MBC Pharma Inc, 12635 E. Montview Blvd, Aurora, Colorado 80045, United States.
Flint Animal Cancer Center, Colorado State University, Fort Collins, Colorado 80523, United States.
Bioconjug Chem. 2021 Dec 15;32(12):2530-2539. doi: 10.1021/acs.bioconjchem.1c00507. Epub 2021 Nov 15.
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.
患有癌症骨病的患者，包括骨肉瘤（OS）等原发性骨癌和其他来源组织的转移，存在着未满足的巨大医疗需求。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之上，并具有吉西他滨（GEM）和多西他赛（DTX）的已知协同作用。本文介绍了合理设计的 GEM-IB 的合成，即 GEM-5'-磷酸与伊班膦酸盐（IB）的缀合物。GEM-IB 作为单一药物或与 DTX 联合使用，可减轻肿瘤负担，保持骨结构，并改善骨肉瘤小鼠模型的存活率。这是首次证明骨靶向缀合物与第二种药物联合使用，在骨腔内产生有效药物比例。
