Properties of poly(lactic-co-glycolic acid) nanospheres containing protease inhibitors: camostat mesilate and nafamostat mesilate.

Poly(lactic-co-glycolic acid) (PLGA) nanospheres containing protease inhibitors, camostat mesilate (CM) and nafamostat mesilate (NM), were prepared by the emulsion solvent diffusion methods in water or in oil, and the w/o/w emulsion solvent evaporation method. The average diameter of PLGA nanospheres prepared in the water system were about 150-300 nm, whereas those prepared in the oil system were 500-600 nm. Among the three methods, these drugs were the most efficiently encapsulated up to 60-70% in PLGA nanospheres in the oil system. Other factors that may influence drug encapsulation efficiency and in vitro release such as drug load, molecular weight of polymer were also investigated. Both the CM- and NM-loaded nanospheres prepared in the water system immediately released about 85% of the drug upon dispersed in the release medium while the drug initial burst of nanospheres prepared by the emulsion solvent diffusion in oil method reduced to 30% and 60% for CM and NM, respectively. Poly(aspartic acid) (PAA), a complexing agent for cationic water soluble drugs, showed little effect on the encapsulation efficiency and release behavior for CM and NM. The DSC study and AFM pictures of nanospheres demonstrated that temperature-dependent drug release behavior was ascribable to the glass transition temperature of the polymer, which also affected the morphology of nanospheres upon dispersed in the release medium and influenced the drug release consequently.

Treatment of peritoneal carcinomatosis using carboplatin-loaded hydroxyapatite particles.

UNLABELLED: The anti-tumor effects and tissue distribution of carboplatin (CBDCA) incorporated into hydroxyapatite (HAP) particles was studied. MATERIALS AND METHODS: Seven days after the intraperitoneal (i.p.) implantation of AH130 tumor cells into Donryu rats, the animals were randomized into four groups: group I was treated with saline i.p.; Group II, with CBDCA i.v.; group III with CBDCA i.p.; and group IV with HAP-CBDCA i.p. RESULTS: The survival rate of group IV was better than that of the other groups (p < 0.05). The area under the ascitic platinum concentration-time curve and tissue concentrations of platinum in the omentum after 24 hours of treatment were higher in group IV than in groups II or III (p < 0.05). The platinum concentrations in the kidneys of group IV were lower than in group III (p < 0.05). CONCLUSION: The HAP-CBDCA combination enhances the anti-tumor effects of the drug and reduces the nephrotoxicity in rats with peritoneal carcinomatosis.

Distribution of protease inhibitors in lipid emulsions: gabexate mesilate and camostat mesilate.

Gabexate mesilate (GM) and camostat mesilate (CM) are protease inhibitors used for the treatment of pancreatitis, and have been reported to show anticancer effects in vivo. Lipid emulsions (20% fractionated soybean oil) were investigated in terms of physicochemical interaction between the drugs and lipid emulsions as a possible drug carrier. The result showed that the drugs did not distribute in the oil phase but were adsorbed at the phospholipid interface of oil droplets. With increasing concentration of the drugs, the adsorption amount at the interface rose steeply to around 2.2x10(-11) mol/cm2 for GM and 1.2x10(-11) mol/cm2 for CM, respectively, followed by further adsorption deviated from the Langmuir adsorption manner after the inflection. To interpret this two-stage adsorption of the drugs, surface potential and fluorescence changes were examined in addition to thermodynamics for their interaction with the interfacial lipid layer. The primary adsorption was exothermic and was due to electrostatic interaction and van der Waals interaction between drug molecules and phospholipid molecules. Both acidic and neutral phospholipids in the lipid were involved in the adsorption of GM, while acidic phospholipids were mainly involved in the adsorption of CM. On the other hand, the secondary adsorption was endothermic and was entropy-driven most probably due to hydrophobic interaction for GM and CM in common, including peripheral penetration of drug molecules into the interfacial lipid layer.

Effect of oligopeptides on gene expression: comparison of DNA/peptide and DNA/peptide/liposome complexes.

Plasmid DNA is known to form complexes with a variety of cationic peptides and lipids, which have been explored as possible carriers for DNA transfection in mammalian cells. We synthesized oligopeptides consisting of nine amino acid residues including lysine (K), tryptophan (W), and cysteine (C), and also their symmetrical dimmers with a disulfide bond as possible carriers. The pDNA(pGL3)/oligopeptide complexes generally showed poor transfection efficiencies but little cytotoxicity for HeLa S3. The ternary system of pDNA/oligopeptide/liposome containing cationic liposomes formulated from the cholesterol derivative (DMB-Chol) and dioleoylphosphatidylethanolamine (DOPE) showed 10(4)-10(5)-fold greater effective gene expression (10(8)-10(9) level, RLU/min/mg protein) than those of the corresponding pDNA/oligopeptide complexes. In the presence of 10% serum, the ternary complexes were maintained at 10(7) levels. The ethidium bromide exclusion studies showed the ternary complexes have much greater affinity to pDNA than the corresponding pDNA/oligopeptide complexes. Plasmid sensitivity against DNase I degradation showed that the ternary complexes were well protected from the digestion. Synthetic oligopeptides are active as potential enhancers for DOPE-containing cationic liposome-mediated transfection. These findings have implications for successful in vivo transfection.

Computational consideration of cisplatin hydrolysis and acid dissociation in aqueous media: effect of total drug concentrations.

Cisplatin (cis-DDP) is subject to nucleophilic displacement of chloride in water, forming aquated species, subsequently liberating hydrogen ion(s) with increasing pH. This study intends to theoretically analyze the hydrolysis and polyprotic dissociation behavior of cis-DDP in various aqueous media. A mathematical model was expressed by nonlinear simultaneous equations in terms of the total drug concentration, pH and pCl based on the hydrolysis and acid dissociation constants already published. Some of the interesting simulation results include that (1) in water, cis-DDP behaves in a very complicated manner, highly depending on the total drug concentration, pH and pCl, (2) in normal saline, about 3% of the total concentration is a positively charged chloro-aqua that may be very reactive, (3) in assumed blood (pH 7.4, [Cl(-)]=0.11 mol/l, mu=0.15), the drug is stabilized at the level of 85% and the remnants are the chloro-hydroxo (11%) and the chloro-aqua (4%), (4) in assumed intracellular conditions (pH 7.1, [Cl(-)]=0.01 mol/l, mu=0.15), the drug is converted to a large extent to various species including the parent species (44%), the chloro-hydroxo (30%), hydroxo-aqua (2%), chloro-aqua (24%) diaqua (less than 1%) and dihydroxo (null). The results of this analysis may provide a useful preliminary knowledge of existing species in a system concerned and a rationale for re-evaluating the reactions between cis-DDP and various nucleophilic substances already reported while there are somewhat conflicting interpretations of some cis-DDP reactions.

In vivo genotoxicity evaluation of dimethylarsinic acid in MutaMouse.

Dimethylarsinic acid (DMA) induces DNA damage in the lung by formation of various peroxyl radical species. The present study was conducted to evaluate whether arsenite or its metabolite, DMA, could initiate carcinogenesis via mutagenic DNA lesions in vivo that can be attributed to oxidative damage. A transgenic mouse model, MutaMouse, was used in this study and mutations in the lacZ transgene and in the endogenous cII gene were assessed. When DMA was intraperitoneally injected into MutaMice at a dose of 10.6 mg/kg per day for 5 consecutive days, it caused only a weak increase in the mutant frequency (MF) of the lacZ gene in the lung, which was at most 1.3-fold higher than in the untreated control animals. DMA did not appreciably raise the MF in the bladder or bone marrow. Further analysis of the cII gene in the lung, the organ in which DMA induced the DNA damage, revealed only a marginal increase in the MF. Following DMA administration, no change in the cII mutation spectra was observed, except for a slight increase in the G:C to T:A transversion. Administration of arsenic trioxide (arsenite) at a dose of 7.6 mg/kg per day did not result in any increase in the MF of the lacZ gene in the lung, kidney, bone marrow, or bladder. Micronucleus formation was also evaluated in peripheral blood reticulocytes (RETs). The assay for micronuclei gave marginally positive results with arsenite, but not with DMA. These results suggest that the mutagenicity of DMA and arsenite might be too low to be detected in the MutaMouse.

Pain relief of oral ulcer by dibucaine-film.

A water-soluble three-layered oral mucosa-adhesive film made from hydroxypropyl cellulose containing dibucaine (0.25 mg of drug/cm(2)) was designed for alleviation of severe pain due to oral ulcers, caused by chemotherapy and/or radiotherapy. We report two patients with constant severe pain ulcers treated with the dibucaine film. Patients were asked to record the time that pain was relieved while chewing following first application of the film. Pain relief lasted for 2-5 h after application of the dibucaine film.