pH and reduction-activated polymeric prodrug nanoparticles based on a 6-thioguanine-dialdehyde sodium alginate conjugate for enhanced intracellular drug release in leukemia

For enhanced intracellular drug release in leukemia, the structure of 6-thioguanine (6-TG) based pH/reduction responsive polymeric prodrug nanoparticles was constructed by conjugating 6-TG to dialdehyde sodium alginate (DSA) via acid-labile Schiff base linkage followed by the ultrasound-assisted oxidation of thiol groups to disulfide cross-links. The nanoparticles are stable at pH 7.4 containing 0 and 10 mu M glutathione (GSH) with almost no drug release, but a cumulative drug release rate of up to 98.6% in 228 h was observed at pH 5.0 with 20 mM GSH and the cumulative drug release in the first 48 hours was over three times as much as that in the case of 10 mM GSH, indicating that GSH and pH dual-stimulation can significantly elevate tumour cell-selective drug release. In comparison with free 6-TG, this system exhibited a slightly higher inhibition ratio on HL-60 cancer cells, while an obviously reduced cytotoxicity was observed for healthy liver cell line L-O2. Furthermore, in vitro cell studies further confirmed the efficient cellular uptake of the system and enhanced intracellular drug release in the HL-60 cells.