Uønsket opptak av store molekyler i lever et problem som ... Fate of i.v. administered macromolecule ... The human adult liver weighs approx 2 kg, has a blood flow of 2 liters per

Biomedisinsk produktutvikling – hva skal til for å lykkes; Oslo 2015.03.26

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

Bård Smedsrød

Founder and CSO



Time after injection (min) Time after injection (min)

I.v. inj of 125I-FSA (25µg/kg) in mouse (Elvevold et al., Hepatology 48:2007-2015, 2008)

Blood clearance Degradation Organ distribution

(I.v. inj. of 125I-FSA (25µg/kg) in mice)

(10 min after injection)

Blood clearance function of the liver: Fate of i.v. administered macromolecule (125I-FSA)


The human adult liver weighs approx 2 kg, has ablood flow of 2 liters per min, and about 1 billion1mm in-parallel sinusoids or capillaries with totalsurface area about that of a tennis-court.


Sinusoids

Hepatocytes


Sinusoid

Hepatocyte

Kupffer cell

Liver sinusoidal endothelial cell


Kupffer cell

Stellate cell

Liver sinusoidal endothelial cell

Liver sinusoid


Cellular composition of liver

Volume %

LSEC3.3%

KC2.5%

SC1.7%

PC92.5%

Number %

PC65.0%

LSEC21.0%

KC8.5%

SC5.5%

Surface exposed to

blood borne largemolecules and

nanoparticles

LSEC80.0%

KC21.0%

PC5.5%


The liver is a scavenging machine



Size matters!The dual cell principle of waste clearance

KCLSEC

10 nm1 nm 10 µm1 µm10 0 nm

Virus

Oligonucleot ides

Bacteria

Proteins Red blood cells

Nanopart icles


Stabilin-1 & Stabilin-2

(Scavenger receptors

SR-H1 & SR-H2)Mannose

receptor

FcRIIb2

LSEC

Major endocytosis receptors in LSEC


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?)


1.The dual cell principle of waste clearance

2. Size matters!

3. Hepatic RES = Kupffer cells + LSECs

- design strategies to control liver uptake of large molecule drugs and nanoformulations

Without this awareness it is difficult to

- understand the mechanism of hepatotoxicity caused by administration of large molecule drugs and nano formulations

and

Take-home messages


D’Liver tilbyr:

D’Liver utfører analyser i eget laboratorium (bestemmer PK, organdistribusjon, opptak, metabolisme, reseptorspesifisitet ogtoksikologi i ulike typer leverceller)

D’Liver tilbyr konsulenttjenester basert på spesialkompetanse

D’Liver har egen in-house utvikling

- spesialkompetanse til klienter som har utfordringer med uønsketopptak av makromolekylære og nanopartikulære legemiddel-kandidater i lever.


Analysing the role of the liver, liver cells, and

receptors in clearance of large molecule

drugs and nano formulations

Since January 2011

Tromsø, Norway

[email protected]

Documents

Uønsket opptak av store molekyler i lever et problem som ... Fate of i.v. administered macromolecule ... The human adult liver weighs approx 2 kg, has a blood flow of 2 liters per