Distribution characteristics of carboxymethylpullulan-peptide-doxorubicin conjugates in tumor-bearing rats: different sequence of peptide spacers and doxorubicin contents.
Plasma and tissue distribution of conjugates of carboxymethylpullulan (CMPul) and doxorubicin (DXR), either bound directly or through three types of tetrapeptide spacers, was studied after intravenous injection to rats bearing Walker 256 carcinosarcoma and compared with that of DXR. In contrast to DXR, each conjugate retained high levels of DXR in the conjugated form in plasma and displayed high accumulation in the tumor at 6 h after the administration. Disposition characteristics of [3H]CMPul in rats bearing Walker 256 carcinosarcoma indicate that pullulan, which had molecular weight over 50 kDa, is a suitable macromolecular carrier for tumor targeting in cancer chemotherapy by carboxymethylation. We find that the in vivo antitumor effect of the conjugates depends on the tumor AUC of free DXR released from the conjugates. CMPul-DXR conjugates were also distributed in the reticuloendothelial organs, such as liver, spleen and bone marrow; however, the tissue concentrations of the conjugates in the heart, lung and muscle were lower than those of DXR. We next investigated the effect of the DXR contents of CMPul-DXR conjugates on their body distribution in rats bearing Walker 256. The half life of CMPul-DXR conjugates in plasma were shorter and the conjugates had greater accumulation in the reticuloendothelial system, while they showed lower concentrations in the tumor with increasing DXR contents. Antitumor activity of CMPul-DXR conjugates were reduced and the lethal toxicities of CMPul-DXR conjugates were amplified with increasing DXR contents.
Nogusa
H
H
Drug Delivery System Institute, Ltd., Noda, Chiba, Japan. hideo.nogusa@shionogi.co.jp
Yamamoto
K
K
Yano
T
T
Kajiki
M
M
Hamana
H
H
Okuno
S
S
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D002240:Carbohydrate Sequence; D002296:Carcinosarcoma / Q000188:drug therapy / Q000378:metabolism*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D005260:Female; D005936:Glucans / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000008:administration & dosage / Q000737:chemistry; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014316:Tritium
D000970:Antineoplastic Agents; D005936:Glucans; D010455:Peptides; C410955:carboxymethylpullulan; D014316:Tritium; D004317:Doxorubicin