Versatile preparation of intracellular-acidity-sensitive oxime-linked polysaccharide-doxorubicin conjugate for malignancy therapeutic.

Recently, chemotherapy has been one of the most important therapeutic approaches for malignant tumors. The tumor tissular or intracellular microenvironment-sensitive polymer-doxorubicin (DOX) conjugates demonstrate great potential for improved antitumor efficacy and reduced side effects. In this work, the acid-sensitive dextran-DOX conjugate (noted as Dex-O-DOX) was synthesized through the versatile efficient oximation reaction between the terminal aldehyde group of polysaccharide and the amino group in DOX in the buffer solution of sodium acetate/acetic acid. The insensitive one, i.e., Dex-b-DOX, was prepared similarly as Dex-O-DOX with a supplemented reduction reaction. The DOX release from Dex-O-DOX was pH-dependent and accelerated by the decreased pH. The efficient intracellular DOX release from Dex-O-DOX toward the human hepatoma HepG2 cells was further confirmed. Furthermore, Dex-O-DOX exhibited a closer antiproliferative activity to free DOX·HCl as the extension of time. More importantly, compared with Dex-b-DOX, Dex-O-DOX exhibited higher antitumor activity and lower toxicity, which were further confirmed by the systemic histological and immunohistochemical analyses. Hence, the facilely prepared smart polysaccharide-DOX conjugates, i.e., Dex-O-DOX, exhibited great potential in the clinical chemotherapy of malignancy.