多种放射性核素标记聚多巴胺纳米载体的初步应用评价  

Preliminary application evaluation of polydopamine nano-carriers labeled with multiple radionuclides

作　　者：李亚渊 安杰[1] 贺鑫怡 菅少洁 崔曹哲 鄢敏[1] 高洁 武志芳[1] Li Yayuan;An Jie;He Xinyi;Jian Shaojie;Cui Caozhe;Yan Min;Gao Jie;Wu Zhifang(Department of Nuclear Medicine,First Hospital of Shanxi Medical University,Taiyuan 030001,China;National Atomic Energy Agency Nuclear Technology(Non Clinical Evaluation of Radioactive Drugs)Center,Taiyuan 030006,China)

机构地区：[1]山西医科大学第一医院核医学科,太原030001 [2]国家原子能机构核技术(放射性药物非临床评价)研发中心,太原030006

出　　处：《中华核医学与分子影像杂志》2023年第6期365-370,共6页Chinese Journal of Nuclear Medicine and Molecular Imaging

基　　金：国家自然科学基金(81971655,82102103)。

摘　　要：目的制备^(131)I、^(99)Tc^(m)和^(177)Lu标记的表面修饰了声敏剂原卟啉(PpⅨ)的聚多巴胺(PDA),探讨这些新型化纳米探针在乳腺癌诊断与联合治疗中的价值。方法采用水相氧化法合成PDA颗粒,并在其表面分别修饰1层聚乙二醇(PEG)和PpⅨ,合成PDA-PEG-PpⅨ。然后分别进行^(131)I、^(99)Tc^(m)和^(177)Lu标记,检测标记产率与稳定性。进行细胞毒性实验,比较^(131)I-PDA-PEG-PpⅨ组和游离^(131)I组小鼠乳腺癌细胞4T1的存活率差异;设PDA-PEG-PpⅨ、PDA-PEG-PpⅨ+光热治疗(PTT)或声动力治疗(SDT)、^(131)I-PDA-PEG-PpⅨ+PTT或SDT、^(131)I-PDA-PEG-PpⅨ+PTT+SDT(100μg/ml PDA-PEG-PpⅨ,925 kBq/ml^(131)I)组和对照组(DMEM培养基),比较各组4T1细胞的存活率。经荷4T1乳腺癌BALB/c小鼠尾静脉(29.6 MBq)或瘤内(14.8 MBq)注射^(99)Tc^(m)-PDA-PEG-PpⅨ后,用γ相机观察肿瘤的显像剂摄取情况。采用两独立样本t检验和单因素方差分析进行数据分析。结果PDA颗粒大小均一,粒径为(160.0±1.5)nm,具有良好的光热转换效果。PDA-PEG-PpⅨ紫外-可见吸收光谱中出现了与PpⅨ(400 nm)相一致的特征峰。在放射性浓度为1.850、3.700和7.400 MBq/ml时,^(131)I-PDA-PEG-PpⅨ组较游离^(131)I组细胞存活率降低[(72.18±6.57)%与(86.07±5.17)%、(59.31±9.06)%与(80.85±4.21)%、(42.90±1.30)%与(72.99±5.73)%;t值:3.71、4.82、11.46,P值:0.006、0.001、<0.001]。^(131)I-PDA-PEG-PpⅨ+PTT+SDT的三模态联合治疗对4T1肿瘤细胞的杀伤效果优于^(131)I-PDA-PEG-PpⅨ+PTT或SDT治疗[细胞存活率:(10.09±2.50)%、(16.04±2.63)%和(28.65±4.72)%;F=351.66,P<0.001]。γ显像示,^(99)Tc^(m)-PDA-PEG-PpⅨ在小鼠体内稳定且能够在肿瘤内有效富集。结论成功制备了以PDA为载体的多功能纳米探针。核素标记方法简单有效,稳定性好。^(131)I-PDA-PEG-PpⅨ对4T1细胞杀伤能力强。^(99)Tc^(m)-PDA-PEG-PpⅨ在荷4T1乳腺癌小鼠模型内有明显的肿瘤浓聚效果。Objective To prepare nanoprobes by using polydopamine(PDA)as a carrier which is modified with the sonosensitizer protoporphyrinⅨ(PpⅨ)and labeled with ^(131)I,^(99)Tc^(m) or ^(177)Lu,and to explore the value of these new nanoprobes in diagnosis and combination therapy of breast cancer.Methods PDA particles were synthesized by aqueous oxidation,and a layer of polyethylene glycol(PEG)and PpⅨwere modified on the surface to product PDA-PEG-PpⅨ.Then the nuclides ^(131)I,^(99)Tc^(m) and ^(177)Lu were labeled on PDA,respectively,and the labeling yield and stability were determined.The cytotoxicity test was conducted by comparing the viabilities of 4T1 tumor cells in free ^(131)I group and ^(131)I-PDA-PEG-PpⅨgroup.The 4T1 cells were divided into 7 groups according to different treatment methods:PDA-PEG-PpⅨgroup,PDA-PEG-PpⅨ+photothermal therapy(PTT)group,PDA-PEG-PpⅨ+sonodynamic therapy(SDT)group,^(131)I-PDA-PEG-PpⅨ+PTT group,^(131)I-PDA-PEG-PpⅨ+SDT group,^(131)I-PDA-PEG-PpⅨ+PTT+SDT group(100μg/ml PDA-PEG-PpⅨ,925 kBq/ml ^(131)I),and the control group(DMEM culture medium).The cell viabilities of those groups were compared to evaluate the therapeutic effect.4T1 tumor bearing mouse models were established,then ^(99)Tc^(m)-PDA-PEG-PpⅨwas injected through the tail vein(29.6 MBq)or intratumorally(14.8 MBq)to perform gamma imaging.The independent-sample t test and one-way analysis of variance were used for data analysis.Results The PDA particles were uniform in size,with a particle size of(160.0±1.5)nm.They had a good photothermal conversion effect.A characteristic peak consistent with PpⅨ(400 nm)appeared in the UV-Vis absorption spectrum of PDA-PEG-PpIX.In the cytotoxicity test,when the radioactivity was 1.850 or 3.700 or 7.400 MBq/ml,the cell viabilities of free ^(131)I group and ^(131)I-PDA-PEG-PpⅨgroup were significantly different((72.18±6.57)%vs(86.07±5.17)%,(59.31±9.06)%vs(80.85±4.21)%,(42.90±1.30)%vs(72.99±5.73)%;t values:3.71,4.82,11.46,P values:0.006,0.001,<0.001).The ^(131)I-PDA-PEG-

关 键 词：乳腺肿瘤 纳米粒子 聚合物 原卟啉类 同位素标记 肿瘤细胞 培养的 小鼠 

分 类 号：R817.9[医药卫生—影像医学与核医学]