Characteristics of tissue distribution of various polysaccharides as drug carriers: influences of molecular weight and anionic charge on tumor targeting.
Using the Walker 256 model for carcinosarcoma-bearing rats, we intravenously administered 5 polysaccharide carriers with various molecular weights (MWs) and electric charges and tested for their plasma and tissue distribution. Two carriers, carboxymethylated-D-manno-D-glucan (CMMG) and CMdextran (CMDex), showed higher plasma AUC than the other carriers tested, namely, CMchitin (CMCh), N-desulfated N-acetylated heparin (DSH), and hyaluronic acid (HA). This was consistently found to be true over the range of MWs tested. For CMDex, the maximum value of plasma AUC was obtained when the MW exceeded 150 kDa. As for the anionic charge, CMDex (110-180 kDa) with a degree of substitution (DS) of the CM groups ranging from 0.2 to 0.6, showed maximum plasma AUC values. Twenty-four hours after administration, the concentration of CMDex (180-250 kDa; DS: 0.6-1.2) in tumors was more than 3% of dose/g--approximately 10-fold higher than those observed with CMCh, DSH and HA. Doxorubicin (DXR) was bound to these carriers via a peptide spacer, GlyGlyPheGly (GGFG), to give carrier-GGFG-DXR conjugates (DXR content: 4.2-7.0 (w/w)%), and the antitumor effects of these conjugates were tested with Walker 256 carcinosarcoma-bearing rats by monitoring the tumor weights after a single intravenous injection. Compared with free DXR, CMDex-GGFG-DXR and CMMG-GGFG-DXR conjugates significantly suppressed tumor growth, while the CMCh-GGFG-DXR, DSH-GGFG-DXR, and HA-GGFG-DXR conjugates in a similar comparison showed weak tumor growth inhibition. These findings suggest that the antitumor effect of the carrier-DXR conjugates was related to the extent with which the carriers accumulated in the tumors.
Sugahara
S
S
Drug Deliver System Institute, Ltd., Noda, Chiba, Japan. sugawara.sb@om.asahi-kasei.co.jp
Okuno
S
S
Yano
T
T
Hamana
H
H
Inoue
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002279:Carcinoma 256, Walker / Q000188:drug therapy; D004317:Doxorubicin / Q000008:administration & dosage; D004337:Drug Carriers; D005260:Female; D008970:Molecular Weight; D011134:Polysaccharides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D004337:Drug Carriers; D011134:Polysaccharides; D004317:Doxorubicin