Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly
Abstract Background Autophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinom...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-12-01
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| Series: | Journal of Nanobiotechnology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12951-021-01189-5 |
| _version_ | 1828109556824145920 |
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| author | Yesi Shi Gan Lin Huili Zheng Dan Mu Hu Chen Zhixiang Lu Pan He Yang Zhang Chao Liu Zhongning Lin Gang Liu |
| author_facet | Yesi Shi Gan Lin Huili Zheng Dan Mu Hu Chen Zhixiang Lu Pan He Yang Zhang Chao Liu Zhongning Lin Gang Liu |
| author_sort | Yesi Shi |
| collection | DOAJ |
| description | Abstract Background Autophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinoma (HCC). Therefore, a vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors. Results In this work, we developed a biomimetic nanoformulation (TH-NP) co-encapsulating Oxaliplatin (OXA)/hydroxychloroquine (HCQ, an autophagy inhibitor) to execute targeted autophagy inhibition, reduce tumor cell migration and invasion in vitro and attenuate metastasis in vivo. The tumor cell-specific ligand TRAIL was bioengineered to be stably expressed on HUVECs and the resultant membrane vesicles were wrapped on OXA/HCQ-loaded PLGA nanocores. Especially, TH-NPs could significantly improve OXA and HCQ effective concentration by approximately 21 and 13 times in tumor tissues compared to the free mixture of HCQ/OXA. Moreover, the tumor-targeting TH-NPs released HCQ alkalized the acidic lysosomes and inhibited the fusion of autophagosomes and lysosomes, leading to effective blockade of autophagic flux. In short, the system largely improved chemotherapeutic performance of OXA on subcutaneous and orthotopic HCC mice models. Importantly, TH-NPs also exhibited the most effective inhibition of tumor metastasis in orthotopic HCCLM3 models, and in the HepG2, Huh-7 or HCCLM3 metastatic mice models. Finally, we illustrated the enhanced metastasis inhibition was attributed to the blockade or reverse of the autophagy-mediated degradation of focal adhesions (FAs) including E-cadherin and paxillin. Conclusions TH-NPs can perform an enhanced chemotherapy and antimetastatic effect, and may represent a promising strategy for HCC therapy in clinics. Graphical Abstract |
| first_indexed | 2024-04-11T11:05:26Z |
| format | Article |
| id | doaj.art-960393ccc97c482499e5b31585411d85 |
| institution | Directory Open Access Journal |
| issn | 1477-3155 |
| language | English |
| last_indexed | 2024-04-11T11:05:26Z |
| publishDate | 2021-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Nanobiotechnology |
| spelling | doaj.art-960393ccc97c482499e5b31585411d852022-12-22T04:28:22ZengBMCJournal of Nanobiotechnology1477-31552021-12-0119111710.1186/s12951-021-01189-5Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassemblyYesi Shi0Gan Lin1Huili Zheng2Dan Mu3Hu Chen4Zhixiang Lu5Pan He6Yang Zhang7Chao Liu8Zhongning Lin9Gang Liu10State Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen UniversityState Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen UniversityDepartment of Anesthesiology, Zhongshan Hospital of Xiamen UniversityState Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen UniversityState Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen UniversityState Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen UniversityState Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen UniversityState Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen UniversityState Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen UniversityState Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen UniversityState Key Laboratory of Molecular Vaccinology and Molecular, Diagnostics & Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen UniversityAbstract Background Autophagy is a conserved catabolic process, which plays an important role in regulating tumor cell motility and degrading protein aggregates. Chemotherapy-induced autophagy may lead to tumor distant metastasis and even chemo-insensitivity in the therapy of hepatocellular carcinoma (HCC). Therefore, a vast majority of HCC cases do not produce a significant response to monotherapy with autophagy inhibitors. Results In this work, we developed a biomimetic nanoformulation (TH-NP) co-encapsulating Oxaliplatin (OXA)/hydroxychloroquine (HCQ, an autophagy inhibitor) to execute targeted autophagy inhibition, reduce tumor cell migration and invasion in vitro and attenuate metastasis in vivo. The tumor cell-specific ligand TRAIL was bioengineered to be stably expressed on HUVECs and the resultant membrane vesicles were wrapped on OXA/HCQ-loaded PLGA nanocores. Especially, TH-NPs could significantly improve OXA and HCQ effective concentration by approximately 21 and 13 times in tumor tissues compared to the free mixture of HCQ/OXA. Moreover, the tumor-targeting TH-NPs released HCQ alkalized the acidic lysosomes and inhibited the fusion of autophagosomes and lysosomes, leading to effective blockade of autophagic flux. In short, the system largely improved chemotherapeutic performance of OXA on subcutaneous and orthotopic HCC mice models. Importantly, TH-NPs also exhibited the most effective inhibition of tumor metastasis in orthotopic HCCLM3 models, and in the HepG2, Huh-7 or HCCLM3 metastatic mice models. Finally, we illustrated the enhanced metastasis inhibition was attributed to the blockade or reverse of the autophagy-mediated degradation of focal adhesions (FAs) including E-cadherin and paxillin. Conclusions TH-NPs can perform an enhanced chemotherapy and antimetastatic effect, and may represent a promising strategy for HCC therapy in clinics. Graphical Abstracthttps://doi.org/10.1186/s12951-021-01189-5BiomimeticTargeted co-deliveryAutophagy inhibitionFocal adhesionsMetastasis |
| spellingShingle | Yesi Shi Gan Lin Huili Zheng Dan Mu Hu Chen Zhixiang Lu Pan He Yang Zhang Chao Liu Zhongning Lin Gang Liu Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly Journal of Nanobiotechnology Biomimetic Targeted co-delivery Autophagy inhibition Focal adhesions Metastasis |
| title | Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly |
| title_full | Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly |
| title_fullStr | Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly |
| title_full_unstemmed | Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly |
| title_short | Biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly |
| title_sort | biomimetic nanoparticles blocking autophagy for enhanced chemotherapy and metastasis inhibition via reversing focal adhesion disassembly |
| topic | Biomimetic Targeted co-delivery Autophagy inhibition Focal adhesions Metastasis |
| url | https://doi.org/10.1186/s12951-021-01189-5 |
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