The anthracycline group has been one of the most extensively studied groups of drugs used in polymer-drug conjugate delivery systems, especially in the 1980s. Based on the assumption that greater selectivity toward tumors over normal tissues can be achieved if PG-ADR conjugates only degrade and release ADR after being endocytosed by tumor cells, Van Heeswijk and colleagues30 investigated three different PG conjugates containing ADR where the amine group in ADR was bound to the side chain carboxyl groups of high-molecular-weight PG either directly (with an amide bond) or indirectly through GlyGly and GlyGlyGlyLeu spacers, respectively. They investigated the degradability of the conjugates mediated by lysosomal enzymes and the subsequent release of ADR or ADR-peptide products with low molecular weights using reverse-phase high-performance liquid chromatography. The total amount of ADR released after 77 h of incubation was 3.6% for PG-Gly-GlyGlyLeu-ADR; 1.0% for PG-GlyGly-ADR; and 0.5% for PG-ADR, suggesting the importance of introducing an enzymatically degradable spacer between PG and the drug. In vitro, these conjugates exhibited reduced cytotoxicity against L1210 leukemia cells when compared with free ADR. In vivo, animals treated with the polymer conjugate containing the tetrapeptide spacer showed a similar mean survival duration as compared to those treated with free ADR, whereas the conjugate without a peptide spacer was completely inactive.28,31

Some have used hydrolytically labile ester bonds32 and hydrozone bonds33 to couple doxor-ubicin or daunorubicin (Dau) with PG. In these studies, the ester bond was formed by a reaction of 14-bromo-daunorubicin with the carboxylic group of PG via a nucleophilic substitution reaction in an alkaline aqueous medium. With intravenous administration of these conjugates into mice bearing MS-2 sarcoma or Gross' leukemia, these investigators found that the drug conjugates' potency and efficacy were correlated with the molecular weight of the carrier. For example, anti-tumor activity improved when the molecular weight increased from 14,000 to 60,000 Da at an equivalent doxorubicin dose of 30 mg/kg. These results can be attributed to the increased circulation times of conjugates with high molecular weights. Condensing the methylketone in Dau with hydrazide-derived PG yielded PG-hydrazone-Dau conjugates. The acid-sensitive conjugates were less cytotoxic than free Dau was in vitro against mouse lymphoma cells. However, these conjugates showed significant anti-tumor activity when intravenously injected into mice bearing intraperitoneally inoculated Yac lymphoma.33

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