卡铂@葡聚糖纳米载体的自组装/聚合一步法制备及生物应用

doi:10.7503/cjcu20180860

高等学校化学学报 ›› 2019, Vol. 40 ›› Issue (6): 1301.doi: 10.7503/cjcu20180860

卡铂@葡聚糖纳米载体的自组装/聚合一步法制备及生物应用

高苗苗¹, 王成龙¹, 窦红静¹(), 许国雄²()

1. 上海交通大学材料科学与工程学院, 金属基复合材料国家重点实验室, 上海 200240
2. 复旦大学附属金山医院中心实验室, 上海 201508

收稿日期:2018-12-24 出版日期:2019-06-10 发布日期:2019-04-04
作者简介:
联系人简介: 窦红静, 女, 博士, 教授, 主要从事大分子生物功能材料及超分子自组装方面的研究. E-mail:hjdou@sjtu.edu.cn; 许国雄, 男, 博士, 教授, 主要从事肿瘤细胞生物学、基础医学和转化医学方面的研究. E-mail: guoxiong.xu@fudan.edu.cn
基金资助:
国家自然科学基金(批准号: 21871180, 81872121)、上海市“科技创新行动计划”基础研究领域项目(批准号: 18JC1413500 )、上海高校特聘教授(东方学者)计划(批准号: SHDP201802)和上海市教委“曙光计划”(批准号: 12SG12)资助.

One-step Self-assembly/polymerization Fabrication and Biomedical Application of Carboplatin@Dextran Nanocarrier^†

GAO Miaomiao¹, WANG Chenglong¹, DOU Hongjing¹(), XU Guoxiong²()

1. State Key Laboratory of Metal Matrix Composites, School of Materials Science and Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
2. Central Laboratory, Jinshan Hospital of Fudan University, Shanghai 201508, China

Received:2018-12-24 Online:2019-06-10 Published:2019-04-04
Supported by:
† Supported by the National Natural Science Foundation of China(No.21871180, 81872121), the Fundamental Research Project of Shanghai “Science and Technology Innovation Action”, China(No.18JC1413500), the Program for Professor of Special Appointment(Eastern Scholar) at Shanghai Institutions of Higher Learning, China(No.SHDP201802) and the “Shuguang Program” of Shanghai Municipal Education Commission, China(No.12SG12).

摘要/Abstract

摘要：

在接枝共聚辅助自组装(GISA)制备葡聚糖纳米载体的过程中, 利用丙烯酸单体与卡铂之间的非共价键作用, 使得卡铂参与到葡聚糖纳米载体的形成中, 从而一步实现了卡铂@葡聚糖纳米载体的制备, 并使用肿瘤还原性环境敏感的二硫键来交联纳米载体, 得到了对肿瘤还原环境响应的纳米药物载体. 对纳米药物载体的结构、粒径及形貌进行表征, 结果显示, 纳米药物载体粒径为(92±0.2) nm, Zeta电位为(-8±0.3) eV. 通过体外药物释放研究发现, 在还原性环境中, 载体可持续72 h释放药物, 最大释放量达80%. 细胞摄取实验表明负载卡铂的纳米药物载体可在4 h内高效地进入细胞核; 其半抑制浓度(IC₅₀)为25.32 μg/mL, 达到和相同浓度游离卡铂相仿的促肿瘤细胞凋亡效果. 此一步法所制备的卡铂@葡聚糖纳米载体具有良好的生物应用前景.

关键词: 一步法, 接枝聚合诱导自组装, 卡铂@葡聚糖纳米载体, 还原环境敏感

Abstract:

We introduced disulfide bond in the crosslinking points of the carboplatin@dextran to endow the reducing environmental sensitivity to the nanocarriers. Its structure, particle size and morphology of the nanocarrier were characterized by means of dynamic light scattering(DLS), ¹H NMR and FTIR. The results showed that the size of the nanocarrier was (92±0.2) nm. In vitro drug release studies disclosed that the carboplatin inside the nanocarrier can be released for 80% in 72 h in a reducing environment. The cell uptake experiments showed that the nanocarriers loaded with carboplatin could efficiently enter the cell nuclei within 4 h. The half maximal inhibitory concentration(IC₅₀) of the carboplatin@dextran nanocarrier was 25.32 μg/mL, which had similar cytotoxicity to the free carboplatin at the same concentration. The above results demonstrate that carboplatin@dextran nanocarrier prepared by the one-step method has a good biomedical application prospect.

Key words: One-stepfabrication, Graft polymerization assisted self-assembly, Carboplatin@dextran nanocarrier, Reducing environmental responsivity

中图分类号:

O636.1

TrendMD:

高苗苗, 王成龙, 窦红静, 许国雄. 卡铂@葡聚糖纳米载体的自组装/聚合一步法制备及生物应用. 高等学校化学学报, 2019, 40(6): 1301.

GAO Miaomiao,WANG Chenglong,DOU Hongjing,XU Guoxiong. One-step Self-assembly/polymerization Fabrication and Biomedical Application of Carboplatin@Dextran Nanocarrier^†. Chem. J. Chinese Universities, 2019, 40(6): 1301.

图/表 10

Scheme 1 Schematic illustration depicting the fabrication of the DAPt and their tumor-microenvironment sensitive drug release behavior

Fig.1 1H NMR(A) and FTIR(B) spectra of Dextran(a), D2A2(b) and D2A2Pt80(c)

Scheme 2 Molecular structure of DAPt

Table 1 Characteristics of DAPt

Sample	n_Glu∶n_Monoter	m_Dextran∶m_CBP	Size/nm	PDI	EE(%)	LC(%)
D2A1Pt160	1∶0.5	80∶1	73±0.7	0.34	11.59	0.15
D2A2Pt160	1∶1	80∶1	88±0.6	0.23	13.14	0.15
D2A3Pt160	1∶1.5	80∶1	105±0.6	0.31	23.42	0.27
D2A2Pt80	1∶1	40∶1	92±0.2	0.23	29.18	0.63

Fig.2 TEM image(A) and DLS(B) of D2A2Pt80

Fig.3 Drug release curves of D2A2Pt80 in different conditions a. pH=7.4 PBS; b. pH=7.4 PBS+10 mmol/L GSH.

Fig.4 Cell viability of D2A2(A) and free CBP+D2A2Pt80(B)

Fig.5 Flow cytometry histogram profile of D2A2Pt80 on cancer cellular uptake in vitro

Fig.6 Mean fluorescence intensity vs. different incubating time

Fig.7 CLSM images of OVCar-3 cells treated with FD2A2Pt80 for different incubating time

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卡铂@葡聚糖纳米载体的自组装/聚合一步法制备及生物应用

One-step Self-assembly/polymerization Fabrication and Biomedical Application of Carboplatin@Dextran Nanocarrier^†

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卡铂@葡聚糖纳米载体的自组装/聚合一步法制备及生物应用

One-step Self-assembly/polymerization Fabrication and Biomedical Application of Carboplatin@Dextran Nanocarrier†

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One-step Self-assembly/polymerization Fabrication and Biomedical Application of Carboplatin@Dextran Nanocarrier^†