Synergistic chemoradiotherapy of cervical cancer cells using a pH- and radiation-sensitive doxorubicin-loaded β-cyclodextrin-based nanocomposite hydrogel containing MnO2 nanoparticles

Abstract

It is an undoubted fact that remarkable clinical outcomes have demonstrated by synergistic chemoradiotherapy (CRT) approach, in comparison to solitary radiation therapy (RT) or chemotherapy (CT). Therefore, a novel pH- and radiation-sensitive nanocomposite hydrogel, β-cyclodextrin-graft-poly(succinic ethyl methacrylate)/MnO2 nanoparticles (β-CD-g-PSEMA/MnO2 NPs), was designed and developed through grafting 2-hydroxyethyl methacrylate (HEMA) onto functionalized β-CD through atom transfer radical polymerization (ATRP) followed by crosslinking β-CD-g-PHEMA-Br and bromine end-capped MnO2 NPs with Na2Se moiety to incorporate radiation-sensitive bonds into the hydrogel. The hydroxyl groups of PHEMA segments were converted to monomethyl succinate groups to induce pH sensitivity. Subsequently, the system was physically loaded with doxorubicin (Dox). In vitro drug release study revealed pH-dependent drug release behavior and the highest drug release value was obtained as 64.7% at pH 5. Oxygen generation from the developed drug delivery system (DDS) was confirmed, which the DDS could improve the efficiency of radiation therapy by oxygen generating in the cancer hypoxia environment. Intracellular uptake of the DDS was confirmed via FITC dye conjugation strategy. In contrast to free Dox, the developed DDS exhibited higher anticancer activity after 48 hours as validated by MTT and DAPI staining methods by synergistic CRT approach in moderate radiation dose.

Keywords

• Stimuli-responsive nanocomposite hydrogels
• MnO2 nanoparticles
• Radiosensitizers
• Chemoradiotherapy
• Cervical cancer