Medical Isotopes Research Center and Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, P. R. China.
Key Laboratory of Protein and Peptide Pharmaceuticals, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, P. R. China.
Theranostics. 2019 Jan 24;9(3):747-760. doi: 10.7150/thno.29989. eCollection 2019.
Doxorubicin (DOX) has been clinically used as a broad-spectrum chemotherapeutic agent for decades, but its clinical application is hindered by the lack of tumour specificity, severe cardiotoxicity and haematotoxicity. Pre-targeted strategies are highly tumour-specific, therapeutic approaches. Herein, a novel pre-targeted system was constructed, aiming to enhance anticancer efficacy of DOX and maximally reduce its side effects. The DOX prodrug (bDOX) was first synthesized by conjugating DOX with mini-PEGylated (mPEGylated) biotin through a pH-sensitive bond. During the pre-targeted treatment, avidin was first administrated. After an optimized interval, bDOX was second administrated. The nontoxic prodrug bDOX was eventually transformed into the toxic anticancer form (DOX) by a pH-triggered cleavage specifically in tumour cells. The drug efficacy and side effect of the two-step, pre-targeted treatment were fully compared with free DOX and . The prodrug bDOX was quite stable under neutral conditions and nearly nontoxic, but was immediately transformed into the toxic anticancer form (DOX) under acidic conditions. Compared to free DOX, the pre-targeted bDOX exhibited a higher cellular uptake by human colorectal tumour cells (LS180 and HT-29 cells). evaluation performed on LS180 xenograft animal model demonstrated that the pre-targeted bDOX achieved a much more significant tumour inhibition than free DOX. The largely decreased, unwanted bystander toxicity was demonstrated by changes in body weight, cardiomyocyte apoptosis, blood routine examination and splenic pathological changes. The high therapeutic efficacy, together with the minimal side effects, of this easily synthesized, pre-targeted system exhibited immense potentiality for the clinical application of DOX delivery.
阿霉素（DOX）作为一种广谱化疗药物已在临床上应用数十年，但由于缺乏肿瘤特异性、严重的心毒性和血液毒性，其临床应用受到限制。前靶向策略是一种高度肿瘤特异性的治疗方法。本文构建了一种新型前靶向系统，旨在提高 DOX 的抗癌疗效，并最大限度地降低其副作用。首先通过 pH 敏感键将 DOX 与聚乙二醇化（mPEGylated）生物素偶联合成 DOX 前药（bDOX）。在前靶向治疗中，首先给予亲和素。经过优化的间隔后，第二次给予 bDOX。无毒前药 bDOX 最终在肿瘤细胞中通过 pH 触发的特异性裂解转化为毒性抗癌形式（DOX）。两步前靶向治疗的药效和副作用与游离 DOX 和 进行了充分比较。在中性条件下，前药 bDOX 相当稳定且几乎无毒，但在酸性条件下立即转化为毒性抗癌形式（DOX）。与游离 DOX 相比，前体药物 bDOX 对人结直肠肿瘤细胞（LS180 和 HT-29 细胞）的细胞摄取率更高。在 LS180 异种移植动物模型上进行的评估表明，前体药物 bDOX 比游离 DOX 实现了更显著的肿瘤抑制作用。体重变化、心肌细胞凋亡、血常规检查和脾脏病理变化证明了不必要的旁观者毒性大大降低。这种易于合成的前靶向系统具有高效的治疗效果和最小的副作用，为 DOX 传递的临床应用展示了巨大的潜力。
