叶酸靶向药物偶联物EC140的多位点偶联和延长递送。

IF 4 2区 化学 Q1 BIOCHEMICAL RESEARCH METHODS
Yan Zheng, Hong Cheng, Sibo Jiang, Wanyi Tai
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引用次数: 0

摘要

小分子药物偶联(SMDC)是一种与抗体药物偶联并行发展的靶向给药技术。然而,由于其体内循环半衰期有限,SMDC的临床翻译面临挑战。药代动力学的缺点是限制了SMDC在肿瘤组织中的暴露时间,最终降低了治疗效果。在这项研究中,我们在多个位点将叶酸靶向的SMDC EC140化学偶联到长循环的Fc蛋白上,产生了一个稳定的高dar Fc-SMDC偶联物(Fc-EC140)。Fc-EC140每个Fc蛋白可携带约4个EC140分子(药抗体比为4.1),与SMDC比较物相比,在叶酸受体(FR)阳性肿瘤细胞中表现出更强的效力。此外,Fc-EC140保留了fcrn介导的再循环功能,并在小鼠中显示出延长的28小时半衰期。体内抗肿瘤实验表明,15 mg/kg剂量的Fc-EC140 (Q7D × 3)静脉注射几乎治愈了KB肿瘤,远比同等剂量的对照EC140有效。本研究提出了一种新的SMDC靶向递送策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Fc Multisite Conjugation and Prolonged Delivery of the Folate-Targeted Drug Conjugate EC140.

Small molecule-drug conjugate (SMDC) is a targeted drug delivery technology that develops in parallel with the antibody-drug conjugate. However, the clinical translation of SMDC faces challenges due to its limited circulating half-life in vivo. The drawback in pharmacokinetics is that it restricts the exposure time of SMDC to tumor tissues and ultimately reduces the therapeutic efficacy. In this study, we chemically conjugated a folate-targeted SMDC EC140 to the long-circulating Fc protein at multiple sites, yielding a stable and high-DAR Fc-SMDC conjugate (Fc-EC140). Fc-EC140 can bear approximately 4 molecules of EC140 per Fc protein (drug-antibody ratio = 4.1) and display enhanced potency in folate receptor (FR)-positive tumor cells compared to the SMDC comparator. In addition, Fc-EC140 retains the FcRn-mediated recycling function and displays an extended half-life of 28 h in the mice. In vivo, antitumor experiments demonstrate that intravenous administration of Fc-EC140 (Q7D × 3 at a dose of 15 mg/kg) nearly cures the KB tumors, which is far more effective than the comparator EC140 administrated at equivalent doses. This study presents a new strategy for the targeted delivery of SMDC.

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来源期刊
Bioconjugate Chemistry
Bioconjugate Chemistry 生物-化学综合
CiteScore
9.00
自引率
2.10%
发文量
236
审稿时长
1.4 months
期刊介绍: Bioconjugate Chemistry invites original contributions on all research at the interface between man-made and biological materials. The mission of the journal is to communicate to advances in fields including therapeutic delivery, imaging, bionanotechnology, and synthetic biology. Bioconjugate Chemistry is intended to provide a forum for presentation of research relevant to all aspects of bioconjugates, including the preparation, properties and applications of biomolecular conjugates.
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