Nano‐Enabled Reposition of Proton Pump Inhibitors for TLR Inhibition: Toward A New Targeted Nanotherapy for Acute Lung Injury
Abstract Toll‐like receptor (TLR) activation in macrophages plays a critical role in the pathogenesis of acute lung injury (ALI). While TLR inhibition is a promising strategy to control the overwhelming inflammation in ALI, there still lacks effective TLR inhibitors for clinical uses to date. A uniq...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-01-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202104051 |
| _version_ | 1811191551263506432 |
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| author | Liya Sun Yuan Liu Xiali Liu Rui Wang Jiameng Gong Aabida Saferali Wei Gao Aying Ma Huiqiang Ma Stuart E. Turvey Shan‐Yu Fung Hong Yang |
| author_facet | Liya Sun Yuan Liu Xiali Liu Rui Wang Jiameng Gong Aabida Saferali Wei Gao Aying Ma Huiqiang Ma Stuart E. Turvey Shan‐Yu Fung Hong Yang |
| author_sort | Liya Sun |
| collection | DOAJ |
| description | Abstract Toll‐like receptor (TLR) activation in macrophages plays a critical role in the pathogenesis of acute lung injury (ALI). While TLR inhibition is a promising strategy to control the overwhelming inflammation in ALI, there still lacks effective TLR inhibitors for clinical uses to date. A unique class of peptide‐coated gold nanoparticles (GNPs) is previously discovered, which effectively inhibited TLR signaling and protected mice from lipopolysaccharide (LPS)‐induced ALI. To fast translate such a discovery into potential clinical applicable nanotherapeutics, herein an elegant strategy of “nano‐enabled drug repurposing” with “nano‐targeting” is introduced to empower the existing drugs for new uses. Combining transcriptome sequencing with Connectivity Map analysis, it is identified that the proton pump inhibitors (PPIs) share similar mechanisms of action to the discovered GNP‐based TLR inhibitor. It is confirmed that PPIs (including omeprazole) do inhibit endosomal TLR signaling and inflammatory responses in macrophages and human peripheral blood mononuclear cells, and exhibits anti‐inflammatory activity in an LPS‐induced ALI mouse model. The omeprazole is then formulated into a nanoform with liposomes to enhance its macrophage targeting ability and the therapeutic efficacy in vivo. This research provides a new translational strategy of nano‐enabled drug repurposing to translate bioactive nanoparticles into clinically used drugs and targeted nano‐therapeutics for ALI. |
| first_indexed | 2024-04-11T18:14:14Z |
| format | Article |
| id | doaj.art-65a4615acb474b07a65d622f6e2659be |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-11T18:14:14Z |
| publishDate | 2022-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-65a4615acb474b07a65d622f6e2659be2022-12-22T04:10:01ZengWileyAdvanced Science2198-38442022-01-0193n/an/a10.1002/advs.202104051Nano‐Enabled Reposition of Proton Pump Inhibitors for TLR Inhibition: Toward A New Targeted Nanotherapy for Acute Lung InjuryLiya Sun0Yuan Liu1Xiali Liu2Rui Wang3Jiameng Gong4Aabida Saferali5Wei Gao6Aying Ma7Huiqiang Ma8Stuart E. Turvey9Shan‐Yu Fung10Hong Yang11School of Biomedical Engineering The Province and Ministry Co‐Sponsored Collaborative Innovation Center for Medical Epigenetics Intensive Care Unit of the Second Hospital Tianjin Medical University No. 22 Qixiangtai Road, Heping District Tianjin 300070 ChinaSchool of Biomedical Engineering The Province and Ministry Co‐Sponsored Collaborative Innovation Center for Medical Epigenetics Intensive Care Unit of the Second Hospital Tianjin Medical University No. 22 Qixiangtai Road, Heping District Tianjin 300070 ChinaDepartment of Pulmonary and Critical Care Medicine Shanghai General Hospital Shanghai Jiao Tong University School of Medicine No. 650 Xinsongjiang Road Shanghai 201620 ChinaSchool of Biomedical Engineering The Province and Ministry Co‐Sponsored Collaborative Innovation Center for Medical Epigenetics Intensive Care Unit of the Second Hospital Tianjin Medical University No. 22 Qixiangtai Road, Heping District Tianjin 300070 ChinaSchool of Biomedical Engineering The Province and Ministry Co‐Sponsored Collaborative Innovation Center for Medical Epigenetics Intensive Care Unit of the Second Hospital Tianjin Medical University No. 22 Qixiangtai Road, Heping District Tianjin 300070 ChinaChanning Division of Network Medicine Brigham and Women's Hospital Harvard Medical School 181 Longwood Avenue Boston MA 02115 USADepartment of Pulmonary and Critical Care Medicine Shanghai General Hospital Shanghai Jiao Tong University School of Medicine No. 650 Xinsongjiang Road Shanghai 201620 ChinaDepartment of Pulmonary and Critical Care Medicine Shanghai General Hospital Shanghai Jiao Tong University School of Medicine No. 650 Xinsongjiang Road Shanghai 201620 ChinaSchool of Biomedical Engineering The Province and Ministry Co‐Sponsored Collaborative Innovation Center for Medical Epigenetics Intensive Care Unit of the Second Hospital Tianjin Medical University No. 22 Qixiangtai Road, Heping District Tianjin 300070 ChinaBC Children's Research Institute University of British Columbia 950 West 28th Avenue Vancouver BC V5Z 4H4 CanadaDepartment of Immunology Key Laboratory of Immune Microenvironment and Disease (Ministry of Education) The Province and Ministry Co‐Sponsored Collaborative Innovation Center for Medical Epigenetics School of Basic Medical Science Tianjin Medical University No. 22 Qixiangtai Road, Heping District Tianjin 300070 ChinaSchool of Biomedical Engineering The Province and Ministry Co‐Sponsored Collaborative Innovation Center for Medical Epigenetics Intensive Care Unit of the Second Hospital Tianjin Medical University No. 22 Qixiangtai Road, Heping District Tianjin 300070 ChinaAbstract Toll‐like receptor (TLR) activation in macrophages plays a critical role in the pathogenesis of acute lung injury (ALI). While TLR inhibition is a promising strategy to control the overwhelming inflammation in ALI, there still lacks effective TLR inhibitors for clinical uses to date. A unique class of peptide‐coated gold nanoparticles (GNPs) is previously discovered, which effectively inhibited TLR signaling and protected mice from lipopolysaccharide (LPS)‐induced ALI. To fast translate such a discovery into potential clinical applicable nanotherapeutics, herein an elegant strategy of “nano‐enabled drug repurposing” with “nano‐targeting” is introduced to empower the existing drugs for new uses. Combining transcriptome sequencing with Connectivity Map analysis, it is identified that the proton pump inhibitors (PPIs) share similar mechanisms of action to the discovered GNP‐based TLR inhibitor. It is confirmed that PPIs (including omeprazole) do inhibit endosomal TLR signaling and inflammatory responses in macrophages and human peripheral blood mononuclear cells, and exhibits anti‐inflammatory activity in an LPS‐induced ALI mouse model. The omeprazole is then formulated into a nanoform with liposomes to enhance its macrophage targeting ability and the therapeutic efficacy in vivo. This research provides a new translational strategy of nano‐enabled drug repurposing to translate bioactive nanoparticles into clinically used drugs and targeted nano‐therapeutics for ALI.https://doi.org/10.1002/advs.202104051acute lung injurybioactive nanoparticlesdrug repurposinginflammationmacrophagesproton pump inhibitors |
| spellingShingle | Liya Sun Yuan Liu Xiali Liu Rui Wang Jiameng Gong Aabida Saferali Wei Gao Aying Ma Huiqiang Ma Stuart E. Turvey Shan‐Yu Fung Hong Yang Nano‐Enabled Reposition of Proton Pump Inhibitors for TLR Inhibition: Toward A New Targeted Nanotherapy for Acute Lung Injury Advanced Science acute lung injury bioactive nanoparticles drug repurposing inflammation macrophages proton pump inhibitors |
| title | Nano‐Enabled Reposition of Proton Pump Inhibitors for TLR Inhibition: Toward A New Targeted Nanotherapy for Acute Lung Injury |
| title_full | Nano‐Enabled Reposition of Proton Pump Inhibitors for TLR Inhibition: Toward A New Targeted Nanotherapy for Acute Lung Injury |
| title_fullStr | Nano‐Enabled Reposition of Proton Pump Inhibitors for TLR Inhibition: Toward A New Targeted Nanotherapy for Acute Lung Injury |
| title_full_unstemmed | Nano‐Enabled Reposition of Proton Pump Inhibitors for TLR Inhibition: Toward A New Targeted Nanotherapy for Acute Lung Injury |
| title_short | Nano‐Enabled Reposition of Proton Pump Inhibitors for TLR Inhibition: Toward A New Targeted Nanotherapy for Acute Lung Injury |
| title_sort | nano enabled reposition of proton pump inhibitors for tlr inhibition toward a new targeted nanotherapy for acute lung injury |
| topic | acute lung injury bioactive nanoparticles drug repurposing inflammation macrophages proton pump inhibitors |
| url | https://doi.org/10.1002/advs.202104051 |
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