Myungmo Lee

Targeted and sustained delivery of hydrocortisone to normal and stratum corneum-removed skin without enhanced skin absorption using a liposome gel

A liposome-gel formulation containing 1% (w/w) hydrocortisone was prepared by blending phosphatidylcholine liposomes of hydrocortisone with Carbopol 934 hydrogel. The liposome-gel was applied topically onto the normal and stratum corneum (SC)-removed skins (3.0 cm2) of hairless mice at a dose of 1 mg as hydrocortisone. Percutaneous absorption of hydrocortisone across the SC-removed skin was significantly faster than that across normal skin, suggesting that SC behaves as a penetration barrier for the liposome-bound drugs. Contrary to previous reports that have suggested enhanced percutaneous penetration of drugs by liposomes, the liposome-gel in this study reduced the skin absorption of hydrocortisone, compared with the conventional ointment formulation. The amount of hydrocortisone absorbed from the liposome-gel after 8 h into the SC-removed skin was less than one-third of that from the conventional ointment. In spite of the reduced absorption, higher and sustained skin concentrations of hydrocortisone were achieved for the liposome-gel as compared to the ointment. Drug concentration in both viable and deep skin reached its maximum within 0.5 h after application of both formulations to both skin types. Drug concentrations in both skins from the ointment declined as a function of time, while those from the liposome-gel were greatly sustained. The sustainment by the liposome-gel was more remarkable in the viable skin than in the deep skin. Drug concentration in the viable skin could be maintained at a nearly constant level for over 8 h by applying the liposome-gel. As a result, a 5-fold higher viable skin drug concentration was obtained from the liposome-gel than from the ointment at 8 h after the application to the SC-removed skin. Nevertheless, the plasma concentration of hydrocortisone at 4 h from the liposome-gel was only one-fourth (p<0.01) the value from the ointment when the drug was applied to the SC-removed skin. Thus, retarded diffusion of the drug from the skin to the systemic blood stream appears to be a potential factor in the sustained skin concentration of hydrocortisone from the liposome-gel. The retarded diffusion was supported by the lower urinary (one-third, p<0.05) and fecal (one-half, p<0.05) excretion of the drug from the liposome-gel as compared to the ointment when the drug was applied to SC-removed skin. Interaction of hydrocortisone in the skin with phosphatidylcholine, a component of the liposomes and skin, may well be a factor in retarding the diffusion of the drug in the skin.

Poly(ADP-ribosyl)ation of p53 induces gene-specific transcriptional repression of MTA1

The metastasis-associated protein 1 (MTA1) is overexpressed in various human cancers and is closely connected with aggressive phenotypes; however, little is known about the transcriptional regulation of the MTA1 gene. This study identified the MTA1 gene as a target of p53-mediated transrepression. The MTA1 promoter contains two putative p53 response elements (p53REs), which were repressed by the p53-inducing drug 5-fluorouracil (5-FU). Notably, 5-FU treatment decreased MTA1 expression only in p53 wild-type cells. p53 and histone deacetylases 1/2 were recruited, and acetylation of H3K9 was decreased on the promoter region including the p53REs after 5-FU treatment. Proteomics analysis of the p53 repressor complex, which was pulled down by the MTA1 promoter, revealed that the poly(ADP-ribose) polymerase 1 (PARP-1) was part of the complex. Interestingly, p53 was poly(ADP-ribose)ylated by PARP-1, and the p53-mediated transrepression of the MTA1 gene required poly(ADP-ribose)ylation of p53. In summary, we report a novel function for poly(ADP-ribose)ylation of p53 in the gene-specific regulation of the transcriptional mode of p53 on the promoter of MTA1.

Highly Enantioselective Total Synthesis of (+)-Isonitramine

A new efficient enantioselective synthetic method of (+)-isonitramine is reported. (+)-Isonitramine was obtained in 12 steps (98% ee and 43% overall yield) from δ-valerolactam via enantioselective phase-transfer catalytic alkylation, Dieckman condensation, and diastereoselective reduction as key steps.

Efficient enantioselective total synthesis of (-)-horsfiline.

A new efficient and concise enantioselective synthetic method for (-)-horsfiline is reported. (-)-Horsfiline could be obtained from diphenylmethyl tert-butyl malonate in 9 steps (32%,>99% ee) by using the enantioselective phase-transfer catalytic allylation (91% ee) as the key step. This approach can be applied as a practical route for the large-scale synthesis of spirooxindole natural products, which enables a systematic investigation of their biological activity to be performed.

Highly enantioselective synthesis of 5-phenyl-2-alkylprolines using phase-transfer catalytic alkylation

An efficient enantioselective synthetic method for the synthesis of (2R)-5-phenyl-2-alkylproline tert-butyl esters was reported. The phase-transfer catalytic alkylation of tert-butyl-5-phenyl-3,4-dihydro-2H-pyrrole-2-carboxylate in the presence of chiral quaternary ammonium catalysts gave the corresponding alkylated products (up to 97% ee). The following diastereoselective reductions afforded chiral 5-phenyl-2-alkylprolines which can be applied to asymmetric synthesis as organocatalysts or synthesis of biologically active proline based compounds, such as chiral α-alkylated analogues of (+)-RP66803, as potential CCK antagonists.

N-methylthioureas as new agonists of retinoic acid receptor-related orphan receptor

Thirty two thiourea derivatives were prepared and their agonistic activities on the retinoic acid receptor-related orphan receptor α (RORα) were evaluated. The replacement of the 3-allyl-2-imino-thiazolidin-4-one moiety of the lead compound CGP52608 (1) with various functional group substituted aromatic rings, improved the agonistic activity of RORα. Among the prepared derivatives, 1-methyl-3-(4-phenoxy-benzyl)-thiourea (32) showed 2.6-fold higher agonistic activity than CGP52608 in the RORα-activation assay.

Enhanced Entrapment of Isopropamide Iodide in Liposomes by Ion-Pairing with Sodium Taurodeoxycholate

AbstractA study was carried out to determine the effect of sodium taurodeoxycholate (TDC) on the encapsulation efficiency of isopropamide iodide(IPM) in large unilamellar liposomes prepared by reverse phase evaporation method. The apparent partition coefficient of IPM between n-octanol and phosphate buffer (pH 7.4) was approximately zero, but it was increased by addition of TDC below CMC(1×l0 −2M). The increased partitioning of IPM into n-octanol seemed be due to ion-pair complex formation between IPM and TDC. The encapsulation efficiency of IPM by the liposome, which was determined by equilibrium dialysis method, was increased from 21% to 62% by the presence of TDC(1x10 −2M). It may be due to the solubilization of the ion-pair in the phospholipid bilayer of the liposome.

New scalable microfabrication method for surface ion traps and experimental results with trapped ions

This paper presents a new microfabrication method for surface ion traps and experimental results with trapped ions. Fabricating ion trap chips is a very formidable task because the top electrodes are vertically spaced more than 10 μm from the bottom electrodes with an indented dielectric layer in the middle. Previous ion traps were fabricated using TEOS timed etch or tungsten sacrificial etch techniques. This paper presents a new microfabrication method, using copper as a sacrificial material for an aluminum-oxide-aluminum ion trap structure. Using the developed method the overhang dimensions of the top aluminum electrodes can be accurately controlled. Fabricated ion trap chips are installed in a 1 × 10-11 Torr vacuum environment for ion trapping experiments. Successful results in trapping strings of 171Yb+ and 174Yb+ ions as well as manipulating 171Yb+ ions for qubit operation are demonstrated.