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

Hua Wang; Lifeng Xiao; Jianguo Tao; Venkat Srinivasan; Brendan F Boyce; Frank H Ebetino; Babatunde O Oyajobi; Robert K Boeckman Jr; Lianping Xing

doi:10.3390/pharmaceutics10030154

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

Pharmaceutics. 2018 Sep 10;10(3):154. doi: 10.3390/pharmaceutics10030154.

Authors

Hua Wang^{1

2}, Lifeng Xiao³, Jianguo Tao⁴, Venkat Srinivasan⁵, Brendan F Boyce^{6

7}, Frank H Ebetino^{8

9}, Babatunde O Oyajobi¹⁰, Robert K Boeckman Jr¹¹, Lianping Xing^{12

13}

Affiliations

¹ Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Box 626, 601 Elmwood Ave, Rochester, NY 14642, USA. [email protected].
² Institute of Stomatology, Nanjing Medical University, Jiangsu Key Laboratory of Oral Diseases, Nanjing 210029, China. [email protected].
³ Department of Chemistry, University of Rochester, P.O. Box 270216, Rochester, NY 14627-0216, USA. [email protected].
⁴ Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Box 626, 601 Elmwood Ave, Rochester, NY 14642, USA. [email protected].
⁵ Department of Chemistry, University of Rochester, P.O. Box 270216, Rochester, NY 14627-0216, USA. [email protected].
⁶ Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Box 626, 601 Elmwood Ave, Rochester, NY 14642, USA. [email protected].
⁷ Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14627-0216, USA. [email protected].
⁸ Department of Chemistry, University of Rochester, P.O. Box 270216, Rochester, NY 14627-0216, USA. [email protected].
⁹ BioVinc, Pasadena, CA 91107, USA. [email protected].
¹⁰ Department of Cell Systems & Anatomy, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA. [email protected].
¹¹ Department of Chemistry, University of Rochester, P.O. Box 270216, Rochester, NY 14627-0216, USA. [email protected].
¹² Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Box 626, 601 Elmwood Ave, Rochester, NY 14642, USA. [email protected].
¹³ Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14627-0216, USA. [email protected].

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.

Keywords: bone targeting; bortezomib; drug delivery; multiple myeloma; velcade.

Abstract

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