针对K-Ras(G12C)突变肿瘤的还原响应型纳米胶束的制备及评价
Preparation and evaluation of reduction-responsive nanomicelles for K-Ras(G12C)mutant tumors
卢贵茹 1刘阳 1刘晶阳 1冯友成 1马孟城 2张壮壮 3付志远4
作者信息
- 1. 信阳职业技术学院附属医院药学部,河南 信阳 464000
- 2. 信阳市中心医院药学部,河南 信阳 464000
- 3. 宁波宝亭生物科技有限公司,浙江 宁波 315000
- 4. 生物治疗全国重点实验室,成都 610000
- 折叠
摘要
目的 以不同分子量的巯基化聚乙二醇和K-Ras(G12C)抑制剂6合成一系列还原敏感型高分子前药(PERI),制备并筛选出最优纳米胶束(PERIs胶束),考察其理化性质和体外抗肿瘤作用.方法 通过二硫键将巯基化聚乙二醇与小分子抑制剂结合,得到还原敏感型PERIs高分子前药,通过其自组装制备PERIs胶束.透射电镜观察其形态;粒度仪测定其粒径和表面电位;芘荧光探针法测定其临界胶束浓度;间接法测定其载药量及包封率;透析法测定其在不同还原条件下的体外释药行为;采用CCK-8法评价其细胞增殖毒性.结果 核磁共振氢谱表明PERIs成功合成;PERIs胶束(Mw:2000)的平均粒径为(95.76±1.8)nm,多分散系数为(0.189±0.0084),Zeta 电位为-(7.07±0.14)mV,临界胶束浓度为 0.875 μg·mL-1,载药量为(11.5±0.16)％,包封率为(71.6士0.83)％;体外释放度实验表明PERIs胶束具有还原敏感性;细胞毒性实验表明PERIs胶束对肿瘤细胞有较强的增殖抑制作用.结论 制备的PERIs胶束(Mw:2000)粒径均一,分散性及稳定性良好,具有控释能力,并对肿瘤细胞有较强的增殖抑制作用.
Abstract
Objective To synthesize a series of reduction-sensitive macromolecular predrugs from thiolated polyethylene glycol of different molecular weights and K-Ras(G12C)inhibitor 6 to prepare nanomicelles,and to screened the optimal nanomicelle(PERIs micelles)to evaluate its physicochemical property and anti-tumor effect in vitro.Methods Through disulfide bonds,the thiolated polyethylene glycol was combined with K-Ras(G12C)inhibitor 6 to form reduction sensitive PERIs predrug nanocarriers,and PERIs micelles were prepared by its self-assembly property.The morphology was observed by transmission electron microscopy.The particle size and Zeta potential were measured by particle size analyzer.The critical micelle concentration was determined by pyrene-based fluorescence probe.Drug loading and encapsulation rate were measured indirectly.Drug release of the micelles was evaluated by dialysis,and cytotoxicity was evaluated by CCK-8.Results A series of reduction-sensitive macromolecular predrugs(PERI)were verified by 1H-NMR.Based on the size,surface potential and drug loading,PERIs micelles(Mw:2000)was screened for subsequent experiments.The mean particle size was(95.76±1.8)nm with a polydispersity index of(0.189±0.0084),Zeta potential was-(7.07±0.14)mV,critical micelle concentration was 0.875 μg·mL-1,the drug loading was(11.5±0.16)％and the encapsulation rate was(71.6±0.83)％.The drug release experiments in vitro showed that PERIs were sensitive to reduction.Cytotoxicity analysis showed that PERIs effectively inhibited the proliferation of tumor cells.Conclusion The prepared PERIs micelles(Mw:2000)exhibits uniform particle size,good dispersion and stability,sustained drug release,and strong proliferation inhibition of tumor cells.
关键词
巯基化聚乙二醇/K-Ras(G12C)抑制剂6/还原敏感/前药纳米胶束Key words
thiolated polyethylene glycol/K-Ras(G12C)inhibitor 6/reduction-sensitive/predrug nanomicelle引用本文复制引用
出版年
2024
NETL
NSTL
万方数据