D’Liver is a contract research organization that aims to reduce the failure rate in the development of biopharmaceuticals (large molecule drugs). Based on our specialized knowledge on liver uptake mechanisms we provide unique products and services that address bioavailability challenges caused by unwanted liver uptake.
A frequently encountered problem associated with the development of biopharmaceuticals is unwanted liver uptake. Efficient liver uptake is likely to obstruct bioavailability and thereby reduce the efficacy of a biopharmaceutical whether administered alone or protected by a nano carrier. Knowing the details of this unwanted uptake is therefore a necessary step for developing a successful biopharmaceutical / nano carrier.
The most important site of uptake of nearly all intravenously administered biopharmaceuticals is the liver sinusoidal endothelial cell (LSEC). When analyzing liver uptake it is therefore necessary to include the LSEC. By including all three liver cell types known to be engaged in blood clearance (parenchymal cells; PC, Kupffer Cells; KC and LSEC) we can determine the exact mechanism(s) and cellular site(s) of unwanted liver uptake. Figure 1 illustrates a typical example of hepatocellular distribution of a biopharmaceutical, here of intravenously administered heparin. The majority of the recovered heparin was found in liver, where almost 80 % of that in the LSECs.
Øie et al. Liver sinusoidal
endothelial cells are the principal
site for elimination of unfractionated
heparin from the circulation. Am J
Physiol Gastrointest Liver Physiol.
2008; 294: G520-8.
WHAT DO WE ANALYSE?
Based on our leading-edge knowledge on liver uptake mechanisms D’Liver offers unique services that will provide in depth knowledge on the interactions between a biopharmaceutical / nano carrier and the cells and receptors responsible for its unwanted uptake in the liver. We use animal models and cell culture systems that closely mimic the human liver uptake system.
D’Liver can analyze how any types of biopharmaceutical candidates (e.g. proteins, glycoconjugates / polysaccharides, lipids, polynucleotides) / nano carriers will interact with the liver blood clearance system, in all stages of the drug development process.
OUR METHODS PORTFOLIO INCLUDES:
• Administration of biopharmaceutical candidates via various routes (iv, ip, im, oral gavage and more)
• Unique techniques to determine the hepatocellular distribution of biopharmaceutical candidates
• Mass isolation of liver cells into pure fractions and cultures of KCs, LSECs, PCs and stellate cells
• Techniques to determine what types of specific receptors on these cells that are responsible for the hepatic sequestration
• Radio- and fluorescence labeling and detection
• Determination of pharmacokinetic parameters (half-life, uptake kinetics, AUC) and tissue distribution in rats, mice or pigs
• Measuring fluorescence and radioactivity on whole body, organ and isolated cell levels
• Possibility to use primary human liver cells, freshly prepared, as a final check to determine if the results from studies in animal models reflect the uptake pattern in human liver
• Immunostaining for light/fluorescence and electron microscopy; correlated light and electron microscopy
INSTRUMENTS AND PLATFORMS WE HAVE ACCESS TO INCLUDE:
• Well-equipped animal housing facilities with highly skilled personnel to perform in vivo studies
• Beta and gamma counters
• High resolution fluorescence and confocal microscopes
• Flow cytometers and cell sorter
• MS instruments as well as other advanced equipment for analysis and preparation of molecules based on molecular weight and charge
• Electron microscopes (TEM and SEM)
• PET imaging for small animals
• Sample oxidizer for accurate assessment of beta-emitting isotopes in tissues