Antitumor effects and toxicities of carboxymethylpullulan-peptide-doxorubicin conjugates.

In vivo antitumor effects of the conjugates of doxorubicin (DXR) with carboxymethylpullulan (CMPul) through tetrapeptide spacers were compared with those of DXR against tumor-bearing rats. CMPul-DXR conjugates bound through Gly-Gly-Phe-Gly and Gly-Phe-Gly-Gly spacers were found to be more potent than DXR after a single intravenous injection in rats bearing Walker 256 carcinosarcoma. These conjugates were also more effective than DXR in rats bearing Yoshida sarcoma. However, CMPul-DXR conjugate bound through Gly-Gly-Gly-Gly was less effective against Walker 256-bearing rats than DXR. Body weight loss of CMPul-DXR conjugates in rats, on the other hand, was less than that of DXR at a DXR dose of 10 mg/kg. Lethal doses of CMPul-DXR conjugates in CDF1 mice were about 3-times higher than that of DXR. These data suggest that the therapeutic index of CMPul-DXR conjugates bound through appropriate peptide spacers was increased more than that of DXR. However, CMPul-DXR conjugates tested were all less effective than DXR against Walker 256 cells in vitro. Also, 125I-labeled CMPul-DXR conjugate accumulated much less in the cells than 14C-DXR.

Tissue-targeting ability of saccharide-poly(L-lysine) conjugates.

To evaluate the effect of introducing a saccharide moiety to poly(amino acids) on tissue distribution, several glycoconjugates of epsilon-(2-methoxyethoxyacetyl)-poly(L-lysine) of three molecular weights were synthesized using an octylene spacer between the sugar and polymer chain. Methoxyethoxyacetylation of the epsilon-amino group of the lysine unit in poly(L-lysine) was useful for avoiding nonspecific distribution to many tissues as the result of cationic charges. The tissue-targeting ability of each saccharide moiety was considered as the actual amount changed in each tissue caused by saccharide modification. Galactose terminated saccharides such as galactose, lactose and N-acetylgalactosamine accumulated exclusively in the liver, probably by the hepatic receptor. These conjugates could therefore be good carriers for a drug delivery system to the liver. On the other hand, the mannosyl and fucosyl conjugates were preferentially delivered to the reticuloendothelial systems such as those in the liver, spleen and bone marrow. In particular, fucosyl conjugates accumulated more in the bone marrow than in the spleen. Xylosyl conjugates accumulated mostly in the liver and lung. Generally, the accumulated amount in the target tissue increased with increasing molecular weight and an increased number of saccharides on one molecule of polymer.