In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy
Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with a survival rate of 3 to 6 mo for those with advanced disease despite great efforts to develop effective therapies. Thus, there is an urgent clinical need for innovative and more effe...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Proceedings of the National Academy of Sciences
2024
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| Online Access: | https://hdl.handle.net/1721.1/156885 |
| _version_ | 1811086706721423360 |
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| author | Guimarães, Pedro PG Figueroa-Espada, Christian G Riley, Rachel S Gong, Ningqiang Xue, Lulu Sewastianik, Tomasz Dennis, Peter S Loebel, Claudia Chung, Amanda Shepherd, Sarah J Haley, Rebecca M Hamilton, Alex G El-Mayta, Rakan Wang, Karin Langer, Robert Anderson, Daniel G Carrasco, Ruben D Mitchell, Michael J |
| author2 | Massachusetts Institute of Technology. Department of Chemical Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Chemical Engineering Guimarães, Pedro PG Figueroa-Espada, Christian G Riley, Rachel S Gong, Ningqiang Xue, Lulu Sewastianik, Tomasz Dennis, Peter S Loebel, Claudia Chung, Amanda Shepherd, Sarah J Haley, Rebecca M Hamilton, Alex G El-Mayta, Rakan Wang, Karin Langer, Robert Anderson, Daniel G Carrasco, Ruben D Mitchell, Michael J |
| author_sort | Guimarães, Pedro PG |
| collection | MIT |
| description | Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with a survival rate of 3 to 6 mo for those with advanced disease despite great efforts to develop effective therapies. Thus, there is an urgent clinical need for innovative and more effective MM therapeutics. Insights suggest that endothelial cells within the bone marrow microenvironment play a critical role. Specifically, cyclophilin A (CyPA), a homing factor secreted by bone marrow endothelial cells (BMECs), is critical to MM homing, progression, survival, and chemotherapeutic resistance. Thus, inhibition of CyPA provides a potential strategy to simultaneously inhibit MM progression and sensitize MM to chemotherapeutics, improving therapeutic response. However, inhibiting factors from the bone marrow endothelium remains challenging due to delivery barriers. Here, we utilize both RNA interference (RNAi) and lipid–polymer nanoparticles to engineer a potential MM therapy, which targets CyPA within blood vessels of the bone marrow. We used combinatorial chemistry and high-throughput in vivo screening methods to engineer a nanoparticle platform for small interfering RNA (siRNA) delivery to bone marrow endothelium. We demonstrate that our strategy inhibits CyPA in BMECs, preventing MM cell extravasation in vitro. Finally, we show that siRNA-based silencing of CyPA in a murine xenograft model of MM, either alone or in combination with the Food and Drug Administration (FDA)-approved MM therapeutic bortezomib, reduces tumor burden and extends survival. This nanoparticle platform may provide a broadly enabling technology to deliver nucleic acid therapeutics to other malignancies that home to bone marrow. |
| first_indexed | 2024-09-23T13:31:33Z |
| format | Article |
| id | mit-1721.1/156885 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:31:33Z |
| publishDate | 2024 |
| publisher | Proceedings of the National Academy of Sciences |
| record_format | dspace |
| spelling | mit-1721.1/1568852024-09-18T03:30:52Z In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy Guimarães, Pedro PG Figueroa-Espada, Christian G Riley, Rachel S Gong, Ningqiang Xue, Lulu Sewastianik, Tomasz Dennis, Peter S Loebel, Claudia Chung, Amanda Shepherd, Sarah J Haley, Rebecca M Hamilton, Alex G El-Mayta, Rakan Wang, Karin Langer, Robert Anderson, Daniel G Carrasco, Ruben D Mitchell, Michael J Massachusetts Institute of Technology. Department of Chemical Engineering Koch Institute for Integrative Cancer Research at MIT Massachusetts Institute of Technology. Institute for Medical Engineering & Science Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with a survival rate of 3 to 6 mo for those with advanced disease despite great efforts to develop effective therapies. Thus, there is an urgent clinical need for innovative and more effective MM therapeutics. Insights suggest that endothelial cells within the bone marrow microenvironment play a critical role. Specifically, cyclophilin A (CyPA), a homing factor secreted by bone marrow endothelial cells (BMECs), is critical to MM homing, progression, survival, and chemotherapeutic resistance. Thus, inhibition of CyPA provides a potential strategy to simultaneously inhibit MM progression and sensitize MM to chemotherapeutics, improving therapeutic response. However, inhibiting factors from the bone marrow endothelium remains challenging due to delivery barriers. Here, we utilize both RNA interference (RNAi) and lipid–polymer nanoparticles to engineer a potential MM therapy, which targets CyPA within blood vessels of the bone marrow. We used combinatorial chemistry and high-throughput in vivo screening methods to engineer a nanoparticle platform for small interfering RNA (siRNA) delivery to bone marrow endothelium. We demonstrate that our strategy inhibits CyPA in BMECs, preventing MM cell extravasation in vitro. Finally, we show that siRNA-based silencing of CyPA in a murine xenograft model of MM, either alone or in combination with the Food and Drug Administration (FDA)-approved MM therapeutic bortezomib, reduces tumor burden and extends survival. This nanoparticle platform may provide a broadly enabling technology to deliver nucleic acid therapeutics to other malignancies that home to bone marrow. 2024-09-17T17:23:35Z 2024-09-17T17:23:35Z 2023-06-20 2024-09-17T17:15:20Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/156885 Guimarães, Pedro PG, Figueroa-Espada, Christian G, Riley, Rachel S, Gong, Ningqiang, Xue, Lulu et al. 2023. "In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy." Proceedings of the National Academy of Sciences, 120 (25). en 10.1073/pnas.2215711120 Proceedings of the National Academy of Sciences Creative Commons Attribution-NonCommercial-NoDerivs License https://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Proceedings of the National Academy of Sciences Proceedings of the National Academy of Sciences |
| spellingShingle | Guimarães, Pedro PG Figueroa-Espada, Christian G Riley, Rachel S Gong, Ningqiang Xue, Lulu Sewastianik, Tomasz Dennis, Peter S Loebel, Claudia Chung, Amanda Shepherd, Sarah J Haley, Rebecca M Hamilton, Alex G El-Mayta, Rakan Wang, Karin Langer, Robert Anderson, Daniel G Carrasco, Ruben D Mitchell, Michael J In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy |
| title | In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy |
| title_full | In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy |
| title_fullStr | In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy |
| title_full_unstemmed | In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy |
| title_short | In vivo bone marrow microenvironment siRNA delivery using lipid–polymer nanoparticles for multiple myeloma therapy |
| title_sort | in vivo bone marrow microenvironment sirna delivery using lipid polymer nanoparticles for multiple myeloma therapy |
| url | https://hdl.handle.net/1721.1/156885 |
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