Bone-Targeted Bortezomib Inhibits Bortezomib-Resistant Multiple Myeloma in Mice by Providing Higher Levels of Bortezomib in Bone

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

Research output: Contribution to journalArticlepeer-review

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, pharmacokinetic 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.

Original languageEnglish (US)
Pages (from-to)629-642
Number of pages14
JournalJournal of Bone and Mineral Research
Volume37
Issue number4
DOIs
StatePublished - Apr 2022

Bibliographical note

Funding Information:
This work was supported by research grants from National Institute of Health USA PHS awards (AR069789, AG059775, AG049994) and Technology Development Fund of University of Rochester). XY was supported by the China Scholarship Council for 1‐year study at the University of Rochester. Some experiments were performed by the Center for Musculoskeletal Research Center cores (μCT) or using core equipment (frozen microtomes, microscopes, and whole slide imaging), which are supported by grants from the National Institutes of Health USA PHS awards (P30AR069655, 1S10RR027340‐01). Mass spectrometric analysis was performed in the Analytical Biochemistry Shared Resource of the University of Minnesota Masonic Cancer Center.

Funding Information:
This work was supported by research grants from National Institute of Health USA PHS awards (AR069789, AG059775, AG049994) and Technology Development Fund of University of Rochester). XY was supported by the China Scholarship Council for 1-year study at the University of Rochester. Some experiments were performed by the Center for Musculoskeletal Research Center cores (μCT) or using core equipment (frozen microtomes, microscopes, and whole slide imaging), which are supported by grants from the National Institutes of Health USA PHS awards (P30AR069655, 1S10RR027340-01). Mass spectrometric analysis was performed in the Analytical Biochemistry Shared Resource of the University of Minnesota Masonic Cancer Center. Authors’ roles: Study design: all authors. Study conduct: JT, VS, XY, YZ, HZ, XL, and XZ. Data collection: JT, VS, XY, YZ, HZ, XL, and XZ. Data analysis: JT, VS, XY, YZ, HZ, XL, and XZ. Data interpretation: JT, XY, YZ, HZ, XL, XZ, BFB, PWV, FHE, KKH, RKB, and LX. Drafting manuscript: JT and LX. Revising manuscript content: VS, BFB, YZ, PWV, FHE, KKH, and RKB. Approving final version of manuscript: all authors. LX takes responsibility for the integrity of the data analysis.

Publisher Copyright:
© 2021 American Society for Bone and Mineral Research (ASBMR).

Keywords

  • BISPHOSPHONATES
  • BONE RESORPTION
  • BONE TARGETING
  • BORTEZOMIB
  • DRUG RESISTANCE
  • MULTIPLE MYELOMA
  • SIDE EFFECTS
  • Bone and Bones/pathology
  • Multiple Myeloma/pathology
  • Bortezomib/pharmacology
  • Tumor Microenvironment
  • Drug Resistance, Neoplasm
  • Antineoplastic Agents/pharmacology
  • Animals
  • Cell Line, Tumor
  • Mice
  • Bone Neoplasms/drug therapy

PubMed: MeSH publication types

  • Journal Article

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