Haeri Azadeh, Zalba Sara, Ten Hagen Timo L M, Dadashzadeh Simin, Koning Gerben A
Department of Pharmaceutics, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Center, Rotterdam, The Netherlands.
Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus MC Cancer Center, Rotterdam, The Netherlands.
Colloids Surf B Biointerfaces. 2016 Oct 1;146:657-69. doi: 10.1016/j.colsurfb.2016.06.012. Epub 2016 Jun 11.
The epidermal growth factor receptor (EGFR) is a promising target for anti-cancer therapy. The aim of this study was to design thermosensitive liposomes (TSL), functionalized with anti-EGFR ligands for targeted delivery and localized triggered release of chemotherapy. For targeting, EGFR specific peptide (GE11) and Fab' fragments of cetuximab were used and the effect of ligand density on in vitro tumor targeting was investigated. Ligand conjugation did not significantly change the physicochemical characteristics of liposomes. Fab'-decorated TSL (Fab'-TSL) can specifically and more efficiently bind to the EGFR overexpressed cancer cells as compared to GE11 modified TSL. Calcein labeled Fab'-TSL showed adequate stability at 37°C in serum (<4% calcein released after 1h) and a temperature dependent release at above 40°C. FACS analysis and live cell imaging showed efficient and EGFR mediated cellular association as well as dramatic intracellular cargo release upon hyperthermia. Fab'-conjugation and hyperthermia induced enhanced tumor cell cytotoxicity of doxorubicin loaded TSL. The relative cytotoxicity of Fab'-TSL was also correlated to EGFR density on the tumor cells. These results suggest that Fab'-TSL showed great potential for combinational targeted and triggered release drug delivery.
表皮生长因子受体（EGFR）是抗癌治疗中一个很有前景的靶点。本研究的目的是设计热敏脂质体（TSL），用抗EGFR配体进行功能化修饰，以实现化疗药物的靶向递送和局部触发释放。为了实现靶向，使用了EGFR特异性肽（GE11）和西妥昔单抗的Fab'片段，并研究了配体密度对体外肿瘤靶向性的影响。配体偶联并未显著改变脂质体的物理化学特性。与GE11修饰的TSL相比，Fab'修饰的TSL（Fab'-TSL）能更特异性、更有效地结合过表达EGFR的癌细胞。钙黄绿素标记的Fab'-TSL在37°C血清中显示出足够的稳定性（1小时后钙黄绿素释放<4%），且在40°C以上有温度依赖性释放。流式细胞术分析和活细胞成像显示，热疗后有高效的、EGFR介导的细胞结合以及显著的细胞内药物释放。Fab'偶联和热疗诱导了载有多柔比星的TSL对肿瘤细胞的细胞毒性增强。Fab'-TSL的相对细胞毒性也与肿瘤细胞上的EGFR密度相关。这些结果表明，Fab'-TSL在组合靶向和触发释放药物递送方面具有巨大潜力。
