Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma

Smart nanoscale drug delivery systems that target acidic tumor microenvironments (TME) could offer controlled release of drugs and modulate the hypoxic TME to enhance cancer therapy. The majority of previously reported MnO.sub.2 nanostructures are nanoparticles, nanosheets, or nanocomposites incorporated with other types of nanoparticles, which may not offer the most effective method for drug loading or for the controlled release of therapeutic payloads. Previous studies have designed MnO.sub.2 nanoshells that achieve tumor-specific and enhanced combination therapy for localized advanced cancer. However, the therapeutic effect of MnO.sub.2 nanoshells on metastatic cancer is still uncertain. Here, intelligent "theranostic" platforms were synthesized based on hollow mesoporous MnO.sub.2 (H-MnO.sub.2) nanoshells that were loaded with chemotherapy agents docetaxel and cisplatin (TP) to form H-MnO.sub.2-PEG/TP nanoshells, which were designed to alleviate tumor hypoxia, attenuate angiogenesis, trigger the dissolution of Mn.sup.2+, and synergize the efficacy of first-class anticancer chemotherapy. The obtained H-MnO.sub.2-PEG/TP nanoshells decomposed in the acidic TME, releasing the loaded drugs (TP) and simultaneously attenuated tumor hypoxia and hypoxia-inducible factor-1[alpha] (HIF-1[alpha]) expression by inducing endogenous tumor hydrogen peroxide (H.sub.2O.sub.2) decomposition. In vitro experiments showed that compared with the control group, the proliferation, colony formation and migration ability of CAL27 and SCC7 cells were significantly reduced in H-MnO.sub.2-PEG/TP group, while cell apoptosis was enhanced, and the expression of hypoxia-inducible factor-1[alpha](HIF-1[alpha]) was down-regulated. In vivo experiments showed that tumor to normal organ uptake ratio (T/N ratio) of mice in H-MnO.sub.2-PEG/TP group was significantly higher than that in TP group alone (without the nanoparticle), and tumor growth was partially delayed. In the H-MnO.sub.2-PEG/TP treatment group, HE staining showed that most of the tumor cells were severely damaged, and TUNEL assay showed cell apoptosis was up-regulated. He staining of renal and liver sections showed no obvious fibrosis, necrosis or hypertrophy, indicating good biosafety. Fluorescence staining showed that HIF-1[alpha] expression was decreased, suggesting that the accumulation of MnO.sub.2 in the tumor caused the decomposition of H.sub.2O.sub.2 into O.sub.2 and alleviated the hypoxia of the tumor. In conclusion, a