Uønsket opptak av store molekyler i lever et problem som kan overkommes?

Transkript

1 Uønsket opptak av store molekyler i lever et problem som kan overkommes? Bård Smedsrød Founder and CSO

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3 Blood clearance function of the liver: Fate of i.v. administered macromolecule ( 125 I-FSA) Blood clearance Degradation Organ distribution (I.v. inj. of 125 I-FSA (25µg/kg) in mice) (10 min after injection) Time after injection (min) Time after injection (min) I.v. inj of 125 I-FSA (25µg/kg) in mouse (Elvevold et al., Hepatology 48: , 2008)

4 The human adult liver weighs approx 2 kg, has a blood flow of 2 liters per min, and about 1 billion 1mm in-parallel sinusoids or capillaries with total surface area about that of a tennis-court. Biomedisinsk produktutvikling hva skal til for å lykkes; Oslo

5 Sinusoids Hepatocytes

6 Liver sinusoidal endothelial cell Kupffer cell Sinusoid Biomedisinsk produktutvikling hva skal til for å lykkes; Oslo Hepatocyte

7 Liver sinusoid Biomedisinsk produktutvikling hva skal til for å lykkes; Oslo Liver sinusoidal endothelial cell Kupffer cell Stellate cell

8 Cellular composition of liver LSEC 3.3% KC 2.5 % SC 1.7 % PC 92.5% KC 8.5% LSEC 21.0% SC 5.5% PC 65.0% KC 21.0% PC 5.5% LSEC 80.0% Volume % Number % Surface exposed to blood borne large molecules and nanoparticles

9 The liver is a scavenging machine Biomedisinsk produktutvikling hva skal til for å lykkes; Oslo

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11 Size matters! The dual cell principle of waste clearance LSEC KC Virus Bact eria Olig onucleot id es Nanop art icles Prot eins Red b lood cells 1 nm 10 nm 10 0 nm 1 µm 10 µm

12 Major endocytosis receptors in LSEC Mannose receptor Stabilin-1 & Stabilin-2 (Scavenger receptors SR-H1 & SR-H2) Fc RIIb2 LSEC

13 All classes of macromolecules and nanoparticles are endocytosed and metabolized in LSECs Polysaccharides (e.g. hyaluronan, chondroitin sulphate, heparin) Proteins [proteins that carry terminal mannose, e.g. lysosomal enzymes, tissue plasminogen activator, some propeptides of procollagen; several types of modified proteins (e.g. oxldls, AGEs); free collagen alpha chains; IgG immune complexes] Oligo/Polynucleotides (DNA, RNA) Lipids (e.g. via modified lipoproteins) Nanoparticles (e.g. virus, liposomes, nanocrystals, nanogold, exosomes?)

14 Take-home messages 1.The dual cell principle of waste clearance 2. Size matters! 3. Hepatic RES = Kupffer cells + LSECs Without this awareness it is difficult to - design strategies to control liver uptake of large molecule drugs and nanoformulations and - understand the mechanism of hepatotoxicity caused by administration of large molecule drugs and nano formulations

15 D Liver tilbyr: - spesialkompetanse til klienter som har utfordringer med uønsket opptak av makromolekylære og nanopartikulære legemiddelkandidater i lever. D Liver utfører analyser i eget laboratorium (bestemmer PK, organdistribusjon, opptak, metabolisme, reseptorspesifisitet og toksikologi i ulike typer leverceller) D Liver tilbyr konsulenttjenester basert på spesialkompetanse D Liver har egen in-house utvikling

16 Analysing the role of the liver, liver cells, and receptors in clearance of large molecule drugs and nano formulations Since January 2011 Tromsø, Norway