长循环双靶向重组蛋白药物偶联体用于抗肿瘤治疗

袁洋; 蒋惠忆; 陈伟芝; 蒋锡群

doi:10.11777/j.issn1000-3304.2024.24189

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长循环双靶向重组蛋白药物偶联体用于抗肿瘤治疗

研究论文 | 更新时间：2025-01-24

- 长循环双靶向重组蛋白药物偶联体用于抗肿瘤治疗
- Long-circulated Dual-targeted Recombinant Protein Drug Conjugates for Antitumor Therapy
- 高分子学报 2025年56卷第2期页码：266-277
- 作者机构：
  
  南京大学化学化工学院高性能高分子材料与技术教育部重点实验室南京 210023
- 作者简介：
  
  E-mail: chenwz@nju.edu.cn;
  E-mail: ; jiangx@nju.edu.cn
- 基金信息：
  
  国家自然科学基金(基金号 ┣92163214;52333003);52373288┫;江苏省自然科学基金(基金号 BK20202002);中央高校基本科研业务费专项资金(基金号 020514380274)
- DOI：10.11777/j.issn1000-3304.2024.24189
  中图分类号：
- CSTR：32057.14.GFZXB.2024.7291
- 纸质出版日期：2025-02-20，
  
  网络出版日期：2024-11-27，
  
  收稿日期：2024-06-30，
  
  录用日期：2024-08-16
- 稿件说明：
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袁洋, 蒋惠忆, 陈伟芝, 蒋锡群. 长循环双靶向重组蛋白药物偶联体用于抗肿瘤治疗[J]. 高分子学报, 2025,56(2):266-277.

YANG YUAN, HUI-YI JIANG, WEI-ZHI CHEN, XI-QUN JIANG. Long-circulated Dual-targeted Recombinant Protein Drug Conjugates for Antitumor Therapy. [J]. Acta polymerica sinica, 2025, 56(2): 266-277.
袁洋, 蒋惠忆, 陈伟芝, 蒋锡群. 长循环双靶向重组蛋白药物偶联体用于抗肿瘤治疗[J]. 高分子学报, 2025,56(2):266-277. DOI： 10.11777/j.issn1000-3304.2024.24189. CSTR： 32057.14.GFZXB.2024.7291.

YANG YUAN, HUI-YI JIANG, WEI-ZHI CHEN, XI-QUN JIANG. Long-circulated Dual-targeted Recombinant Protein Drug Conjugates for Antitumor Therapy. [J]. Acta polymerica sinica, 2025, 56(2): 266-277. DOI： 10.11777/j.issn1000-3304.2024.24189. CSTR： 32057.14.GFZXB.2024.7291.

摘要

药物的靶向性以及体内长效循环特性对于药物在病灶部位的累积和疗效发挥着至关重要的作用. 本研究设计合成了长循环双靶向重组蛋白药物偶联体RPDC-L (long-circulated dualtargeted recombinant protein drug conjugate)，用于抗肿瘤治疗. RPDC-L包含4个部分，分别是靶向人表皮生长因子受体2 (HER2)的anti-HER2纳米抗体、整合素受体

的多肽配体RGD、白蛋白结合域以及小分子化疗药物阿霉素. 其中，anti-HER2纳米抗体和RGD多肽提供肿瘤靶向功能；白蛋白结合域通过结合血液中的白蛋白，赋予药物较长的体内循环时间；化疗药物阿霉素通过酸响应聚乙二醇-腙键连接子与重组蛋白偶联，在微酸性的肿瘤微环境中通过pH响应性释放，进行肿瘤杀伤. 与非长循环双靶向重组蛋白相比，融合表达白蛋白结合单元后，长循环双靶向重组蛋白在小鼠体内的半衰期时间提升到了1.51倍. 与抗肿瘤药物阿霉素偶联后，药物在肿瘤组织中的累积提升到了1.6倍. 体内抗肿瘤试验表明，RPDC-L实现安全高效的抗肿瘤效果，肿瘤抑制率达到78.4%，是非长循环双靶向重组蛋白药物偶联体的1.50倍.

Abstract

Improved tumor specificity and

in vivo

pharmacokinetic behaviors are vital for enhancing drug accumulation at the tumor site and achieving desirable antitumor outcomes. In this study

we designed and synthesized a long-circulated dual-targeted recombinant protein drug conjugate RPDC-L

which is composed of four parts

including a nanobody against human epidermal growth factor receptor 2 (HER2)

integrin receptor

-binding

ligand RGD

albumin binding domain (ABD) and chemotherapeutics doxorubicin. Anti-HER2 nanobody and RGD served as tumor-targeting groups. ABD could elongate the

in vivo

circulation time by binding to albumin within the serum. Doxorubicin was conjugated with recombinant protein

via

an acid-responsive polyethylene glycol hydrazone linker

which was beneficial for the controlled drug release at the weak acidic tumor microenvironment. ABD fusion extended the half-life time of the drug about 1.51-fold. In addition

RPDC-L improved doxorubicin accumulation at the tumor site to 6.1% ID/g (injection dose per gram) up to 1.6-fold of that for the conjugate without ABD fusion (RPDC-S

3.7% ID/g). Finally

in the mouse xenograft subcutaneous tumor models of cervical carcinoma HeLa

RPDC-L showed high biocompatibility and exhibited efficient antitumor efficacy with a tumor inhibition rate of 78.4%

up to 1.5-fold of RPDC-S.

关键词

药物递送大分子药物双靶向重组蛋白药物偶联体长循环

Keywords

Drug deliveryMacromolecular drugDual-targeted recombinant protein drug conjugateLong circulation

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