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Pharmaceutics 2018, 10(3), 154; https://doi.org/10.3390/pharmaceutics10030154

Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice

1
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Box 626, 601 Elmwood Ave, Rochester, NY 14642, USA
2
Institute of Stomatology, Nanjing Medical University, Jiangsu Key Laboratory of Oral Diseases, Nanjing 210029, China
3
Department of Chemistry, University of Rochester, P.O. Box 270216, Rochester, NY 14627-0216, USA
4
Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14627-0216, USA
5
BioVinc, Pasadena, CA 91107, USA
6
Department of Cell Systems & Anatomy, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 3 August 2018 / Revised: 29 August 2018 / Accepted: 2 September 2018 / Published: 10 September 2018
(This article belongs to the Special Issue Bone Targeted Drug Delivery)
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Abstract

Multiple myeloma (MM) is the most common cancer affecting the bone and bone marrow and remains incurable for most patients; novel therapies are therefore needed. Bortezomib (Btz) is an FDA-approved drug for the treatment of patients with MM. However, its severe side effects require a dose reduction or the potential discontinuation of treatment. To overcome this limitation, we conjugated Btz to a bisphosphonate (BP) residue lacking anti-osteoclastic activity using a novel chemical linker and generated a new bone-targeted Btz-based (BP-Btz) proteasome inhibitor. We demonstrated that BP-Btz, but not Btz, bound to bone slices and inhibited the growth of MM cells in vitro. In a mouse model of MM, BP-Btz more effectively reduced tumor burden and bone loss with less systemic side effects than Btz. Thus, BP-Btz may represent a novel therapeutic approach to treat patients with MM. View Full-Text
Keywords: drug delivery; bortezomib; velcade; bone targeting; multiple myeloma drug delivery; bortezomib; velcade; bone targeting; multiple myeloma
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Wang, H.; Xiao, L.; Tao, J.; Srinivasan, V.; Boyce, B.F.; Ebetino, F.H.; Oyajobi, B.O.; Boeckman, R.K., Jr.; Xing, L. Synthesis of a Bone-Targeted Bortezomib with In Vivo Anti-Myeloma Effects in Mice. Pharmaceutics 2018, 10, 154.

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