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 intravenousl y administered 5 polysaccharide carriers with various molecular weights (MW s) and electric charges and tested for their plasma and tissue distribution . Two carriers, carboxymethylated-D-manno-D-glucan (CMMG) and CMdextran (CM Dex), showed higher plasma AUC than the other carriers tested, namely, CMch itin (CMCh), N-desulfated N-acetylated heparin (DSH), and hyaluronic acid ( HA). This was consistently found to be true over the range of MWs tested. F or 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 s ubstitution (DS) of the CRI groups ranging from 0.2 to 0.6, showed maximum plasma AUC values. Twenty-four hours after administration, the concentratio n 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, GlyGlyP heGly (GGFG), to give carrier-GGFG-DXR conjugates (DNR 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 si ngle 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 antitu mor effect of the carrier-DXR conjugates was related to the extent with whi ch the carriers accumulated in the tumors.