Preparation and biological evaluation of a novel pH-sensitive poly (β-malic acid) conjugate for antitumor drug delivery

Abstract

Poly (β-malic acid), referred to as PMLA, has been synthesized and introduced as a polymeric drug carrier due to its desirable biological properties. In the present study, a novel pH-sensitive polymer-drug conjugate based on PMLA, PMLA-Hz-doxorubicin (DOX), was prepared, and another conjugate, PMLA-ami-D OX, was synthesized as a comparison. The structures, conjugation efficiency, and drug release properties of the prodrugs were determined. The cytotoxicity and cell uptake were assessed using the HT1080 human fibrosarcoma cell line as an in vitro cell model. The release of DOX in the two conjugates were pH-dependent in PBS buffer at a pH of 5.6, 6.0, 6.8 and 7.4. The quantity of drug released increased with the decrease in pH, and PMLA-ami-D OX released twice as much as PMLA-Hz-D OX (12 h). The cytotoxicity of PMLA-Hz-D OX at pH 7.4 was lower than that of free DOX and increased with the decrease in pH, indicating that the cytotoxicity of PMLA-Hz-D OX was pH-sensitive. Flow cytometry and confocal experiments confirmed the efficiency of the PMLA-Hz-D OX conjugate. Therefore, bonding DOX to PMLA via an acid-sensitive hydrazone bond may be used to reduce its toxic side effects on normal tissues while responding to tumor pH and releasing the drug.