海藻酸钠前药纳米粒在肿瘤光动力治疗中的应用研究  

Redox-sensitive Alginate Prodrug Nanoparticles for Tumor Photodynamic Therapy

作　　者：秦怡博 杨鹏翔 时圣彬 孙洪范[1] 张闯年 孔德领[1,2] Yi-bo Qin;Peng-xiang Yang;Sheng-bin Shi;Hong-fan Sun;Chuang-nian Zhang;De-ling Kong(Tianjin Key Laboratory of Biomaterial Research,Institute of Biomedical Engineering,Chinese Academy of Medical Science ＆ Peking Union Medical College,Tianjin 300192;Key Laboratory of Bioactive Materials,Ministry of Education,State Key Laboratory of Medicinal Chemical Biology,College of Life Science,Nankai University,Tianjin 300071)

机构地区：[1]生物医学工程研究所天津市生物医用材料重点实验室中国医学科学院北京协和医学院,天津300192 [2]生物活性材料教育部重点实验室药物化学生物学国家重点实验室南开大学生命科学学院,天津300071

出　　处：《高分子学报》2018年第7期909-916,共8页Acta Polymerica Sinica

基　　金：国家自然科学基金(基金号21604095);中国医学科学院医学与健康科技创新工程项目(项目号2017-I2M-3-022)资助

摘　　要：利用具有还原敏感性的胱胺将疏水性光敏剂脱镁叶绿酸盐A(Pheo A)偶联到天然多糖海藻酸钠(ALG)上,得到同时具有光敏性和还原敏感性的两亲性多糖前药(Pheo A-ALG),再通过疏水相互作用自组装形成前药纳米粒(Pheo A-ALG NPs),应用于肿瘤光动力治疗.对Pheo A-ALG NPs的理化性质进行了评价,体外考察Pheo A-ALG NPs的释药行为、细胞胞吞及胞内ROS,并重点研究了Pheo A-ALG NPs的体外细胞毒性以及体内抑瘤活性.Nanoparticles have been extensively explored as an effective means to deliver photosensitizers for photodynamic therapy（PDT） against cancer. In this work, Pheophorbide A（Pheo A）, a hydrophobic photosensitizer, was conjugated to natural polysaccharide alginate（Pheo A-ALG） via a redox-sensitive disulfide linkage. The critical aggregation concentration（CAC） of Pheo A-ALG in aqueous solution was 73.51 μg/m L,detected by pyrene monomer fluorescence probe technology. The resulting amphiphilic Pheo A-ALG could form self-assembled nanoparticles（Pheo A-ALG NPs） in an aqueous medium as prodrug nanoparticles for tumor photodynamic therapy. The physical and chemical properties of Pheo A-ALG NPs were studied. TEM and DLS revealed that Pheo A-ALG NPs were monodisperse spherical structures with a hydrodynamic diameter about198 nm. Pheo A release profiles in vitro indicated that Pheo A release from Pheo A-ALG NPs was redox-sensitive.Whereafter, the cellular uptake and cytotoxicity of Pheo A-ALG NPs were investigated in vitro. Cellular uptake results showed that Pheo A-ALG NPs were readily taken up by B16 tumor cells and enhanced Pheo A uptake was detectable in Pheo A-ALG NPs-treated B16 cells in comparison to carrier free drugs. Under light irradiation,Pheo A-ALG NPs also elicited intracellular ROS generation, which led to an enhanced toxicity in B16 cells both in vitro and in vivo. The CCK-8 assay showed that Pheo A-ALG NPs had good cellular compatibility without cytotoxic in vitro without light irradiation, and Pheo A-ALG NPs exhibited light dependent cytotoxic response to B16 cells. After light irradiation, IC50 of Pheo A-ALG NPs decreased to 0.16 μg m L-1, which was about 0.67-fold lower than those of the free Pheo A groups with light irradiation. In vivo anti-tumor efficacy of Pheo A-ALG NPs was assessed using B16 tumor-bearing mice. Notably, mice treated with Pheo A-ALG NPs under light irradiation displayed the highest inhibition ratio of 72.8%, among those treated with free Pheo A（45.8%）. These r

关 键 词：海藻酸钠 还原敏感性 前药纳米粒 光动力治疗 

分 类 号：TB383.1[一般工业技术—材料科学与工程] TQ460.1[化学工程—制药化工]