The production capacity bottleneck.
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Biotechnology↗
Biomedical subjects
J L De Keyser
Publications and source records attributed to J L De Keyser.
Targeting of drug to the hepatocytes by fatty acids. Influence of the carrier (albumin or galactosylated albumin) on the fate of the fatty acids and their analogs.
PURPOSE: The aim of this study was to evaluate the potential of fatty acids as shuttles to deliver xenobiotic inside the hepatocytes as well as to study the mechanism of incorporation into isolated hepatocytes when bound to native albumin or galactosylated albumin. Theoretically, they can enter into the hepatocytes after recognition of the Fatty Acid Binding Protein (FABPPM), or remain bound to galactosylated proteins and enter into these cells by a process known as receptor mediated endocytosis after selective recognition of the asialoglycoprotein receptor (ASGPR). METHODS: We synthesized a 3H-benzoyl adduct of lauric acid (BLA) (benzoyl adduct chosen to mimic any low molecular weight drug or contrast agent), and compared the behavior of BLA with oleic acid for their binding properties to carrier-proteins and the uptake mechanism by isolated hepatocytes. RESULTS: No significant difference was found in the binding properties of BLA for albumin and galactosylated albumin. The incorporation into the hepatocytes was found essentially depending on the FABPPM transport system whenever BLA was bound to albumin or to galactosylated albumin in the incubation medium: indeed, the transport was inhibited by phloretin (inhibitor of sodium dependent transport), increased when the free part of BLA was higher, and BLA was recovered in the cytosolic fraction of the hepatocytes. CONCLUSIONS: This study showed the convenience in using fatty acids as drug carriers possessing tropism for the hepatocytes.
Albumins↗
The effects of pasteurisation on albumin: an EPR binding assay for polymeric albumin.
The ability of a nitroxyl fatty acid (NFA) to bind specifically to albumin is abolished when, in the absence of stabilizers, a 4% solution of this protein is heated above a critical temperature of 60 degrees C. This treatment leads to the formation of "albumin polymers" as classically evidenced by GPC. Since the bound fraction is evidenced in EPR spectroscopy by a large anisotropic component, the presence of this anisotropy can be used in the assessment of the quality of the pharmaceutical preparations of albumin, which are usually pasteurized in order to inactivate viruses. Moreover, in sharp contrast with the behavior of albumin dispersions, lyophilised albumin subjected to heat treatment at 70 degrees C for 24 h left the protein untouched regarding its NFA binding and GPC profile.
Chromatography, Gel↗
Spin labelled arabinogalactan as MRI contrast agent.
In this study, we report the synthesis and the evaluation as MRI contrast agent of arabinogalactan/pyrrolidinoxyl radicals (PCA) covalent adduct (SLAG:Spin Labelled ArabinoGalactan). Arabinogalactan was used as targeting device, as it is recognized by the asialoglycoprotein receptor specific to the hepatocytes. The higher relaxivity R1 in water of SLAG, compared with small hydrophilic nitroxyl radicals, was explained by the molecular dynamics study using EPR spectroscopy that showed some immobilization of the radical into the polysaccharide. A binding study on isolated hepatocytes revealed that SLAG still recognizes the asialoglycoprotein receptor. MR imaging was performed using spin-echo T1 weighted images on mice to compare the contrast effect obtained with SLAG and PCA after IV injection (1 mmol/kg free radical). The percent signal enhancement observed in the liver 5 min after IV injection was 40 +/- 3% and 13 +/- 5% for SLAG and PCA, respectively. The signal was also dramatically increased in the renal cortex. This latter effect as well as the prolonged duration of the contrast (+/- 3 h), indicates at least a partial nonselective biodistribution; the high concentration needed to obtain a contrast effect could account for the saturation of the asialoglycoprotein receptor and hence for the apparent nonselective biodistribution.
Animals↗
Poly(diethyl methylidenemalonate) nanoparticles as a potential drug carrier: preparation, distribution and elimination after intravenous and peroral administration to mice.
Polymerization of diethyl methylidenemalonate (DEMM, 1a) in 0.1 M phosphate buffer containing 1% dextran 70 yields nanoparticles of a diameter ranging from 140 to 250 nm depending on the pH value (6.7 to 8.7). The weight-average and number-average molecular weight of the resulting polymer were 3791 and 1084, respectively. Approximately 95% of the 14C-labeled poly(DEMM) nanoparticles were found in liver and spleen 1 h after iv administration. A statistically significant (p less than 0.01) approximately 10% decrease of the radioactivity was observed in the liver over a 3-month period. The poly(DEMM) nanoparticles were not absorbed and were totally cleared from the gastrointestinal tract 24 h after oral dosage. The very slow bioelimination process observed after iv administration limits the usefulness of poly(DEMM) nanoparticles as a systemic drug carrier. Nevertheless, their oral administration as bioavailability enhancers can be envisaged. Moreover, the fact that nanoparticles are readily produced in a medium near neutrality should be emphasized.
Administration, Oral↗