RGD修饰共载多烯紫杉醇和苏拉明脂质体乳腺癌靶向治疗研究  

RGD modified Docetaxel and Suramin loaded liposome for breast cancer targeting therapy

作　　者：王晓珊[1] 黄艳[2] 刘迪[1] 梁良[1] 罗树春[1] 刘锦平[1] 

机构地区：[1]四川省人民医院肿瘤科,四川成都610072 [2]四川省人民医院乳腺外科,四川成都610072

出　　处：《中华肿瘤防治杂志》2014年第22期1783-1787,1793,共6页Chinese Journal of Cancer Prevention and Treatment

基　　金：四川省人民医院2013青年基金(30305030605)

摘　　要：目的构建RGD修饰共载多烯紫杉醇(docetaxel,DOC)和苏拉明(suramin,Su)的靶向脂质体(RGDLP-DOC/Su),研究RGDLP-DOC/Su对乳腺癌的靶向性和治疗效果。方法用薄膜分散法制备RGDLP-DOC/Su,研究其粒径、电位和包封率等理化性质。以PBS组为对照,将MCF-7细胞和血管内皮细胞HUVEC细胞分为未修饰共载药脂质体组(LP-DOC/Su)、RGD修饰多烯紫杉醇脂质体组(RGDLP-DOC)、RGD修饰苏拉明脂质体组(RGDLP-Su)和RGD修饰共载药脂质体组(RGDLP-DOC/Su)。MTT法检测不同脂质体对MCF-7细胞和HUVEC细胞增殖的影响,流式细胞术检测MCF-7细胞和HUVEC细胞对脂质体摄取效率。构建乳腺癌MCF-7细胞体外肿瘤球模型,研究脂质体的肿瘤球穿透能力;构建裸鼠乳腺癌异位模型,研究不同脂质体对肿瘤的生长抑制能力。结果 RGDLP-DOC/Su的粒径为(130±15.5)nm,电位为(4±1.55)mV,DOC与Su的包封率分别为(82.5±5.5)%和(85.6±8.1)%。MTT实验结果显示,乳腺癌MCF-7细胞给药48h后,对乳腺癌MCF-7细胞抑制率LP-DOC/Su为(36.4±2.01)%,RGDLP-DOC为(48.5±3.12)%,RGDLP-Su为(32.2±2.84)%,RGDLP-DOC/Su为(78.7±5.44)%。RGD修饰DOC脂质体和Su脂质体联合对MCF-7乳腺癌细胞增殖抑制率存在交互效应,F=230.075,P<0.001。HUVEC细胞给药48h后,对HUVEC细胞抑制率LP-DOC/Su为(34.5±2.58)%,RGDLP-DOC为(44.8±2.95)%,RGDLP-Su为(42.6±3.11)%,RGDLP-DOC/Su为(88.2±6.18)%,RGD修饰DOC脂质体和Su脂质体对HUVEC细胞增殖抑制率存在交互效应,F=197.093,P<0.001。MCF-7细胞对RGDLP的摄取效率是普通脂质体的2.4倍,差异有统计学意义,t=35.877,P<0.001;HUVEC细胞对RGDLP的摄取效率是普通脂质体的3.1倍,差异有统计学意义,t=70.159,P<0.001。相比于PBS组,LP-DOC/Su、RGDLP-DOC、RGDLP-Su和RGDLP-DOC/Su对肿瘤生长的抑制率分别为(21.4±5.5)%、(38.5±7.2)%、(28.6±6.4)%和(72.5±8.3)%,RGD修饰DOC脂质体和Su脂质体对肿瘤生长的抑制率存在交互效应,F=37.420,P<0.001。PBS、LP-DOC/Su、RGDLP-DOC、RGDLP-Su和OBJECTIVE To prepare RGD conjugated docetaxel （DOC） and suramin （Su） loaded liposome （RGDLP-DOC/Su）and evaluate their anti-cancer effect on the treatment of breast cancer. METHODS The liposomes were prepared by thin film hydration method. The appearance, particle size and Zeta potential were evaluated. The anti- proliferation efficiency of （RGDLP-DOC/Su） was evaluated by MTT assay. The efficiency of cellular uptake on MCF-7 cells and HUVEC cells in vitro was evaluated. Tumor spheroids were also used to evaluate penetration of RGDLP. MCF-7 cells were xenografted in mice to establish the animal model, which were used to evaluate the effect of anti-tumor. RESULTS The particle diameter of the liposome was （130 ±15.5） nm with the Zeta potential of （4±1.55） inV. The entrapment effieiencies of DOC and Su were （82.5±5.5） % and （85.6±8.1）% respectively. The MCF-7 cells inhibitoryrate was （36.4±2.01）%,（48.5±3.12）%0 ,（32.2±2.84）% and （78.7±5.44）% for LP-DOC/Su,RGDLP DOC, RG- DLP-Su and RGDLP-DOC/Su（F = 230. 075, P〈0. 001）% The HUVEC ceils inhibitory rate was （34. 5±2. 58）%, （44.8±2.95） %, （42.6±3.11）% and （88.2±6.18）% for LP-DOC/Su,RGDLP-DOC,RGDLP-Su and RGDLP-DOC/Su （F=197. 093, P〈0. 001）; The result demonstrated that RGDLP uptaken by MCF-7 cells were 2.4 times higher than that of LP（t=35. 877,P〈0. 001） ;RGDLP uptaken by HUVEC cells were 3.1 times higher than that of LP（t=70. 159, P〈0. 001）;compare to PBS,the tumor inhibitory rate was （21.4±5.5）%, （38.5±7.2）%, （28.6±6.4）% and （72.5±8.3）% in vivo for LP-DOC/Su, RGDLP-DOC, RGDLP-Su and RGDLP-DOC/Su（F = 37. 420, P〈 0.001）. The quality of PBS,LP-DOC/Su,RGDLP-DOC,RGDLP Su, RGDLP-DOC/Su were （5.82±0.35） g, （4.57±0.28） g, （3.58±0.37） g, （4.16±0.45） g and （1.60±0.22） g respectively. CONCLUSION RGDLP-DOC/Su showed highly affinity to MCF-7 ceils and HUVEC cells and it is a potential delivery system for tumor and new vascular targeting

关 键 词：整合素受体 苏拉明 多烯紫杉醇 脂质体 乳腺肿瘤 

分 类 号：R737.9[医药卫生—肿瘤]