用于肝癌治疗的核酸药物递送体系研究进展

doi:10.6023/A24090258

化学学报 ›› 2024, Vol. 82 ›› Issue (12): 1260-1273.DOI: 10.6023/A24090258 上一篇下一篇

综述

用于肝癌治疗的核酸药物递送体系研究进展

刘婉婉^a, 李丹^a, 邓可欣^a, 刘君禹^a, 张吉松^c, 张灿阳^a^,^b^,^d^,^e^,^*()

a 清华大学深圳国际研究生院广东深圳 518055
b 工业生物催化教育部重点实验室(清华大学) 北京 100084
c 清华大学化学工程系北京 100084
d 活性蛋白多肽绿色生物制造广东普通高校重点实验室(清华大学深圳国际研究生院) 广东深圳 518055
e 深圳湾实验室广东深圳 518132

投稿日期:2024-09-03 发布日期:2024-11-10

作者简介:

刘婉婉, 就读于清华大学深圳国际研究生院, 2021级材料与化工专业硕士. 主要研究方向为核酸药物递送体系开发与肿瘤治疗.

李丹, 就读于清华大学深圳国际研究生院, 2022级材料与化工专业硕士. 主要研究方向为有机-无机杂合生物载体材料制备及肿瘤治疗.

邓可欣, 就读于清华大学深圳国际研究生院, 2021级材料与化工专业硕士. 主要研究方向为治疗性肿瘤疫苗的开发与评价.

刘君禹, 就读于清华大学深圳国际研究生院, 化学工程与技术专业博士. 主要研究方向为口服递送系统设计、天然产物体内外功效及机制研究、生物信息学分析等.

张吉松, 2014年博士毕业于清华大学化学工程专业, 现任清华大学化学工程系副教授. 目前从事流动化学和微填充床气液固反应研究, 主要包括: (1)基于微填充床技术的加氢和氧化反应; (2)医药中间体的连续高效合成; (3)基于微器件的在线表征和分析技术.

张灿阳, 2014年博士毕业于华南理工大学化学工程专业, 现任清华大学深圳国际研究生院副教授、博士生导师. 研究方向面向生物医药与生命健康领域重大需求与关键问题, 聚焦生命物质与非生物元件互作与适配及规模化制备研究, 基于靶向递送技术, 理性设计和开发工程化的活性物质生物杂合体系, 实现功能调控与性能超越, 优化多种重大疾病的治疗, 如癌症、感染、自身免疫性疾病.

基金资助:
广东省珠江人才计划(2021QN02Y225); 清华大学深圳国际研究生院海外科研合作基金(HW2023009); 化工系-iBHE专项合作联合基金资助

Advances in Nucleic Acid Drug Delivery Systems for Liver Cancer Treatment

Wanwan Liu^a, Dan Li^a, Kexin Deng^a, Junyu Liu^a, Jisong Zhang^c, Can Yang Zhang^a^,^b^,^d^,^e()

a Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, Guangdong, China
b Key Laboratory of Industrial Biocatalysis, Ministry of Education; Tsinghua University, Beijing 100084, China
c Department of Chemical Engineering, Tsinghua University, Beijing 100084, China
d Key Laboratory of Active Proteins and Peptides Green Biomanufacturing of Guangdong Higher Education Institutes, Tsinghua Shenzhen International Graduate School, Shenzhen 518055, Guangdong, China
e Shenzhen Bay Laboratory, Shenzhen 518132, Guangdong, China

Received:2024-09-03 Published:2024-11-10
Contact: * E-mail: zhang.cy@sz.tsinghua.edu.cn
Supported by:
Pearl River Talent Project(2021QN02Y225); Overseas Research Cooperation Fund of Shenzhen International Graduate School, Tsinghua University(HW2023009); Department of Chemical Engineering-iBHE Cooperation Joint Fund Project

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摘要/Abstract

肝癌致死率高、预后差, 已成为人类健康的重大威胁. 随着核酸生物技术的发展, 核酸药物在肝癌治疗领域逐渐显示出巨大的应用潜力. 核酸药物特异性强, 潜在作用靶点丰富, 研发周期相对较短, 但核酸分子稳定性差, 难以进入细胞, 且无法逃逸溶酶体, 转染效果差, 因而核酸药物的应用离不开递送体系的开发. 核酸药物递送体系包括病毒载体与非病毒载体, 非病毒载体包括共价连接体系、无机纳米颗粒、脂质纳米颗粒(LNP)、聚合物纳米颗粒(PNP)和DNA纳米颗粒等. 本文总结了面向肝癌的基因治疗策略, 并系统性综述了各种递送手段的特点、适用场景及研究进展, 为新型肝癌核酸药物递送体系的研究与开发提供了借鉴和参考.

关键词: 肝癌, 递送体系, 核酸药物, 基因治疗, 非病毒载体

Liver cancer has become a major threat to human health due to its high lethality, poor prognosis and strong drug resistance. With the in-depth researches on liver cancer and the development of nucleic acid biotechnology, nucleic acid drugs have gradually shown great potential in liver cancer treatment. Compared with traditional therapeutic drugs like chemical drugs, nucleic acid drugs have the characteristics of strong specificity, rich potential targets, relatively short development cycle, and negligible toxic side effects, etc. However, due to the poor stability of nucleic acid molecules, it is difficult to achieve long circulation time in body, high internalization activity, and lysosomal escape capacity in cell, which leads to the low transfection efficiency and prevents it from exerting the therapeutic effect. Therefore, it’s of great importance to develop drug delivery systems for nucleic acid drugs to improve the therapeutic effect and enhance the stability as well as the targeting of nucleic acid drugs in vivo. Currently, the delivery vectors for nucleic acid drugs include viral vectors and non-viral vectors. Viral vectors, including adenovirus, lentivirus, etc., have the advantages of high transfection efficiency and high specificity, but their application prospect is greatly restricted due to the safety and ethical issues. Non-viral vectors are safer, more stable and structurally tunable compared with viral vectors. Non-viral vectors, including covalently attached systems, inorganic nanoparticles, lipid nanoparticles (LNP), polymer nanoparticles (PNP), DNA nanoparticles etc., have high application prospects due to their rich types, diverse and adjustable structures, and good biocompatibility. In this paper, we systematically summarize the current nucleic acid drug delivery systems, especially for liver cancer, and carefully classify the application scenarios and characteristics of the current delivery systems and introduce all the delivery systems as exhaustively as possible. It provides reference for the research and development of innovative nucleic acid drug delivery systems tailored for liver cancer. Collectively, we think that drug delivery systems for nucleic acid drugs could be potential in clinic to promote the improvement of liver cancer therapy.

Key words: liver cancer, delivery system, nucleic acid drugs, gene therapy, non-viral vectors

引用此文

刘婉婉, 李丹, 邓可欣, 刘君禹, 张吉松, 张灿阳. 用于肝癌治疗的核酸药物递送体系研究进展[J]. 化学学报, 2024, 82(12): 1260-1273.

Wanwan Liu, Dan Li, Kexin Deng, Junyu Liu, Jisong Zhang, Can Yang Zhang. Advances in Nucleic Acid Drug Delivery Systems for Liver Cancer Treatment[J]. Acta Chimica Sinica, 2024, 82(12): 1260-1273.

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图/表 7

图1. 肝癌用药与核酸药物发展历程[8,15,30]

Figure 1. Development of liver cancer therapeutics and nucleic acid drugs[8,15,30]

图2. 甘露糖修饰的siRNA靶向巨噬细胞和树突状细胞[75] (a)修饰后的siRNA递送到目标受体与起效过程示意图; (b)细胞水平基因沉默效果; (c)体内稳定性与分布情况; (d)体系在体内高效靶向巨噬细胞

Figure 2. Targeted delivery to macrophages and dendritic cells by chemically modified mannose ligand-conjugated siRNA (a) Schematic procedure for conjugated siRNA to target receptors and take effect; (b) gene silencing capability at the cellular level; (c) in vivo stability and distribution; (d) conjugated siRNA targets spleen macrophages and exhibits remarkable gene silencing effect. Cited and reproduced from ref. [75]

图3. 壳聚糖接枝聚赖氨酸金纳米团簇靶向递送shRNA[84] (a)体系构建和起效过程示意图; (b)凝胶阻滞实验结果; (c)体外转染与基因沉默效果; (d)体内分布与肿瘤靶向性; (e)体内肿瘤抑制效果评价

Figure 3. Chitosan-graft-poly(l-lysine) dendron-assisted self-assembly of Au nanoclusters and targeted delivery of shRNA (a) Schematic procedure of the system constructing and taking effect; (b) result of gel retardation assay; (c) in vitro transfection and gene silencing; (d) in vivo distribution and tumor targeting; (e) in vivo tumor suppression effect. Cited and reproduced from ref. [84]

图4. LNP负载CRISPR/Cas9核酸实现高效基因编辑与肿瘤治疗[108] (a)负载CRISPR-Cas9 RNA的脂质体纳米颗粒制备过程; (b) sgGFP cLNP在多种肿瘤细胞实现高效基因编辑; sgPLK1 cLNP诱导鼠多形性胶质母细胞瘤细胞(c)和人卵巢癌细胞(d)死亡; (e)瘤内注射sgPLK1 cLNP有效抑制鼠多形性胶质母细胞瘤生长; 腹腔注射 anti-hEGFR抗体修饰的sgPLK1 cLNP实现人卵巢癌异种移植瘤的体内靶向(f)与肿瘤抑制(g)

Figure 4. CRISPR-Cas9 genome editing using targeted lipid nanoparticles for cancer therapy (a) Preparation of CRISPR-Cas9 RNA loaded LNP; (b) sgGFP cLNP exhibited significant gene editing efficiency in multiple cancer cell lines; in vitro inhibition of (c) murine glioblastoma multiforme and (d) human serous ovarian adenocarcinomas cells; (e) intratumoral injection of sgPLK1-cLNPs significantly reduced murine glioblastoma multiforme tumor growth; intraperitoneal injection of sgPLK1-cLNPs significantly targeted (f) and therapied (g) human serous ovarian adenocarcinomas in vivo. Cited and reproduced from ref. [108]

图5. 用于核酸药物递送的阳离子聚合物[112-113]

Figure 5. Cationic polymers for nucleic acid drug delivery[112-113]

图6. 基于阳离子聚合物PBAE的CRISPR/Cas9 pDNA递送[121] (a)体系设计思路图; (b)阳离子聚合物合成及表征; (c) PBAE-pDNA复合物通过基因编辑恢复细胞中EGFP的表达; (d) PBAE-pDNA复合物在荷瘤小鼠体内对肿瘤的靶向性及基因编辑能力验证

Figure 6. Cationic polymer PBAE based CRISPR/Cas9 pDNA delivery (a) Schematic procedure of the system constructing and taking effect; (b) synthesis and characterization of a series of PBAEs; (c) PBAE-pDNA complex exhibit significant gene editing effects in cells; (d) targeting and gene editing capability of PBAE-pDNA in tumor bearing mice. Cited and reproduced from ref. [121]

图7. DNA纳米凝胶递送PD-L1 siRNA与光敏剂, 实现癌症的光免疫疗法[129] (a)体系设计思路图; (b)治疗后收集的所有DC细胞中成熟DC细胞的比例; (c) DNA纳米凝胶原子力显微镜成像; (d)对小鼠静脉注射DNA纳米凝胶后1、12和24 h的肿瘤切片共聚焦显微镜图像; (e)治疗期间肿瘤的生长曲线; (f)治疗后解剖所得肿瘤图像

Figure 7. DNA nanogel delivery of PD-L1 siRNA with photosensitizer for photoimmunotherapy of cancer (a) System design idea diagram; (b) the summarized frequency of mature DCs in all collected DCs after the treatment; (c) the morphology of siRNA/PPA-NG revealed by AFM imaging; (d) CLSM images of the tumor sections obtained from the mice at 1, 12, and 24 h postinjection after intravenously administrating the siRNA/PPA-NG to mice; (e) growth curves of tumours during treatment; (f) the images of tumors after the treatment. Cited and reproduced from ref. [129]

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用于肝癌治疗的核酸药物递送体系研究进展

Advances in Nucleic Acid Drug Delivery Systems for Liver Cancer Treatment

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