基于海藻酸钠衍生物的肝靶向纳米前药的构建及抗肿瘤活性研究

doi:10.7503/cjcu20131236

高等学校化学学报 ›› 2014, Vol. 35 ›› Issue (8): 1835.doi: 10.7503/cjcu20131236

基于海藻酸钠衍生物的肝靶向纳米前药的构建及抗肿瘤活性研究

郭华, 杨承玲, 王蔚, 赖全勇, 袁直()

南开大学高分子化学研究所, 功能高分子材料教育部重点实验室, 天津化学化工协同创新中心, 天津 300071

收稿日期:2013-12-17 出版日期:2014-08-10 发布日期:2019-08-01
作者简介:联系人简介: 袁直, 女, 博士, 教授, 博士生导师, 主要从事生物医用材料研究. E-mail: zhiy@nankai.edu.cn
基金资助:
国家自然科学基金(批准号: 51073080, 51273095)、天津市自然科学基金(批准号: 13JCYBJC25100)和教育部创新团队PCSIRT 项目(批准号: IRT1257)资助

Preparation of Liver-targeted Nano-prodrug Based on Sodium Alginate Derivative and the Study on Antitumor Activity^†

GUO Hua, YANG Chengling, WANG Wei, LAI Quanyong, YUAN Zhi^*()

Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, Collaborative Innovation Center of Chemical Science and Engineering(Tianjin), Nankai University, Tianjin 300071, China

Received:2013-12-17 Online:2014-08-10 Published:2019-08-01
Contact: YUAN Zhi E-mail:zhiy@nankai.edu.cn
Supported by:
Supported by the National Natural Science Foundation of China(Nos.51073080, 51273095), the Natural Science Foundation of Tianjin, China(No.13JCYBJC25100) and the Program for Changjiang Scholars and Innovative Research Team in University, China(No IRT1257)

摘要/Abstract

摘要：

利用寡聚乙二醇(mOEG)修饰海藻酸钠(ALG), 有效降低了ALG的黏度, 提高了其对疏水性肝靶向配体甘草次酸(GA)的负载量. 结果表明, 靶向材料(GA-ALG-mOEG)的GA负载量为11.8%, 是对照组(GA-ALG)的1.97倍. 在此基础上, 以物理交联的方式引入pH响应的阿霉素前药(DOX-ALG-mOEG), 制备了肝靶向纳米前药(DOX-ALG-mOEG/GA-ALG-mOEG NPs). 细胞实验及抑瘤实验结果表明, 该前药较对照组(DOX-ALG/GA-ALG NPs)具有更高的肝靶向性和药物利用率, 其对肝癌细胞的半致死率浓度(IC₅₀)为58.1 ng/mL, 是对照组(IC₅₀=141.7 ng/mL)的41%; 动物实验结果显示, 该前药的抑瘤率达到了88.4%, 比对照组提高了11.5%.

关键词: 海藻酸钠衍生物, 寡聚乙二醇, 甘草次酸, 抗肿瘤活性

Abstract:

The high viscosity of sodium alginate(ALG) causes its insufficient targeted ligand loading, and further influences the targeted recognition effect of nano-prodrug. Here, oligomeric ethylene glycol modified-sodium alginate(ALG-mOEG) was used as a carrier to improve the targeted-ligands loading. Results showed that ALG-mOEG significantly improved glycyrrhetinic acid(GA) loading compared with unmodified ALG(11.8% vs. 6.9%, 1.97-fold increase). On this basis, the liver targeted nano-prodrug(DOX-ALG-mOEG/GA-ALG-mOEG NPs) was self-assembled via dialysis method by mixing GA-ALG-mOEG and DOX-ALG-mOEG. Cell cytotoxicity experiment showed that DOX-ALG-mOEG/GA-ALG-mOEG NPs inhibited HepG2 proliferation with an half maximal inhibitory concentration(IC₅₀) value of 58.1 ng/mL while the IC₅₀ of control group was 141.7 ng/mL; the tumor growth inhibition rate(IR) reached to 88.4%, improved by 11.5% compared to that of the control group. This study show that the liver targeted nano-prodrug based on ALG-mOEG can effectively improve the drug utilization, and provide a reference for the preparation of other polysaccharide targeted nano-prodrug.

Key words: Sodium alginate derivative, Ethylene glycol oligomer, Glycyrrhetinic acid, Antitumor activity

中图分类号:

O631
O636.9

TrendMD:

郭华, 杨承玲, 王蔚, 赖全勇, 袁直. 基于海藻酸钠衍生物的肝靶向纳米前药的构建及抗肿瘤活性研究. 高等学校化学学报, 2014, 35(8): 1835.

GUO Hua, YANG Chengling, WANG Wei, LAI Quanyong, YUAN Zhi. Preparation of Liver-targeted Nano-prodrug Based on Sodium Alginate Derivative and the Study on Antitumor Activity^†. Chem. J. Chinese Universities, 2014, 35(8): 1835.

图/表 9

Fig.1 Structures of DOX-ALG-mOEG(A) and GA-ALG-mOEG(B) and schematic representation of DOX-ALG-mOEG/GA-ALG-mOEG NPs from DOX-ALG-mOEG and GA-ALG-mOEG(C)

Fig.2 1H NMR(A) and FTIR(B) spectra of ALG(a) and GA-ALG-mOEG(b)

Fig.3 CAC(A) and size distribution(B) of DOX-ALG-mOEG/GA-ALG-mOEG NPs Inset is TEM image of DOX-ALG-mOEG/GA-ALG-mOEG.

Table 1 Characterization of DOX-ALG-mOEG/GA-ALG-mOEG NPs and GA-ALG/DOX-ALG NPs

Sample	D_h/nm	PDI^*	Zeta potential/mV	CAC/(mg·L^-1)
DOX-ALG/GA-ALG NPs	253.5	0.123	-44.4	58.34
DOX-ALG-mOEG/GA-ALG-mOEG NPs	254.2	0.207	-35.1	5.52

Fig.4 In vitro cumulative release of DOX-ALG-mOEG/GA-ALG-mOEG NPs(a, b) and DOX-ALG/GA-ALG NPs(c, d) in PBS under acidic(pH=4.0)(a, c) and neutral(pH=7.4)(b, d) condition

Fig.5 CLSM images of HepG2 cells after the treatment with DOX-ALG/GA-ALG NPs(A1—A3) and DOX-ALG-mOEG/GA-ALG-mOEG NPs(B1—B3) (A1, B1) DOX; (A2, B2) Hoechst; (A3, B3) Overlay.

Fig.6 CLSM images of HepG2 cells after treatment with DOX/GA-ALG NPs(A1—A3) and DOX/GA-ALG NPs+PEG-GA(B1—B3) (A1, B1) DOX; (A2, B2) Hoechst; (A3, B3) Overlay.

Fig.7 Cytotoxicity(A) and the IC50(B) of DOX-ALG-mOEG NPs, DOX-ALG/GA-ALG NPs and DOX-ALG-mOEG/GA-ALG-mOEG NPs against HepG2 cells[Mean±SD(n=3)]

Fig.8 Representative photographs(A) and ultimate tumor mass(B) of excised H22 tumors from mice treated with saline(a), DOX·HCl(b), DOX-ALG/GA-ALG NPs(c) and DOX-ALG-mOEG/GA-ALG-mOEG NPs(d)[means±SD(n=3—5), * P<0.05]

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基于海藻酸钠衍生物的肝靶向纳米前药的构建及抗肿瘤活性研究

Preparation of Liver-targeted Nano-prodrug Based on Sodium Alginate Derivative and the Study on Antitumor Activity^†

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基于海藻酸钠衍生物的肝靶向纳米前药的构建及抗肿瘤活性研究

Preparation of Liver-targeted Nano-prodrug Based on Sodium Alginate Derivative and the Study on Antitumor Activity†

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Preparation of Liver-targeted Nano-prodrug Based on Sodium Alginate Derivative and the Study on Antitumor Activity^†