Oral uptake and translocation of a polylysine dendrimer with a lipid surface

Abstract

A series of lipidic peptide dendrimers based on lysine with 16 surface alkyl (C 12) chains has been synthesised in our laboratories. One of the series, a fourth generation dendrimer with a diameter of 2.5 nm was chosen to study its absorption after oral administration to female Sprague–Dawley rats (180 g, 9 weeks old). It was synthesised as the tritiated derivative (all acetyl portions) and had a molecular weight of 6300 and log P (octanol/water) of 1.24. First a single oral dose 14 mg/kg was administered by gavage. Maximum levels of dendrimer observed were 15% in the small intestine, 5% in the large intestine and 3% in the blood at 6 h after administration, while 1.5% reached the liver, 0.1% the spleen and 0.5% the kidneys. In a parallel study with a higher dose of 28 mg/kg, approximately 1% was absorbed via Peyer’s patches of the small intestine at 3 h. The maximum uptake by small intestine enterocytes was 4% of the dose after 3 h. After 12 h, 0.3 and 4% dendrimer was measured respectively in Peyer’s patches and enterocytes of the large intestine. When calculated on the basis of target tissue weight, the total percentage of the dose absorbed through Peyer’s patches was greater than through normal enterocytes in the small intestine after 3 and 24 h, but the opposite was true in the large intestine. These levels of uptake and translocation are lower than those exhibited by polystyrene particles in the range from 50 to 3000 nm. This might suggest that there is an optimum size for nanoparticulate uptake by the gut.