BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma
Abstract Bortezomib (BTZ) is a standard-of-care treatment in multiple myeloma (MM); however, adverse side effects and development of resistance limit its long term benefit. To improve target specificity, therapeutic efficacy, and overcome resistance, we designed nanoparticles that encapsulate BTZ an...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-12-01
|
| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-023-00955-y |
| _version_ | 1797388548454744064 |
|---|---|
| author | Debasmita Dutta Jiye Liu Kenneth Wen Keiji Kurata Mariateresa Fulciniti Annamaria Gulla Teru Hideshima Kenneth C. Anderson |
| author_facet | Debasmita Dutta Jiye Liu Kenneth Wen Keiji Kurata Mariateresa Fulciniti Annamaria Gulla Teru Hideshima Kenneth C. Anderson |
| author_sort | Debasmita Dutta |
| collection | DOAJ |
| description | Abstract Bortezomib (BTZ) is a standard-of-care treatment in multiple myeloma (MM); however, adverse side effects and development of resistance limit its long term benefit. To improve target specificity, therapeutic efficacy, and overcome resistance, we designed nanoparticles that encapsulate BTZ and are surface-functionalized with BCMA antibodies (BCMA-BTZ-NPs). We confirmed efficient cellular internalization of the BCMA-BTZ-NPs only in BCMA-expressing MM cells, but not in BCMA-knockout (KO) cells. In addition, BCMA-BTZ-NPs showed target-specific cytotoxicity against MM cell lines and primary tumor cells from MM patients. The BCMA-BTZ-NPs entered the cell through receptor-mediated uptake, which escapes a mechanism of BTZ resistance based on upregulating P-glycoprotein. Furthermore, BCMA-BTZ-NPs induced cell death more efficiently than non-targeted nanoparticles or free BTZ, triggering potent mitochondrial depolarization followed by apoptosis. In BTZ-resistant cells, BCMA-BTZ-NPs inhibited proteasome activity more effectively than free BTZ or non-targeted nanoparticles. Additionally, BCMA-BTZ-NPs enhanced immunogenic cell death and activated the autophagic pathway more than free BTZ. Finally, we found that BCMA-BTZ-NPs selectively accumulated at the tumor site in a murine xenograft model, enhanced tumor reduction, and prolonged host survival. These results suggest BCMA-BTZ-NPs provide a promising therapeutic strategy for enhancing the efficacy of BTZ and establish a framework for their evaluation in a clinical setting. |
| first_indexed | 2024-03-08T22:41:26Z |
| format | Article |
| id | doaj.art-7d50b6f504af47028426c84f41e90866 |
| institution | Directory Open Access Journal |
| issn | 2044-5385 |
| language | English |
| last_indexed | 2024-03-08T22:41:26Z |
| publishDate | 2023-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj.art-7d50b6f504af47028426c84f41e908662023-12-17T12:07:34ZengNature Publishing GroupBlood Cancer Journal2044-53852023-12-0113111310.1038/s41408-023-00955-yBCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myelomaDebasmita Dutta0Jiye Liu1Kenneth Wen2Keiji Kurata3Mariateresa Fulciniti4Annamaria Gulla5Teru Hideshima6Kenneth C. Anderson7Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolAbstract Bortezomib (BTZ) is a standard-of-care treatment in multiple myeloma (MM); however, adverse side effects and development of resistance limit its long term benefit. To improve target specificity, therapeutic efficacy, and overcome resistance, we designed nanoparticles that encapsulate BTZ and are surface-functionalized with BCMA antibodies (BCMA-BTZ-NPs). We confirmed efficient cellular internalization of the BCMA-BTZ-NPs only in BCMA-expressing MM cells, but not in BCMA-knockout (KO) cells. In addition, BCMA-BTZ-NPs showed target-specific cytotoxicity against MM cell lines and primary tumor cells from MM patients. The BCMA-BTZ-NPs entered the cell through receptor-mediated uptake, which escapes a mechanism of BTZ resistance based on upregulating P-glycoprotein. Furthermore, BCMA-BTZ-NPs induced cell death more efficiently than non-targeted nanoparticles or free BTZ, triggering potent mitochondrial depolarization followed by apoptosis. In BTZ-resistant cells, BCMA-BTZ-NPs inhibited proteasome activity more effectively than free BTZ or non-targeted nanoparticles. Additionally, BCMA-BTZ-NPs enhanced immunogenic cell death and activated the autophagic pathway more than free BTZ. Finally, we found that BCMA-BTZ-NPs selectively accumulated at the tumor site in a murine xenograft model, enhanced tumor reduction, and prolonged host survival. These results suggest BCMA-BTZ-NPs provide a promising therapeutic strategy for enhancing the efficacy of BTZ and establish a framework for their evaluation in a clinical setting.https://doi.org/10.1038/s41408-023-00955-y |
| spellingShingle | Debasmita Dutta Jiye Liu Kenneth Wen Keiji Kurata Mariateresa Fulciniti Annamaria Gulla Teru Hideshima Kenneth C. Anderson BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma Blood Cancer Journal |
| title | BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma |
| title_full | BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma |
| title_fullStr | BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma |
| title_full_unstemmed | BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma |
| title_short | BCMA-targeted bortezomib nanotherapy improves therapeutic efficacy, overcomes resistance, and modulates the immune microenvironment in multiple myeloma |
| title_sort | bcma targeted bortezomib nanotherapy improves therapeutic efficacy overcomes resistance and modulates the immune microenvironment in multiple myeloma |
| url | https://doi.org/10.1038/s41408-023-00955-y |
| work_keys_str_mv | AT debasmitadutta bcmatargetedbortezomibnanotherapyimprovestherapeuticefficacyovercomesresistanceandmodulatestheimmunemicroenvironmentinmultiplemyeloma AT jiyeliu bcmatargetedbortezomibnanotherapyimprovestherapeuticefficacyovercomesresistanceandmodulatestheimmunemicroenvironmentinmultiplemyeloma AT kennethwen bcmatargetedbortezomibnanotherapyimprovestherapeuticefficacyovercomesresistanceandmodulatestheimmunemicroenvironmentinmultiplemyeloma AT keijikurata bcmatargetedbortezomibnanotherapyimprovestherapeuticefficacyovercomesresistanceandmodulatestheimmunemicroenvironmentinmultiplemyeloma AT mariateresafulciniti bcmatargetedbortezomibnanotherapyimprovestherapeuticefficacyovercomesresistanceandmodulatestheimmunemicroenvironmentinmultiplemyeloma AT annamariagulla bcmatargetedbortezomibnanotherapyimprovestherapeuticefficacyovercomesresistanceandmodulatestheimmunemicroenvironmentinmultiplemyeloma AT teruhideshima bcmatargetedbortezomibnanotherapyimprovestherapeuticefficacyovercomesresistanceandmodulatestheimmunemicroenvironmentinmultiplemyeloma AT kennethcanderson bcmatargetedbortezomibnanotherapyimprovestherapeuticefficacyovercomesresistanceandmodulatestheimmunemicroenvironmentinmultiplemyeloma |