新型氧化/还原双响应递送系统在结直肠癌腹膜转移热灌注化疗中的应用

康焱; 李建霖; 甘志华; 张国超; 喻青松

doi:10.11777/j.issn1000-3304.2024.24320

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新型氧化/还原双响应递送系统在结直肠癌腹膜转移热灌注化疗中的应用

研究论文 | 更新时间：2025-04-07

- 新型氧化/还原双响应递送系统在结直肠癌腹膜转移热灌注化疗中的应用
- Glutathione/Reactive Oxygen Species Dual-Responsive Drug Delivery System for Enhancing Hyperthermic Intraperitoneal Chemotherapy in Colorectal Cancer Peritoneal Metastases
- 高分子学报 2025年页码：1-13
- 作者机构：
  
  1.北京化工大学生命科学与技术学院有机无机复合材料国家重点实验室生物医用材料(北京)实验室北京 100029
  2.中日友好医院普外科北京 100029
- 作者简介：
  
  E-mail: zhgcmd@163.com;
  E-mail: yuqs@mail.buct.edu.cn
- 基金信息：
  
  国家自然科学基金(基金号 ┣52373124;52422316);52033001,52221006┫;中央高校基本科研业务费(基金号 PT2403);中央高水平医院临床科研业务费(基金号 2023-NHLHCRF-YXHZ-MS-01)资助
- DOI：10.11777/j.issn1000-3304.2024.24320
  中图分类号：
- CSTR：32057.14.GFZXB.2025.7353
- 收稿日期：2024-12-31，
  
  录用日期：2025-02-03，
  
  网络出版日期：2025-04-07，
- 稿件说明：
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康焱, 李建霖, 甘志华, 张国超, 喻青松. 新型氧化/还原双响应递送系统在结直肠癌腹膜转移热灌注化疗中的应用. 高分子学报, doi: 10.11777/j.issn1000-3304.2024.24320

Kang, Y.; Li, J. L.; Gan, Z. H.; Zhang, G. C.; Yu, Q. S. Glutathione/reactive oxygen species dual-responsive drug delivery system for enhancing hyperthermic intraperitoneal chemotherapy in colorectal cancer peritoneal metastases. ,Acta Polymerica Sinica, doi: 10.11777/j.issn1000-3304.2024.24320
康焱, 李建霖, 甘志华, 张国超, 喻青松. 新型氧化/还原双响应递送系统在结直肠癌腹膜转移热灌注化疗中的应用. 高分子学报, doi: 10.11777/j.issn1000-3304.2024.24320 DOI： CSTR： 32057.14.GFZXB.2025.7353.

Kang, Y.; Li, J. L.; Gan, Z. H.; Zhang, G. C.; Yu, Q. S. Glutathione/reactive oxygen species dual-responsive drug delivery system for enhancing hyperthermic intraperitoneal chemotherapy in colorectal cancer peritoneal metastases. ,Acta Polymerica Sinica, doi: 10.11777/j.issn1000-3304.2024.24320 DOI： CSTR： 32057.14.GFZXB.2025.7353.

摘要

结直肠癌腹膜转移是其常见的晚期转移形式，细胞减灭术-腹腔热灌注化疗(CRS-HIPEC)是目前唯一有效的临床治疗手段. 然而，HIPEC治疗存在局限性，包括严重的毒副作用以及肿瘤细胞内热休克蛋白90 (HSP90)的激活，导致治疗过程的疗效和安全性受到限制. 为了提高CRS-HIPEC的治疗效率与安全性，本研究设计并开发了一种基于壳聚糖的新型双响应递送系统(CsB)，用于递送具有ROS响应特性的藤黄酸(GA)前药(GB). 纳米前药利用肿瘤微环境中高浓度的谷胱甘肽(GSH)和活性氧(ROS)实现精准药物释放，进一步通过NQO-1底物

-Lapachone显著提高ROS水平，从而加速GB向活性药物GA的转化. GA通过抑制HSP90表达，增强细胞凋亡、降低耐药性并抑制肿瘤血管生成，可显著改善腹腔热灌注治疗的疗效和安全性. 本研究为结直肠癌腹膜转移的精准治疗提供了新的策略，并为未来临床应用奠定了理论和实验基础.

Abstract

Colorectal cancer peritoneal metastases stand as a prevalent form of advanced-stage metastasis. Currently

cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) is the sole clinically effective treatment available. Nevertheless

the efficacy and safety of HIPEC are severely hampered by its intense toxic side effects and the activation of heat shock protein 90 (HSP90) within tumor cells. To enhance the therapeutic efficiency and safety of CRS-HIPEC

this study ingeniously designed and developed a novel redox-responsive chitosan-based delivery system (CsB) for the delivery of the reactive oxygen species (ROS)‍-responsive prodrug gambogenic acid (GB). This nanoprodrug capitalizes on the elevated levels of glutathione (GSH) and ROS in the tumor microenvironment to achieve targeted drug release. Moreover

by incorporating

-lapachone

a substrate of NAD(P)H: quinone oxidoreductase-1 (NQO-1)

the system substantially boosts intracellular ROS levels. As a result

it accelerates the conversion of GB into its active form

gambogenic acid (GA). GA exerts its therapeutic effects through multiple mechanisms. It inhibits HSP90 expression

promotes apoptosis

reduces drug resistance

and suppresses tumor angiogenesis. These combined actions comprehensively improve the efficacy and safety of intraperitoneal hyperthermic therapy. This study presents a novel strategy for the precision treatment of colorectal cancer peritoneal metastases and furnishes a solid th

eoretical and experimental foundation for future clinical applications.

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references

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