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Cancer drug delivery 1986

Comparative distribution of free doxorubicin and poly-L-aspartic acid linked doxorubicin in MS-2 sarcoma bearing mice.

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The plasma and tissue distribution of doxorubicin-poly-L-aspartic acid (DX-PAA) and doxorubicin (DX) at equitoxic doses have been studied by a fluorescence assay in tumor bearing mice following administration of a single i.v. bolus injection. A relatively short distribution phase followed by a slow elimination phase characterized the DX-PAA plasma disappearence: at 48 hr after the treatment the conjugate was still detected in plasma. The plasma under the concentration vs. time curve (AUC) of drug equivalents following free DX administration resulted 2.6 times higher than the plasma AUC of free equivalents produced by DX-PAA treatment. In lung, liver and spleen the DX-PAA was accumulated in high concentrations. Low amount of DX equivalents were found in the heart following the conjugate administration: after 2 hr only traces of free anthracycline equivalents were detectable. On the contrary, drug equivalents following free DX treatment remained evaluable in the heart up to 24 hr from the drug administration. No significative differences were observed in the tumor AUC of free DX equivalents produced by free or polymer-linked DX. These data suggest that DX-PAA might act as a depot system slowly releasing the cytotoxic agent. Furthermore the observed accumulation of the conjugate and free DX equivalents in the lung and in the liver suggest a possible therapeutic advantages of DX-PAA in tumors with potential metastasis in these organs.

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