Shi Wei, Yin Yanxue, Wang Yao, Zhang Bo, Tan Pei, Jiang Ting, Mei Heng, Deng Jun, Wang Huafang, Guo Tao, Pang Zhiqing, Hu Yu
Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology, Wuhan, Hubei, China.
Targeted Biotherapy Key Laboratory of Ministry of Education, Wuhan, Hubei, China.
Oncotarget. 2017 May 9;8(19):32212-32227. doi: 10.18632/oncotarget.12922.
Tumor requires tumor vasculature to supply oxygen and nutrients so as to support its continued growth, as well as provide a main route for metastatic spread. In this study, a TF-cascade-targeted strategy aiming to disrupt tumor blood vessels was developed by combination of TF-targeted HMME-loaded drug delivery system and PDT. PDT is a promising new modality in the treatment of cancers, which employs the interaction between a tumor-localizing photosensitizer and light of an appropriate wavelength to bring about ROS-induced cell death. In vitro results showed that protein EGFP-EGF1modification could significantly contribute to the uptake of nanoparticles by TF over-expressed BCECs. In vivo multispectral fluorescent imaging, the EGFP-EGF1 conjugated nanoparticles showed significantly higher accumulation in tumor tissues than non-conjugated ones. Tumor tissue slides further presented that EGFP-EGF1 conjugated nanoparticles showed significantly higher accumulation in tumor vasculature than non-conjugated ones. In vitro study demonstrated that PDT increased TF expression of BCECs. In vivo imaging, ex vivo imaging and tumor tissue slides showed that PDT further contribute EGFP-EGF1-NP accumulation in tumor. These promising results indicated that PDT enhanced EGFP-EGF1modified PEG-PLGA nanoparticle accumulation in tumor vaculature. Considering that EGFP-EGF1 conjugation enhanced nanoparticles uptake by TF over-expressed endothelium and PDT increased endothelium TF expression. We conclude that PDT triggered a TF cascade targeted effect. A combination of both EGFP-EGF1 modification and PDT provided a positive feed-back target effect to tumor vessels and might have a great potential for tumor therapy.
肿瘤需要肿瘤血管系统来供应氧气和营养物质，以支持其持续生长，并为转移扩散提供主要途径。在本研究中，通过将靶向转铁蛋白（TF）的载有血卟啉单甲醚（HMME）的药物递送系统与光动力疗法（PDT）相结合，开发了一种旨在破坏肿瘤血管的TF级联靶向策略。PDT是一种很有前景的癌症治疗新方法，它利用肿瘤定位光敏剂与适当波长的光之间的相互作用，引发活性氧（ROS）诱导的细胞死亡。体外结果表明，蛋白质增强型绿色荧光蛋白-表皮生长因子1（EGFP-EGF1）修饰可显著促进转铁蛋白过表达的脑微血管内皮细胞（BCECs）对纳米颗粒的摄取。在体内多光谱荧光成像中，与未偶联的纳米颗粒相比，EGFP-EGF1偶联的纳米颗粒在肿瘤组织中的积累显著更高。肿瘤组织切片进一步显示，与未偶联的纳米颗粒相比，EGFP-EGF1偶联的纳米颗粒在肿瘤血管系统中的积累显著更高。体外研究表明，PDT可增加BCECs的转铁蛋白表达。体内成像、离体成像和肿瘤组织切片显示，PDT进一步促进了EGFP-EGF1-纳米颗粒（NP）在肿瘤中的积累。这些有前景的结果表明，PDT增强了EGFP-EGF1修饰的聚乙二醇-聚乳酸-羟基乙酸共聚物（PEG-PLGA）纳米颗粒在肿瘤血管中的积累。考虑到EGFP-EGF1偶联增强了纳米颗粒被转铁蛋白过表达的内皮细胞摄取，且PDT增加了内皮细胞转铁蛋白表达。我们得出结论，PDT触发了TF级联靶向效应。EGFP-EGF1修饰和PDT的联合为肿瘤血管提供了正反馈靶向效应，可能在肿瘤治疗中具有巨大潜力。
