Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma
Abstract Background Accumulation of malignant plasma cells in the bone marrow causes lytic bone lesions in 80% of multiple myeloma patients. Frequently fracturing, they are challenging to treat surgically. Myeloma cells surviving treatment in the presumably protective environment of bone lesions imp...
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2024-12-01
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| Series: | Journal of Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s13045-024-01636-4 |
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| author | Dirk Hose Seemun Ray Sina Rößler Ulrich Thormann Reinhard Schnettler Kim de Veirman Thaqif El Khassawna Christian Heiss Anne Hild Daniel Zahner Francisca Alagboso Anja Henss Susanne Beck Martina Emde-Rajaratnam Jürgen Burhenne Juliane Bamberger Eline Menu Elke de Bruyne Michael Gelinsky Marian Kampschulte Marcus Rohnke Sabine Wenisch Karin Vanderkerken Thomas Hanke Anja Seckinger Volker Alt |
| author_facet | Dirk Hose Seemun Ray Sina Rößler Ulrich Thormann Reinhard Schnettler Kim de Veirman Thaqif El Khassawna Christian Heiss Anne Hild Daniel Zahner Francisca Alagboso Anja Henss Susanne Beck Martina Emde-Rajaratnam Jürgen Burhenne Juliane Bamberger Eline Menu Elke de Bruyne Michael Gelinsky Marian Kampschulte Marcus Rohnke Sabine Wenisch Karin Vanderkerken Thomas Hanke Anja Seckinger Volker Alt |
| author_sort | Dirk Hose |
| collection | DOAJ |
| description | Abstract Background Accumulation of malignant plasma cells in the bone marrow causes lytic bone lesions in 80% of multiple myeloma patients. Frequently fracturing, they are challenging to treat surgically. Myeloma cells surviving treatment in the presumably protective environment of bone lesions impede their healing by continued impact on bone turnover and can explain regular progression of patients without detectable minimal residual disease (MRD). Locally applicable biomaterials could stabilize and foster healing of bone defects, simultaneously delivering anti-cancer compounds at systemically intolerable concentrations, overcoming drug resistance. Methods We developed silica-collagen xerogels (sicXer) and bortezomib-releasing silica-collagen xerogels (boXer) for local treatment of osteolytic bone disease and MRD. In vitro and in vivo (tissue sections) release of bortezomib was assessed by ultrahigh-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Material impact on bone formation was assessed in vitro regarding osteoclast/osteoblast numbers and activity. In vivo, drilling defects in a rat- and the 5T33-myeloma mouse model were treated by both materials and assessed by immunohistochemistry, UPLC-MS/MS, µCT, and ToF-SIMS. The material’s anti-myeloma activity was assessed using ten human myeloma cell lines (HMCLs) and eight primary myeloma cell samples including four patients refractory to systemic bortezomib treatment. Results sicXer and boXer show primary stability comparable to trabecular bone. Granule size and preparation method tailor degradation as indicated by release of the xerogel components (silica and collagen) and bortezomib into culture medium. In vitro, both materials reduce osteoclast activity and do not negatively interfere with osteoblast differentiation and function. The presumed resulting net bone formation with maintained basic remodeling properties was validated in vivo in a rat bone defect model, showing significantly enhanced bone formation for boXer compared to non-treated defects. Both materials induce myeloma cell apoptosis in all HMCLs and primary myeloma cell samples. In the 5T33-myeloma mouse model, both materials stabilized drilling defects and locally controlled malignant plasma cell growth. Conclusions The combination of stabilization of fracture-prone lesions, stimulation of bone healing, and anti-tumor effect suggest clinical testing of sicXer and boXer as part of a combined systemic/local treatment strategy in multiple myeloma and non-malignant diseases. |
| format | Article |
| id | doaj-art-33c78200635b4a1bb72c9c05f70ea87c |
| institution | Kabale University |
| issn | 1756-8722 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj-art-33c78200635b4a1bb72c9c05f70ea87c2025-01-26T12:48:50ZengBMCJournal of Hematology & Oncology1756-87222024-12-0117112010.1186/s13045-024-01636-4Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myelomaDirk Hose0Seemun Ray1Sina Rößler2Ulrich Thormann3Reinhard Schnettler4Kim de Veirman5Thaqif El Khassawna6Christian Heiss7Anne Hild8Daniel Zahner9Francisca Alagboso10Anja Henss11Susanne Beck12Martina Emde-Rajaratnam13Jürgen Burhenne14Juliane Bamberger15Eline Menu16Elke de Bruyne17Michael Gelinsky18Marian Kampschulte19Marcus Rohnke20Sabine Wenisch21Karin Vanderkerken22Thomas Hanke23Anja Seckinger24Volker Alt25Laboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit BrusselExperimentelle Unfallchirurgie (ForMED), Justus-Liebig-Universität GießenInstitut für Werkstoffwissenschaft, Max-Bergmann-Zentrum für Biomaterialien, Technische Universität DresdenExperimentelle Unfallchirurgie (ForMED), Justus-Liebig-Universität GießenJustus-Liebig-Universität GießenLaboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit BrusselExperimentelle Unfallchirurgie (ForMED), Justus-Liebig-Universität GießenExperimentelle Unfallchirurgie (ForMED), Justus-Liebig-Universität GießenKlinische Anatomie und Experimentelle Chirurgie C/O Institut für Veterinär-Anatomie, -Histologie und -Embryologie, Justus-Liebig-Universität GießenJustus-Liebig-Universität GießenExperimentelle Unfallchirurgie (ForMED), Justus-Liebig-Universität GießenI. Physikalisches Institut, Justus-Liebig-Universität GießenLaboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit BrusselLaboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit BrusselInnere Medizin IX - Abteilung für Klinische Pharmakologie und Pharmakoepidemiologie, Medizinische Fakultät/Universitätsklinikum HeidelbergLabor Für Experimentelle Radiologie, Justus-Liebig-Universität GießenLaboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit BrusselLaboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit BrusselZentrum für Translationale Knochen-, Gelenk- und Weichgewebeforschung, Technische Universität DresdenLabor Für Experimentelle Radiologie, Justus-Liebig-Universität GießenPhysikalisch-Chemisches Institut, Justus-Liebig-Universität GießenKlinische Anatomie und Experimentelle Chirurgie C/O Institut für Veterinär-Anatomie, -Histologie und -Embryologie, Justus-Liebig-Universität GießenLaboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit BrusselInstitut für Werkstoffwissenschaft, Max-Bergmann-Zentrum für Biomaterialien, Technische Universität DresdenLaboratory of Hematology and Immunology & Labor für Myelomforschung, Vrije Universiteit BrusselExperimentelle Unfallchirurgie (ForMED), Justus-Liebig-Universität GießenAbstract Background Accumulation of malignant plasma cells in the bone marrow causes lytic bone lesions in 80% of multiple myeloma patients. Frequently fracturing, they are challenging to treat surgically. Myeloma cells surviving treatment in the presumably protective environment of bone lesions impede their healing by continued impact on bone turnover and can explain regular progression of patients without detectable minimal residual disease (MRD). Locally applicable biomaterials could stabilize and foster healing of bone defects, simultaneously delivering anti-cancer compounds at systemically intolerable concentrations, overcoming drug resistance. Methods We developed silica-collagen xerogels (sicXer) and bortezomib-releasing silica-collagen xerogels (boXer) for local treatment of osteolytic bone disease and MRD. In vitro and in vivo (tissue sections) release of bortezomib was assessed by ultrahigh-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) and time-of-flight secondary ion mass spectrometry (ToF-SIMS). Material impact on bone formation was assessed in vitro regarding osteoclast/osteoblast numbers and activity. In vivo, drilling defects in a rat- and the 5T33-myeloma mouse model were treated by both materials and assessed by immunohistochemistry, UPLC-MS/MS, µCT, and ToF-SIMS. The material’s anti-myeloma activity was assessed using ten human myeloma cell lines (HMCLs) and eight primary myeloma cell samples including four patients refractory to systemic bortezomib treatment. Results sicXer and boXer show primary stability comparable to trabecular bone. Granule size and preparation method tailor degradation as indicated by release of the xerogel components (silica and collagen) and bortezomib into culture medium. In vitro, both materials reduce osteoclast activity and do not negatively interfere with osteoblast differentiation and function. The presumed resulting net bone formation with maintained basic remodeling properties was validated in vivo in a rat bone defect model, showing significantly enhanced bone formation for boXer compared to non-treated defects. Both materials induce myeloma cell apoptosis in all HMCLs and primary myeloma cell samples. In the 5T33-myeloma mouse model, both materials stabilized drilling defects and locally controlled malignant plasma cell growth. Conclusions The combination of stabilization of fracture-prone lesions, stimulation of bone healing, and anti-tumor effect suggest clinical testing of sicXer and boXer as part of a combined systemic/local treatment strategy in multiple myeloma and non-malignant diseases.https://doi.org/10.1186/s13045-024-01636-4Bone substitute materialBortezomibMultiple myelomaOsteolytic bone lesionsLocal treatmentMinimal residual disease |
| spellingShingle | Dirk Hose Seemun Ray Sina Rößler Ulrich Thormann Reinhard Schnettler Kim de Veirman Thaqif El Khassawna Christian Heiss Anne Hild Daniel Zahner Francisca Alagboso Anja Henss Susanne Beck Martina Emde-Rajaratnam Jürgen Burhenne Juliane Bamberger Eline Menu Elke de Bruyne Michael Gelinsky Marian Kampschulte Marcus Rohnke Sabine Wenisch Karin Vanderkerken Thomas Hanke Anja Seckinger Volker Alt Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma Journal of Hematology & Oncology Bone substitute material Bortezomib Multiple myeloma Osteolytic bone lesions Local treatment Minimal residual disease |
| title | Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma |
| title_full | Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma |
| title_fullStr | Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma |
| title_full_unstemmed | Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma |
| title_short | Bortezomib-releasing silica-collagen xerogels for local treatment of osteolytic bone- and minimal residual disease in multiple myeloma |
| title_sort | bortezomib releasing silica collagen xerogels for local treatment of osteolytic bone and minimal residual disease in multiple myeloma |
| topic | Bone substitute material Bortezomib Multiple myeloma Osteolytic bone lesions Local treatment Minimal residual disease |
| url | https://doi.org/10.1186/s13045-024-01636-4 |
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