Multistage O-producing liposome for MRI-guided synergistic chemodynamic/chemotherapy to reverse cancer multidrug resistance.

Reduced drug uptake and elevated drug efflux are two major mechanisms in cancer multidrug resistance (MDR). In the present study, a new multistage O-producing liposome with NAG/R8-dual-ligand and stimuli-responsive dePEGylation was developed to address the abovementioned issues simultaneously. The designed C-NAG-R8-PTXL/MnO-lip could also achieve magnetic resonance imaging (MRI)-guided synergistic chemodynamic/chemotherapy (CDT/CT). In vitro and in vivo studies showed that C-NAG-R8-PTXL/MnO-lip enhanced circulation time by PEG and targeted the tumor site. After tumor accumulation, endogenous l-cysteine was administered, and the PEG-attached disulfide bond was broken, resulting in the dissociation of PEG shells. The previously hidden positively charged R8 by different lengths of PEG chains was exposed and mediated efficient internalization. In addition, the oxygen (O) generated by C-NAG-R8-PTXL/MnO-lip relieved the hypoxic environment within the tumor, thus reducing the efflux of chemotherapeutic drug. O was able to burst liposomes and triggered the release of PTXL. The toxic hydroxyl radical (·OH), which was produced by HO and Mn, strengthened CDT/CT. C-NAG-R8-PTXL/MnO-lip was also used as MRI contrast agent, which blazed the trail to rationally design theranostic agents for tumor imaging.