Distribution characteristics of carboxymethylpullulan-peptide-doxorubicin conjugates in tumor-bearing rats: Different sequence of peptide spacers anddoxorubicin contents

Plasma and tissue distribution of conjugates of carboxymethylpullulan (CMPu l) and doxorubicin (DXR), either bound directly or through three types of t etrapeptide spacers, was studied after intravenous injection to rats bearin g Walker 256 carcinosarcoma and compared with that of DXR. In contrast to D XR, each conjugate retained high levels of DXR in the conjugated form in pl asma and displayed high accumulation in the tumor at 6 h after the administ ration, Disposition characteristics of [H-3]CMPul in rats bearing Walker 25 6 carcinosarcoma indicate that pullulan, which had molecular weight over 50 kDa, is a suitable macromolecular carrier for tumor targeting in cancer ch emotherapy by carboxymethylation. We find that the in vivo antitumor effect of the conjugates depends on the tumor AUC of free DXR released from the c onjugates. CMPul-DXR conjugates were also distributed in the reticuloendoth elial organs, such as liver, spleen and bone marrow; however, the tissue co ncentrations of the conjugates in the heart, lung and muscle were lower tha n those of DXR. We nest investigated the effect of the DXR contents of CMPu l-DXR conjugates on their body distribution in rats bearing Walker 256. The half life of CMPul-DXR conjugates in plasma were shorter and the conjugate s had greater accumulation in the reticuloendothelial system, while they sh owed lon-er concentrations in the tumor with increasing DXR contents. Antit umor activity of CMPul-DXR conjugates were reduced and the lethal toxicitie s of CMPul-DXR conjugates were amplified with increasing DXR contents.