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, Jianguo Tao Department of Pathology and Laboratory Medicine University of Rochester Medical Center Rochester NY USA Search for other works by this author on: Oxford Academic Venkat Srinivasan Department of Chemistry University of Rochester Rochester NY USA Search for other works by this author on: Oxford Academic Xiangjiao Yi Department of Pathology and Laboratory Medicine University of Rochester Medical Center Rochester NY USA Search for other works by this author on: Oxford Academic Yingchun Zhao Masonic Cancer Center University of Minnesota Minneapolis MN USA Search for other works by this author on: Oxford Academic Hengwei Zhang Department of Pathology and Laboratory Medicine University of Rochester Medical Center Rochester NY USA Search for other works by this author on: Oxford Academic Xi Lin Department of Pathology and Laboratory Medicine University of Rochester Medical Center Rochester NY USA Search for other works by this author on: Oxford Academic Xichao Zhou Department of Pathology and Laboratory Medicine University of Rochester Medical Center Rochester NY USA Search for other works by this author on: Oxford Academic Brendan F Boyce Center for Musculoskeletal Research University of Rochester Medical Center Rochester NY USA Department of Pathology and Laboratory Medicine University of Rochester Medical Center Rochester NY USA Search for other works by this author on: Oxford Academic Peter W Villalta Masonic Cancer Center University of Minnesota Minneapolis MN USA Search for other works by this author on: Oxford Academic Frank H Ebetino BioVinc Pasadena CA USA Department of Chemistry University of Rochester Rochester NY USA Search for other works by this author on: Oxford Academic
https://orcid.org/0000-0002-3473-9212 , Koc Kan Ho Ionova Life Science Co., Ltd Shenzhen China Search for other works by this author on: Oxford Academic Robert K Boeckman, Jr Department of Chemistry University of Rochester Rochester NY USA Search for other works by this author on: Oxford Academic Lianping Xing Center for Musculoskeletal Research University of Rochester Medical Center Rochester NY USA Department of Pathology and Laboratory Medicine University of Rochester Medical Center Rochester NY USA Address correspondence to: Lianping Xing, PhD, Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. E‐mail: lianping_xing@urmc.rochester.edu Search for other works by this author on: Oxford Academic
Journal of Bone and Mineral Research, Volume 37, Issue 4, 1 April 2022, Pages 629–642, https://doi.org/10.1002/jbmr.4496
Published:
30 December 2021
Article history
Received:
01 October 2021
Revision received:
18 December 2021
Accepted:
21 December 2021
Published:
30 December 2021
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Jianguo Tao, Venkat Srinivasan, Xiangjiao Yi, Yingchun Zhao, Hengwei Zhang, Xi Lin, Xichao Zhou, Brendan F Boyce, Peter W Villalta, Frank H Ebetino, Koc Kan Ho, Robert K Boeckman, Lianping Xing, Bone‐Targeted Bortezomib Inhibits Bortezomib‐Resistant Multiple Myeloma in Mice by Providing Higher Levels of Bortezomib in Bone, Journal of Bone and Mineral Research, Volume 37, Issue 4, 1 April 2022, Pages 629–642, https://doi.org/10.1002/jbmr.4496
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ABSTRACT
Limited treatment options exist for cancer within the bone, as demonstrated by the inevitable, pernicious course of metastatic and blood cancers. The difficulty of eliminating bone‐residing cancer, especially drug‐resistant cancer, necessitates novel, alternative treatments to manipulate tumor cells and their microenvironment, with minimal off‐target effects. To this end, bone‐targeted conjugate (BP‐Btz) was generated by linking bortezomib (Btz, an anticancer, bone‐stimulatory drug) to a bisphosphonate (BP, a targeting ligand) through a cleavable linker that enables spatiotemporally controlled delivery of Btz to bone under acidic conditions for treating multiple myeloma (MM). Three conjugates with different linkers were developed and screened for best efficacy in mouse model of MM. Results demonstrated that the lead candidate BP‐Btz with optimal linker could overcome Btz resistance, reduced tumor burden, bone destruction, or tumor metastasis more effectively than BP or free Btz without thrombocytopenia and neurotoxicity in mice bearing myeloma. Furthermore, pharmaco*kinetic and pharmacodynamic studies showed that BP‐Btz bound to bone matrix, released Btz in acidic conditions, and had a higher local concentration and longer half‐life than Btz in bone. Our findings suggest the potential of bone‐targeted Btz conjugate as an efficacious Btz‐resistant MM treatment mechanism. © 2021 American Society for Bone and Mineral Research (ASBMR).
BONE TARGETING, BORTEZOMIB, MULTIPLE MYELOMA, BONE RESORPTION, BISPHOSPHONATES, DRUG RESISTANCE, SIDE EFFECTS
© 2021 American Society for Bone and Mineral Research (ASBMR).
This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)
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