碳酸钙纳米粒子用于靶向光动力治疗胰腺癌的实验研究  

Targeting photodynamic therapy using calcium carbonate nanoparticles against pancreatic cancer

作　　者：郭坤雄 王志华 郭婵娟 范应方[1] GUO Kunxiong;WANG Zhihua;GUO Chanjuan;FAN Yingfang(Department of Hepatobiliary Surgery,Zhujiang Hospi-tal,Southern Medical University,Guangzhou 510280,China)

机构地区：[1]南方医科大学珠江医院肝胆一科,广州510280

出　　处：《实用医学杂志》2022年第16期2024-2030,共7页The Journal of Practical Medicine

基　　金：广州市科技计划资助项目(编号:202206010093);广东省重点领域研发计划资助项目(编号:2020B010165004)。

摘　　要：目的观察碳酸钙纳米粒子靶向光动力治疗胰腺癌的疗效,并对其作用机制进行探索。方法采用气体扩散法制备装载光敏剂二氢卟吩e6(chlorine e6,Ce6)纳米粒子Ce6@CaCO3,聚乙二醇修饰后,物理吸附胰岛素样生长因子1受体(insulin-like growth factor 1 receptor,IGF-1R)的配体Linsitinib,最终合成酸响应的主动靶向型纳米粒子Ce6/Lins@CaCO3-PEG(CLCP),并进行理化性质表征。通过细胞和动物实验,观察CLCP主动靶向性及光动力治疗胰腺癌的效果。结果CLCP水合粒径为(121.5±5.2)nm,电镜下呈均匀分散的球形;CLCP中Ce6的包封率为63.2%、包载率为16.37%;CLCP在酸性(pH=6.5)环境下可迅速降解。细胞摄取实验表明胰腺癌细胞对CLCP摄取较非靶向组明显增多(P<0.001);活/死细胞染色及CCK-8实验表明,与非靶向组比较,CLCP光动力治疗后胰腺癌细胞活力明显下降(P<0.01)、死亡增多(P<0.001)。CLCP光动力治疗组小鼠生存期明显延长,病理提示肿瘤组织细胞凋亡增多,且流式细胞术表明肿瘤组织中CD8+T细胞比例增大。结论成功构建了基于IGF-1R的碳酸钙纳米粒子CLCP,靶向递送光敏剂Ce6并介导光动力治疗直接杀伤肿瘤细胞和激活抗肿瘤免疫,有效抑制了胰腺癌的生长,为胰腺癌的治疗提供了新思路。Objective The aim of this study was to explore the therapeutic effect and potential mechanism of targeting photodynamic therapy using calcium carbonate nanoparticles in pancreatic cancer.Methods Ce6@CaCO3were prepared by gas diffusion method to load Ce6,and then modified with polyethylene glycol.Linsitinib was used to target insulin-like growth factor 1 receptor(IGF-1R)to prepare CLCP nanoparticles with acid-responsive and active targeting abilities.The characterization of CLCP was investigated.The active targeting ability and the therapeutic effect of CLCP were evaluated in vitro and in vivo.Results The average hydrated size of CLCP was(121.5±5.2)nm with spherical shape under the electron microscope.The loading efficiency of Ce6 was 63.2%and the loading content was 16.37%.CLCP degraded rapidly in a weak acidic(pH=6.5)environment.Pancreatic cancer cells have increased uptake of CLCP(P<0.001).CLCP-mediated photodynamic therapy decreased cell viability(P<0.01)by inducing wider cells death compared with untargeted group(P<0.001).CLCP-mediated photodynamic therapy effectively prolonged the survival period of mice and pathologically caused cancer cells apoptosis increased.Besides,CLCP-mediated photodynamic therapy enhanced the recruitment of CD8+T cells in tumors.Conclusion We successfully synthesized the targeting CLCP based on IGF-1R to efficiently deliver Ce6,and CLCP-mediated photodynamic therapy has satisfactory therapeutic effect due to the direct killing of cancer cells and the activation of anti-tumor immune,which provides a novel strategy for pancreatic cancer treatment.

关 键 词：胰腺癌 碳酸钙 纳米粒子 光动力治疗 

分 类 号：R735.9[医药卫生—肿瘤]