State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China.
Bioorg Med Chem. 2011 Jun 15;19(12):3750-6. doi: 10.1016/j.bmc.2011.05.004. Epub 2011 May 8.
Bone tumor is a notoriously difficult disease to manage, requiring frequent and heavy doses of systemically administered chemotherapy. Targeting anticancer drug to the bone after systemic administration may provide both greater efficacy of treatment and less frequent administration. In this paper, a series of bone targeting Asp oligopeptides 5-fluorouracil conjugates have been synthesized in a convergent approach and well characterized by NMR and MS techniques. Their hydroxyapatite (HAP) affinity, drug release and cytotoxicity characteristics were evaluated in in vitro conditions. All the prodrugs were water soluble and exhibited high affinity to HAP .The efficient release of the active drug moiety occurring by the cleavage of different linkage in physiological conditions significantly reduced the number of viable human cancer cells. From in vivo distribution, we get these compounds with high bone-selectivity and long halflife. These results provided an effective entry to the development of new bone targeting chemotherapeutic drugs.
骨肿瘤是一种难以治疗的疾病，需要频繁且大剂量地进行全身性化疗。在全身性给药后将抗癌药物靶向到骨中，可能会提高治疗效果，并减少给药频率。在本文中，我们采用收敛方法合成了一系列骨靶向 Asp 寡肽 5-氟尿嘧啶缀合物，并通过 NMR 和 MS 技术对其进行了很好的表征。在体外条件下评估了它们的羟基磷灰石 (HAP) 亲和力、药物释放和细胞毒性特征。所有前药均溶于水，并表现出对 HAP 的高亲和力。在生理条件下通过不同键的断裂可有效释放活性药物部分，从而显著降低了人类癌细胞的存活率。从体内分布来看，这些化合物具有高骨选择性和长半衰期。这些结果为开发新型骨靶向化疗药物提供了有效途径。
