Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy
Abstract PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sit...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-10-01
|
| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-024-01983-1 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850181433554894848 |
|---|---|
| author | Liuqing Yang Ye Yang Jing Zhang Minghui Li Long Yang Xing Wang Meifang Chen Hua Zhang Bing He Xueqing Wang Wenbing Dai Yiguang Wang Qiang Zhang |
| author_facet | Liuqing Yang Ye Yang Jing Zhang Minghui Li Long Yang Xing Wang Meifang Chen Hua Zhang Bing He Xueqing Wang Wenbing Dai Yiguang Wang Qiang Zhang |
| author_sort | Liuqing Yang |
| collection | DOAJ |
| description | Abstract PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sites. Herein, based on the ultra-pH-sensitive and enzyme-sensitive nanotechnology, a type of polymer PROTAC conjugated and pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following the construction of the PROTAC for Cyclin-dependent kinase 4 and 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds to many treatments even immune checkpoint blockades was selected as the tumor model in this study. As a result, PSRNs were found to maintain nanostructure (40 nm) in circulation and efficiently accumulated in tumors via enhanced permeation and retention effect. Then, they were dissociated into unimers (<10 nm) in response to an acidic tumor microenvironment, facilitating tumor penetration and cellular internalization. Eventually, the CDK4/6 degrading PROTACs were released intracellularly following the cleavage of cathepsin B. Importantly, PSRNs led to the enhanced degradation of target protein in vitro and in vivo. The degradation of CDK4/6 also augmented the efficacy of immune checkpoint blockades, through the upregulation of programmed cell death-ligand 1 (PD-L1) expression in cancer cells and the suppression of regulatory T cells cell proliferation in tumor microenvironment. By combination with α-PD-1, an enhanced anti-tumor outcome is well achieved in CT26 tumor model. Overall, our study verifies the significance of precise intracellular delivery of PROTACs and introduces a promising therapeutic strategy for the targeted combination treatment of CRC. |
| format | Article |
| id | doaj-art-e07d3e9cf4d94719a4f231ead56c7595 |
| institution | OA Journals |
| issn | 2059-3635 |
| language | English |
| publishDate | 2024-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-e07d3e9cf4d94719a4f231ead56c75952025-08-20T02:17:53ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352024-10-019111310.1038/s41392-024-01983-1Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapyLiuqing Yang0Ye Yang1Jing Zhang2Minghui Li3Long Yang4Xing Wang5Meifang Chen6Hua Zhang7Bing He8Xueqing Wang9Wenbing Dai10Yiguang Wang11Qiang Zhang12Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityBeijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems, State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking UniversityAbstract PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sites. Herein, based on the ultra-pH-sensitive and enzyme-sensitive nanotechnology, a type of polymer PROTAC conjugated and pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following the construction of the PROTAC for Cyclin-dependent kinase 4 and 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds to many treatments even immune checkpoint blockades was selected as the tumor model in this study. As a result, PSRNs were found to maintain nanostructure (40 nm) in circulation and efficiently accumulated in tumors via enhanced permeation and retention effect. Then, they were dissociated into unimers (<10 nm) in response to an acidic tumor microenvironment, facilitating tumor penetration and cellular internalization. Eventually, the CDK4/6 degrading PROTACs were released intracellularly following the cleavage of cathepsin B. Importantly, PSRNs led to the enhanced degradation of target protein in vitro and in vivo. The degradation of CDK4/6 also augmented the efficacy of immune checkpoint blockades, through the upregulation of programmed cell death-ligand 1 (PD-L1) expression in cancer cells and the suppression of regulatory T cells cell proliferation in tumor microenvironment. By combination with α-PD-1, an enhanced anti-tumor outcome is well achieved in CT26 tumor model. Overall, our study verifies the significance of precise intracellular delivery of PROTACs and introduces a promising therapeutic strategy for the targeted combination treatment of CRC.https://doi.org/10.1038/s41392-024-01983-1 |
| spellingShingle | Liuqing Yang Ye Yang Jing Zhang Minghui Li Long Yang Xing Wang Meifang Chen Hua Zhang Bing He Xueqing Wang Wenbing Dai Yiguang Wang Qiang Zhang Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy Signal Transduction and Targeted Therapy |
| title | Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy |
| title_full | Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy |
| title_fullStr | Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy |
| title_full_unstemmed | Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy |
| title_short | Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy |
| title_sort | sequential responsive nano protacs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy |
| url | https://doi.org/10.1038/s41392-024-01983-1 |
| work_keys_str_mv | AT liuqingyang sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT yeyang sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT jingzhang sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT minghuili sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT longyang sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT xingwang sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT meifangchen sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT huazhang sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT binghe sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT xueqingwang sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT wenbingdai sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT yiguangwang sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy AT qiangzhang sequentialresponsivenanoprotacsforpreciseintracellulardeliveryandenhanceddegradationefficacyincolorectalcancertherapy |