Gemcitabine-Ibandronate Conjugate Enables the Bone-Targeted Combination Therapy in Bone Cancer: Synthesis and Efficacy in Combination with Docetaxel.

Kristen B Farrell, Shawn Zinnen, Douglas H Thamm, Alexander Karpeisky

Bioconjugate chemistry 2021 Dec 15

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Patients with cancer-induced bone disease, including primary bone cancers such as osteosarcoma (OS) and metastases from other tissues of origin, present a high unmet medical need. We present a potential therapeutic approach built upon a proven bone-targeting bisphosphonate conjugate platform with the known synergies of gemcitabine (GEM) and docetaxel (DTX). The synthesis of rationally designed GEM-IB, the conjugate of GEM-5'-phosphate with ibandronate (IB), is presented. GEM-IB as a single agent or in combination with DTX demonstrated reduced tumor burden, preservation of the bone architecture, and improved the survival in a murine model of OS. This is the first demonstration of a bone-targeting conjugate in combination with a second drug to create effective drug ratios in the bone compartment.

Citation

Kristen B Farrell, Shawn Zinnen, Douglas H Thamm, Alexander Karpeisky. Gemcitabine-Ibandronate Conjugate Enables the Bone-Targeted Combination Therapy in Bone Cancer: Synthesis and Efficacy in Combination with Docetaxel. Bioconjugate chemistry. 2021 Dec 15;32(12):2530-2539