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Published on: May 1, 2015
Bone-Targeted Bortezomib Inhibits Bortezomib-Resistant Multiple Myeloma in Mice by Providing Higher Levels of
Jianguo Tao1, Venkat Srinivasan2, Xiangjiao Yi1
1Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
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. © 2021 American Society for Bone and Mineral Research (ASBMR).
Insights
A novel bone-targeted conjugate (BP-Btz) effectively treats bortezomib-resistant multiple myeloma (MM) by delivering the drug specifically to bone tumors. This targeted approach reduces tumor burden and bone destruction with minimal side effects.
Area of Science:
- Oncology
- Pharmacology
- Biomedical Engineering
Background:
- Bone cancers, including multiple myeloma (MM), have limited treatment options due to inherent drug resistance and the challenges of targeting bone microenvironments.
- Existing treatments often lack specificity, leading to off-target effects and incomplete eradication of bone-residing tumors.
Purpose of the Study:
- To develop and evaluate a novel bone-targeted conjugate (BP-Btz) for treating bortezomib-resistant multiple myeloma (MM).
- To assess the efficacy, pharmacokinetics, and pharmacodynamics of BP-Btz in a preclinical mouse model of MM.
Main Methods:
- Generated bone-targeted conjugates (BP-Btz) by linking bortezomib (Btz) to a bisphosphonate (BP) via a cleavable linker.
- Screened three different linker designs for optimal efficacy in a mouse model of MM.
- Conducted pharmacokinetic and pharmacodynamic studies to evaluate drug distribution, release kinetics, and local concentration in bone.
Main Results:
- The lead BP-Btz conjugate demonstrated superior efficacy in reducing tumor burden, bone destruction, and metastasis compared to free bortezomib or bisphosphonate alone.
- BP-Btz successfully overcame bortezomib resistance in the MM mouse model.
- The conjugate exhibited favorable safety profiles, notably avoiding thrombocytopenia and neurotoxicity observed with free bortezomib.
Conclusions:
- Bone-targeted bortezomib conjugates represent a promising strategy for treating bortezomib-resistant multiple myeloma.
- Spatiotemporally controlled drug delivery via BP-Btz enhances therapeutic efficacy and minimizes systemic toxicity.
- This approach offers a potential new mechanism for managing challenging bone cancers.
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