactant mixture. As an oil phase for drug incorporation, up to 14% castor oil could be included in the pre-microemulsion concentrate without a significant increase in droplet size. Both drug contents and droplet size increased as the weight ratio of Tween 20 to Tween 85 decreased. Taken together, when microemulsions were prepared from pre-microemulsion concentrate composed of 5:12:18 weight ratio of castor oil:Tween 20:Tween 85, clonixic acid could be incorporated at 3.2 mg mL(-1) in the microemulsion with a droplet size of less than 120 nm. The osmotic pressure of this microemulsion was remarkably lower than the commercial formulation, irrespective of the dilution ratios. The rat paw-lick test was used to compare pain responses among formulations. The microemulsion formulation significantly reduced the number of rats licking their paws as well as the total licking time, suggesting less pain induction by the microemulsion formulation. The pharmacokinetic parameters of clonixic acid after intravenous administration of the clonixic acid microemulsion to rats were not significantly different from those of the commercial formulation, lysine clonixinate. The present study suggests that microemulsion is an alternative formulation for clonixic acid with improved characteristics.

Animals↗

PubMed2002

pH-sensitive, serum-stable and long-circulating liposomes as a new drug delivery system.

The lack of stability in blood and the short blood circulation time of pH-sensitive liposomes are major drawbacks for their application in-vivo. To develop pH-sensitive, serum-stable and long-circulating liposomes as drug delivery systems, the impact of polyethylene glycol-derived phosphatidylethanolamine (DSPE-PEG) on the properties of pH-sensitive liposomes was investigated. pH-sensitive liposomes were prepared with dioleoylphosphatidylethanolamine (DOPE) and oleic acid (DOPE/oleic acid liposome) or DOPE and 1,2-dipalmitoylsuccinylglycerol (DOPE/DPSG liposome). The inclusion of DSPE-PEG enhanced the serum stability of both DOPE/oleic acid and DOPE/DPSG liposomes, but also shifted the pH-response curve of pH-sensitive liposomes to more acidic regions and reduced the maximum leakage percentage. The impact of DSPE-PEG, however, was much lower in the DOPE/DPSG liposomes than in the DOPE/oleic acid liposomes. In tumour tissue homogenates, where the pH is lower than normal healthy tissues, the pH-sensitive DOPE/DPSG liposomes released the entrapped markers rapidly, in comparison with pH-insensitive dipalmitoylphosphatidylcholine/cholesterol/DSPE-PEG liposomes. Moreover, the release rate was not affected by the content of DSPE-PEG. The blood circulation time of methotrexate incorporated in DOPE/UDPSG liposomes was significantly prolonged with increasing content of DSPE-PEG. Taken together, the liposomes composed of DOPE, DPSG and DSPE-PEG (up to 5%) were pH sensitive, plasma stable and had a long circulation time in the blood. The complete destabilization of the liposomes at tumour tissues suggests that the liposomes might be useful for the targeted delivery of drugs such as anticancer agents.

Analysis of Variance↗

PubMedDate not supplied

Effect of chemical modification on the pharmacokinetics and biodistribution of carboxymethyl dextran as a drug carrier.

The in vivo fate of drugs conjugated to macromolecules inevitably depends on that of macromolecules. However, the in vivo fate of macromolecules also may be altered by conjugation to drugs. For the efficient design of carboxymethyldextran (CMD) conjugates of a new analgesic drug, DA5018, we investigated whether the chemical modifications alter the pharmacokinetics and tissue distribution of CMD itself. [(14)C]CMD, oxidized [(14)C]CMD ([(14)C]OCMD), [(14)C]OCMD conjugates of DA5018 ([(14)C]OCMD-DA5018) and [(14)C]OCMD conjugates of ethanolamine ([(14)C]OCMD-EA) were prepared and their molecular sizes were compared by size exclusion HPLC. The pharmacokinetics, biliary excretion, and tissue distribution of total radioactivity were compared after intravenous administration of each CMD derivative, 2.0 MBq/kg, to rats. The effective molecular sizes of CMD derivatives decreased in the order of [(14)C]CMD, [(14)C]OCMD-DA5018, [(14)C]OCMD, and [(14)C]OCMD-EA. After administration of each derivative, the mean AUC values of total radioactivity decreased with the decrease in the effective molecular size. The values of CL, Vss, and the amount of total radioactivity excreted in 24-hr urine increased considerably with the decrease in the effective molecular size. The tissue-to-plasma ratios of total radioactivity remaining in heart, liver, lung, kidney, and spleen at 24 hr also increased in the opposite order of the effective molecular size. Taken together, all these results demonstrate that the chemical modifications and physicochemical properties of attached chemicals can alter the pharmacokinetics and tissue distribution of CMD. One possible reason might be the difference in the effective molecular size of various CMD derivatives. Our study demonstrates that it may be necessary to consider the effect of chemical modification on the in vivo fate of macromolecules in designing macromolecular drug conjugates.

Animals↗

PubMedDate not supplied

N-(4-hydroxyphenyl)-retinamide selectively increases All-TRANS retinoic acid inhibitory effects in HER2/NEU-overexpressing breast cancer cells.

We previously reported that overexpression of the HER2/NEU oncogene induces all-TRANS retinoic acid (ATRA) resistance in breast cancer cells. N-(4-hydroxyphenyl)-retinamide (4HPR), a synthetic analogue of ATRA, has been shown to repress the expression of HER2/neu and its family member, epidermal growth factor receptor (EGFR). We investigated whether 4HPR, by suppressing HER2/neu or EGFR expression, could sensitize breast cancer cells to ATRA. At 1.3 micro M concentration (a clinically pharmacologically achievable dose), 4HPR increased ATRA sensitivity synergistically in HER2/NEU-overexpressing BT-474, MDA-MB-453, and MCF-7/Her2 breast cancer cells. However, 4HPR did not sensitize EGFR-overexpressing MDA-MB-468, Hs578T, and MCF-7/EGFR breast cancer cells to ATRA. The increased inhibitory effects in HER2/NEU-overexpressing cells were not correlated with increases in expression levels of p21(WAF1/CIP1) or retinoblastoma protein. Combining 4HPR with ATRA may lead to a novel, selective therapeutic or chemopreventive strategy against HER2/NEU-overexpressing breast tumors.

Antineoplastic Agents↗