Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma
Abstract Background 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 MnO2 nanostructures are nanoparticles, nanosheets, or nanocom...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-05-01
|
| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-021-00901-9 |
| _version_ | 1811305447908442112 |
|---|---|
| author | Zhi-hang Zhou Si-yuan Liang Tong-chao Zhao Xu-zhuo Chen Xian-kun Cao Ming Qi Ying-ying Huang Wu-tong Ju Meng Yang Dong-wang Zhu Yi-chuan Pang Lai-ping Zhong |
| author_facet | Zhi-hang Zhou Si-yuan Liang Tong-chao Zhao Xu-zhuo Chen Xian-kun Cao Ming Qi Ying-ying Huang Wu-tong Ju Meng Yang Dong-wang Zhu Yi-chuan Pang Lai-ping Zhong |
| author_sort | Zhi-hang Zhou |
| collection | DOAJ |
| description | Abstract Background 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 MnO2 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 MnO2 nanoshells that achieve tumor-specific and enhanced combination therapy for localized advanced cancer. However, the therapeutic effect of MnO2 nanoshells on metastatic cancer is still uncertain. Result Here, intelligent “theranostic” platforms were synthesized based on hollow mesoporous MnO2 (H-MnO2) nanoshells that were loaded with chemotherapy agents docetaxel and cisplatin (TP) to form H-MnO2-PEG/TP nanoshells, which were designed to alleviate tumor hypoxia, attenuate angiogenesis, trigger the dissolution of Mn2+, and synergize the efficacy of first-class anticancer chemotherapy. The obtained H-MnO2-PEG/TP nanoshells decomposed in the acidic TME, releasing the loaded drugs (TP) and simultaneously attenuated tumor hypoxia and hypoxia-inducible factor-1α (HIF-1α) expression by inducing endogenous tumor hydrogen peroxide (H2O2) 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-MnO2-PEG/TP group, while cell apoptosis was enhanced, and the expression of hypoxia-inducible factor-1α(HIF-1α) was down-regulated. In vivo experiments showed that tumor to normal organ uptake ratio (T/N ratio) of mice in H-MnO2-PEG/TP group was significantly higher than that in TP group alone (without the nanoparticle), and tumor growth was partially delayed. In the H-MnO2-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-1α expression was decreased, suggesting that the accumulation of MnO2 in the tumor caused the decomposition of H2O2 into O2 and alleviated the hypoxia of the tumor. Conclusion In conclusion, a remarkable in vivo and in vitro synergistic therapeutic effect is achieved through the combination of TP chemotherapy, which simultaneously triggered a series of antiangiogenic and oxidative antitumor reactions. Graphic abstract |
| first_indexed | 2024-04-13T08:26:44Z |
| format | Article |
| id | doaj.art-47ea400f354f4ebc91d7c160e0dfacf1 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-13T08:26:44Z |
| publishDate | 2021-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-47ea400f354f4ebc91d7c160e0dfacf12022-12-22T02:54:25ZengBMCJournal of Nanobiotechnology1477-31552021-05-0119111410.1186/s12951-021-00901-9Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinomaZhi-hang Zhou0Si-yuan Liang1Tong-chao Zhao2Xu-zhuo Chen3Xian-kun Cao4Ming Qi5Ying-ying Huang6Wu-tong Ju7Meng Yang8Dong-wang Zhu9Yi-chuan Pang10Lai-ping Zhong11Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineDepartment of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineDepartment of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineShanghai Key Laboratory of Stomatology, Shanghai Research Institute of Stomatology, National Clinical Research Center of StomatologyDepartment of Orthopaedics Surgery, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineKey Laboratory of Nuclear Physics and Ion-Beam Application (MOE), Fudan UniversityDepartment of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineDepartment of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineDepartment of Clinical Immunology, Ninth People’s Hospital, Shanghai Jiao Tong University School of MedicineDepartment of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineDepartment of Nuclear Medicine, Tenth People’s Hospital, Tongji University School of MedicineDepartment of Oral and Maxillofacial-Head and Neck Oncology, Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of MedicineAbstract Background 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 MnO2 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 MnO2 nanoshells that achieve tumor-specific and enhanced combination therapy for localized advanced cancer. However, the therapeutic effect of MnO2 nanoshells on metastatic cancer is still uncertain. Result Here, intelligent “theranostic” platforms were synthesized based on hollow mesoporous MnO2 (H-MnO2) nanoshells that were loaded with chemotherapy agents docetaxel and cisplatin (TP) to form H-MnO2-PEG/TP nanoshells, which were designed to alleviate tumor hypoxia, attenuate angiogenesis, trigger the dissolution of Mn2+, and synergize the efficacy of first-class anticancer chemotherapy. The obtained H-MnO2-PEG/TP nanoshells decomposed in the acidic TME, releasing the loaded drugs (TP) and simultaneously attenuated tumor hypoxia and hypoxia-inducible factor-1α (HIF-1α) expression by inducing endogenous tumor hydrogen peroxide (H2O2) 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-MnO2-PEG/TP group, while cell apoptosis was enhanced, and the expression of hypoxia-inducible factor-1α(HIF-1α) was down-regulated. In vivo experiments showed that tumor to normal organ uptake ratio (T/N ratio) of mice in H-MnO2-PEG/TP group was significantly higher than that in TP group alone (without the nanoparticle), and tumor growth was partially delayed. In the H-MnO2-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-1α expression was decreased, suggesting that the accumulation of MnO2 in the tumor caused the decomposition of H2O2 into O2 and alleviated the hypoxia of the tumor. Conclusion In conclusion, a remarkable in vivo and in vitro synergistic therapeutic effect is achieved through the combination of TP chemotherapy, which simultaneously triggered a series of antiangiogenic and oxidative antitumor reactions. Graphic abstracthttps://doi.org/10.1186/s12951-021-00901-9MnO2Tumor microenvironmentOral squamous cell carcinomaHypoxiaAngiogenesisChemotherapy |
| spellingShingle | Zhi-hang Zhou Si-yuan Liang Tong-chao Zhao Xu-zhuo Chen Xian-kun Cao Ming Qi Ying-ying Huang Wu-tong Ju Meng Yang Dong-wang Zhu Yi-chuan Pang Lai-ping Zhong Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma Journal of Nanobiotechnology MnO2 Tumor microenvironment Oral squamous cell carcinoma Hypoxia Angiogenesis Chemotherapy |
| title | Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma |
| title_full | Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma |
| title_fullStr | Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma |
| title_full_unstemmed | Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma |
| title_short | Overcoming chemotherapy resistance using pH-sensitive hollow MnO2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma |
| title_sort | overcoming chemotherapy resistance using ph sensitive hollow mno2 nanoshells that target the hypoxic tumor microenvironment of metastasized oral squamous cell carcinoma |
| topic | MnO2 Tumor microenvironment Oral squamous cell carcinoma Hypoxia Angiogenesis Chemotherapy |
| url | https://doi.org/10.1186/s12951-021-00901-9 |
| work_keys_str_mv | AT zhihangzhou overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT siyuanliang overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT tongchaozhao overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT xuzhuochen overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT xiankuncao overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT mingqi overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT yingyinghuang overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT wutongju overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT mengyang overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT dongwangzhu overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT yichuanpang overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma AT laipingzhong overcomingchemotherapyresistanceusingphsensitivehollowmno2nanoshellsthattargetthehypoxictumormicroenvironmentofmetastasizedoralsquamouscellcarcinoma |