Targeting Bortezomib to Bone Increases Its Bone Anabolic Activity and Reduces Systemic Adverse Effects in Mice

Abstract

Bortezomib (Btz) is a proteasome inhibitor approved by the FDA to treat multiple myeloma. It also increases bone volume by promoting osteoblast differentiation and inhibiting osteoclastogenesis in mice. However, Btz has severe systemic adverse effects, which would limit its use as a bone anabolic agent. Here, we designed and synthesized a bone-targeted form of Btz by conjugating it to a bisphosphonate (BP) with no antiresorptive activity. We report that BP-Btz inhibited osteoclast formation and bone resorption and stimulated osteoblast differentiation in vitro similar to Btz. In vivo, BP-Btz increased bone volume more effectively than Btz in three mouse models: untreated wild-type mice, mice with ovariectomy, and aged mice with tibial factures. Importantly, BP-Btz had significantly less systemic side effects than Btz, including less thymic cell death, sympathetic nerve damage, and thrombocytopenia, and it improved survival rates in aged mice. Thus, BP-Btz represents a novel anabolic agent to treat conditions, such as postmenopausal and age-related bone loss. Bone targeting is an attractive approach to repurpose approved drugs to treat skeletal diseases. Research the BP-linker and Btz in a form of HBr. (C) Principle of bone-targeted Btz. (D) Molecular weight and molar doses of Btz and BP-Btz used in this study. Journal of Bone and Mineral Research n 344 WANG ET AL.Histology and histomorphometric analysis Legs, including femora and tibias, were fixed in 10% buffered formalin, decalcified in 10% EDTA, and embedded in paraffin for sectioning. Paraffin sections (4 μm) were stained with H&E for general histology or Alcian blue/hematoxylin (ABH) for cartilage and woven bone. Adjacent sections were also stained for TRAP Journal of Bone and Mineral Research TARGETING BORTEZOMIB TO BONE INCREASES ITS ANABOLIC ACTIVITY 345 n 51. Roelofs AJ, Stewart CA, Sun S, et al. Influence of bone affinity on the skeletal distribution of fluorescently labeled bisphosphonates in vivo. J Bone Miner Res. 2012;27(4):835-47. Journal of Bone and Mineral Research n 356 WANG ET AL.

Bisphosphonates for delivering drugs to bone

“…BP‐Btz more effectively reduced tumour burden and bone loss than Btz in the 5TGM1 mouse model of MM (Wang, Xiao et al, 2018). In particular, we also demonstrated that BP‐Btz generated significantly less systemic adverse effects, such as thrombocytopenia (Wang, Xiao, et al, 2018) and peripheral neuropathy (Wang et al, 2020), compared with Btz alone.…”

“…Although this topic has been covered recently in general reviews (Cole et al, 2016; Farrell et al, 2018; McKenna et al, 2020; Xing et al, 2020), in this article we assess the success of this approach to two areas of bone disease that continue to be unmet medical needs. Specifically, we review work in which bisphosphonates are chemically linked to drugs used clinically to treat multiple myeloma (Wang, Xiao, et al, 2018; Wang et al, 2020) or bone infections (osteomyelitis) (Sedghizadeh, Sun, et al, 2017) that have been used successfully as drug‐releasing conjugates in animal models of these diseases.…”

Development of Bisphosphonate-Conjugated Antibiotics to Overcome Pharmacodynamic Limitations of Local Therapy: Initial Results with Carbamate Linked Sitafloxacin and Tedizolid

“…The bone-binding affinity of a BP is predominantly determined by its two geminal phosphonate groups (P-C-P), which form strong bi- and tri-dentate interactions with calcium ions [ 41 , 42 ]. Several different types of bone-targeting drug conjugate candidates have been developed by linking them to BP (e.g., bortezomib [ 43 , 44 ]), and the subject has been extensively reviewed [ 45 , 46 ]. We have sought to create a bone-targeted antibiotic conjugate that could achieve sustained concentrations of drug well above the MBEC at the site of bone infection.…”

Osteocyte Vegf-a contributes to myeloma-associated angiogenesis and is regulated by Fgf23

“…In addition, targeted delivery of anti-tumor and anti-vascular therapies using bone and vascular-specific binding motifs are showing promising efficacy in translational studies. Indeed, bone-targeting bortezomib demonstrated improved efficacy in targeting MM as well as reduced side effects compared to conventional bortezomib [51][52][53] . As angiogenesis is a key step in MM progression and interactions between MM and ECs can confer drug resistance, a similar approach in designing and testing bone-targeting anti-angiogenic drugs may be beneficial for MM patients.…”