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

Abstract

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/C5/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.