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化学进展 2023, Vol. 35 Issue (8): 1123-1135 DOI: 10.7536/PC230114   后一篇

• 综述 •

基于阿霉素纳米共递体系的抗肿瘤联合治疗

包予晗, 郭子峰, 李金涛, 张明祖, 何金林*(), 倪沛红   

  1. 苏州大学材料与化学化工学部 新型功能高分子材料国家地方联合工程实验室 江苏省先进功能高分子材料设计及应用重点实验室 苏州市大分子设计与精密合成重点实验室 苏州 215123
  • 收稿日期:2023-02-01 修回日期:2023-03-31 出版日期:2023-08-24 发布日期:2023-04-25
  • 作者简介:

    何金林 2006年本科毕业于苏州大学,2010年受国家留学基金管理委员会资助在美国Akron大学程正迪院士课题组学习,2012年获苏州大学高分子化学与物理专业博士学位并留校工作,2015年晋升为副教授,2018年入选苏州大学优秀青年学者,2021年晋升为教授。先后入选英国皇家化学会J. Mater. Chem. B Emerging Investigator(2018)和ChemComm Pioneering Investigator(2023),现为中国化学会高级会员,苏州市化学化工学会秘书长。主要研究方向为活性阴离子聚合及生物可降解高分子的合成,已发表SCI论文40余篇,获授权中国发明专利6项,先后主持国家自然科学基金2项,江苏省自然科学基金及江苏省高等学校自然科学基金等项目6项。

  • 基金资助:
    江苏省高等学校自然科学研究重大项目(20KJA150009); 江苏省高等学校大学生创新创业训练计划项目(202110285025Z)
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Combination Antitumor Therapy Based on Codelivery Nanosystems of Doxorubicin

Yuhan Bao, Zifeng Guo, Jintao Li, Mingzu Zhang, Jinlin He(), Peihong Ni   

  1. College of Chemistry, Chemical Engineering and Materials Science, State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, Jiangsu Key Laboratory of Advanced Functional Polymer Design and Application, Suzhou Key Laboratory of Macromolecular Design and Precision Synthesis, Soochow University,Suzhou 215123, China
  • Received:2023-02-01 Revised:2023-03-31 Online:2023-08-24 Published:2023-04-25
  • Contact: *e-mail: jlhe@suda.edu.cn
  • About author:
    †These authors contributed equally.
  • Supported by:
    Natural Science Foundation of the Jiangsu Higher Education Institutions of China(20KJA150009); Undergraduate Training Program for Innovation and Entrepreneurship, Soochow University(202110285025Z)

肿瘤是当前全球范围内的主要致死病因,而化疗仍是抗肿瘤治疗的重要手段之一。阿霉素(DOX)是一种临床上广泛使用的蒽环类广谱抗肿瘤药物,但是它的治疗效果受到其严重副作用的限制,包括累积性心脏毒性和剂量限制性骨髓抑制。研究人员长期致力于寻找降低DOX毒副作用的方法,而依托于纳米共递体系的抗肿瘤联合治疗策略获得广泛关注。它们能够实现药物在病灶区域的靶向富集和定点释放,通过药物联用降低DOX对正常细胞组织的不良反应,并在一定程度上逆转肿瘤细胞的多药耐药性。本综述将聚焦于近年来基于DOX的纳米共递体系用于抗肿瘤联合治疗策略的构筑,重点介绍DOX联合其他化疗药物、基因药物、气体分子或天然药物进行抗肿瘤治疗的研究进展,并对其面临的挑战和发展趋势进行展望。

关键词： 阿霉素, 抗肿瘤治疗, 联合治疗, 纳米共递体系, 肿瘤微环境

Tumor has been one of the most common causes of death worldwide, while chemotherapy is still the major tool for antitumor treatment. As a broad-spectrum anthracycline-type antitumor drug, doxorubicin (DOX) has been widely used in different types of tumors in clinical practices. Nevertheless, its serious side effects, including cumulative cardiotoxicity and dose-limiting myelosuppression, present significant challenges to the clinical application. Researchers have long been committed to finding routes to reduce the toxic side effects of DOX, whereas the strategies of combination antitumor therapies based on codelivery nanosystems have received wide attention. They can realize the targeted enrichment and on-demand release of drugs in the lesion area, reducing the adverse reaction of DOX to normal tissues through drug combination and reversing the multi-drug resistance (MDR) of tumor cells to a certain extent. In this review, we focus on the recent progress on the DOX-based combination antitumor therapies together with other chemotherapeutic agents (camptothecin, paclitaxel, cisplatin), genetic drugs (pDNA, siRNA, miRNA), gas molecules (NO, O2, CO, H2S, SO2) or natural medicines (dexrazoxane, berberine, flavonoids). Besides, the current challenges and future trends of DOX-based combination therapies are also prospected.

Contents

1 Introduction

2 Combination therapy of DOX with other chemotherapeutic agents

3 Combination therapy of DOX with genetic drugs

4 Combination therapy of DOX with gas molecules

4.1 DOX in combination with NO

4.2 DOX in combination with O2

4.3 DOX in combination with CO

4.4 DOX in combination with H2S

4.5 DOX in combination with SO2

5 Combination therapy of DOX with natural medicines

6 Conclusion and outlook

Key words: doxorubicin, antitumor therapy, combination therapy, codelivery nanosystem, tumor microenvironment
()
图1 DOX的化学结构和功能单元
Fig.1 Chemical structure and functional moieties of DOX
图2 DOX分别联合CPT和CDDP的胶束结构示意图:(a) 刺激响应性聚合物前药混合胶束用于共载DOX和CPT[26];(b) 自交联纳米胶束用于共载DOX和CDDP[35]
Fig.2 Schematic illustration of micelle structure with DOX in combination with CPT and CDDP respectively. (a) Stimuli-responsive polymer prodrug mixed micelles for co-loading DOX and CPT[26]. Copyright 2016, The Royal Society of Chemistry. (b) Self-crosslinking nanomicelles for co-loading DOX and CDDP[35]. Copyright 2018, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
图3 DOX联合基因治疗示意图:(a)多功能性聚磷酸酯载体用于共载DOX和p53[48];(b) mPEG-PCL-g-PDMAEMA胶束共递送DOX和Cy5-siRNA[56];(c) 两亲性含磷树枝状分子胶束共载DOX和miR-21i[62];(d) TK1 mRNA产生的 lsDNA、荧光探针HP和DOX自组装为DNA纳米球[70]
Fig.3 Schematic illustration of DOX combined gene therapy. (a) Polyphosphate ester multifunctional carrier for the delivery of DOX and p53[48]. Copyright 2018, The Royal Society of Chemistry. (b) mPEG-PCL-g-PDMAEMA micelles co-deliver DOX and Cy5-siRNA[56]. Copyright 2016, American Chemical Society. (c) Amphiphilic containing phosphorus dendrimer micelles co-loading DOX and miR-21i[62]. Copyright 2022, The Royal Society of Chemistry. (d) lsDNA produced by TK1 mRNA, fluorescent hairpins HP and DOX self-assemble into DNA nanosphere[70]. Copyright 2020, American Chemical Society
图4 DOX联合气体治疗示意图。(a) 主链含有可释放NO基元的三嵌段共聚物PEG-b-PNORM-b-PEG与DOX的共组装及光控药物释放[81];(b) 共载DOX和O2的两亲性分子F-IR780-PEG在近红外光照射下产生1O2并释放DOX[86];(c) 包载DOX的含有硝基苯醚与3-HF衍生物的纳米载体在光照下释放CO和DOX[95];(d) 肿瘤特异性脂肪酶响应的DOX药物载体可通过二烯丙基三硫醚与病灶部位的GSH反应释放出H2S[105];(e) 基于PEG化聚(L-谷氨酸)可释放SO2的两亲性聚合物前药结构式[109]
Fig.4 Schematic illustration of DOX combined gas therapy. (a) Self-assembly and photo-triggered drug release of DOX-loading triblock copolymers of PEG-b-PNORM-b-PEG containing NO-releasing moieties within the main chain[81]. Copyright 2020, The Royal Society of Chemistry. (b) The amphiphilic molecule F-IR780-PEG co-loaded with DOX and O2 generates1O2 and releases DOX under near-infrared light irradiation[86]. Copyright 2019, The Royal Society of Chemistry. (c) Nanocarrier containing nitrophenyl ether and 3-HF derivatives loaded with DOX releases CO and DOX under illumination[95]. Copyright 2022, Multidisciplinary Digital Publishing Institute. (d) Tumor specific lipase responsive carrier loaded with DOX can release H2S through diallyl trisulfide reacting with GSH at the lesion site)[105]. Copyright 2022, Frontiers. (e) SO2-releasing amphiphilic polymeric prodrug based on pegylated poly(L-glutamate)[109]
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