Synthesis of 6‐ O ‐carboxymethylchitin immobilizing doxorubicins through tetrapeptide spacer groups and its enzymatic release behavior of doxorubicin in vitro

Chitin is a non‐toxic biodegradable polysaccharide. 6‐ O ‐Carboxymethylchitin (CM‐chitin) is a water‐soluble chitin derivative. In order to provide a water‐soluble macromolecular prodrug of doxorubicin (DXR) reducing the side‐effects and exhibiting high antitumor activity, the fixation of DXRs to CM‐chitin through covalent bonds was carried out. Especially, a lysosomally digestible tetrapeptide (Gly‐Phe‐Leu‐Gly) was used as spacer groups between CM‐chitin and DXRs. In this paper, two kinds of conjugates, CM‐chitin/Gly‐Phe‐Leu‐Gly/DXR conjugate 5 having lysosomally digestible tetrapeptide spacer groups and CM‐chitin/C 5 /DXR conjugate 6 having pentamethylene spacer groups, were synthesized. The effect of introduction of the spacer groups on the release behavior of DXR from the conjugate was investigated. The conjugate 5 having tetrapeptide spacer groups showed a distinct increase in the release rate of DXR in the presence of the lysosomal enzyme cathepsin B at 37°C in vitro; however, the conjugate 6 did not show such specific release behavior.