Gemcitabine–Ibandronate Conjugate Enables the Bone-Targeted Combination Therapy in Bone Cancer: Synthesis and Efficacy in Combination with Docetaxel,Bioconjugate Chemistry

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Gemcitabine–Ibandronate Conjugate Enables the Bone-Targeted Combination Therapy in Bone Cancer: Synthesis and Efficacy in Combination with Docetaxel
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2021-11-15 , DOI: 10.1021/acs.bioconjchem.1c00507
Kristen B Farrell ₁ , Shawn Zinnen ₁ , Douglas H Thamm ₂ , Alexander Karpeisky ₁

Affiliation

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.

中文翻译：

吉西他滨-伊班膦酸盐缀合物实现骨癌的骨靶向联合治疗：与多西紫杉醇联合的合成和疗效

患有癌症引起的骨病的患者，包括原发性骨癌，如骨肉瘤 (OS) 和其他起源组织的转移，存在高度未满足的医疗需求。我们提出了一种潜在的治疗方法，该方法建立在经过验证的骨靶向双膦酸盐缀合物平台上，具有已知的吉西他滨（GEM）和多西紫杉醇（DTX）的协同作用。提出了合理设计的 GEM-IB 的合成，即 GEM-5'-磷酸盐与伊班膦酸盐 (IB) 的缀合物。 GEM-IB 作为单一药物或与 DTX 联合使用，在小鼠 OS 模型中证明可以减少肿瘤负荷，保留骨结构，并提高生存率。这是骨靶向缀合物与第二种药物组合在骨室中产生有效药物比例的首次演示。

更新日期：2021-12-15

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