Biomaterials 2012 Jan;33 (1): 146-62. [IF:7.882]
A paclitaxel-conjugated adenovirus vector for targeted drug delivery for tumor therapy.
Shan L , Cui S , Du C , Wan S , Qian Z , Achilefu S , Gu Y .
Department of Biomedical Engineering, School of Life Science and Technology, China Pharmaceutical University, Nanjing 210009, China; Department of Biochemistry Pharmacy, School of Chemistry and Life Science, SuZhou University, SuZhou 234000, China.
苏州大学生命科学学院，中国药科大学生命科学与技术学院生物医学工程
Abstract
Tumor-targeted drug delivery is an attractive strategy in cancer treatment. Our previous study demonstrated that modified adenovirus has strong tumor targeting ability and less toxicity to surrounding normal tissue. In this study, Paclitaxel (PTX), a widely used clinical anticancer drug, was conjugated to folate-modified adenovirus (Ad) nanoparticles by using succinic anhydride and Fmoc-Glu(OtBu)-OH linkers to form two prodrugs, FA-Ad-Suc-PTX and FA-Ad-ICG02-Glu-PTX. Near-infrared (NIR) fluorescent dye ICG-Der-02 was attached to -NH(2)-Glu(OtBu)-PTX for in vivo optical imaging. In vitro and acute toxicity study demonstrates the low toxicity of the prodrug FA-Ad-Suc-PTX and FA-Ad-ICG02-Glu-PTX compared to the free drug. The dynamic behaviors and targeting ability of FA-Ad-ICG02-Glu-PTX on MDA-MB-231 tumor-bearing mice were investigated by NIR fluorescence imaging. The result show that PTX-conjugated Ad vector could enhance the targeting and residence time in tumor site. In vitro and in vivo studies demonstrate that Coxsackie adenovirus receptor (CAR) or foliate receptor (FR)-mediated uptake of FA-Ad-loaded PTX induced highly anti-tumor activity. The results support the potential of using chemically modified Ad vector as drug-loaded tumor-targeting delivery system.
摘要:
在癌症治疗中，肿瘤靶向给药是一个引人注目的策略。我们以往的研究表明，经修饰的腺病毒有很强的肿瘤靶向能力并且对周围的正常组织的毒性较低。在这项研究中，通过利用丁二酐和Fmoc-Glu(OtBu)-OH(Fmoc保护氨基酸/一种产品名称)连接体使一种广泛应用于临床的抗癌药物紫杉醇（PTH）与经叶酸修饰的腺病毒（Ad）纳米粒结合形成两种前体药物：FA-Ad-Suc-PTX 和 FA-Ad-ICG02-Glu-PTX。在体内光学成像中，近红外（NIR）荧光染料ICG-Der-02被贴附在-NH(2)-Glu(OtBu)-PTX。体外和急性毒力研究表明：前体药物FA-Ad-Suc-PTX 和 FA-Ad-ICG02-Glu-PTX比游离药物的毒性低。FA-Ad-ICG02-Glu-PTX对 MDA-MB-231荷瘤小鼠的能动行为和靶向能力曾用近红外荧光成像调查研究。结果表明：紫杉醇（PTH）-腺病毒结合载体能提高靶向能力和在肿瘤部位的停留时间。体外和体内研究表明：柯萨奇病毒腺病毒受体（CAR）或叶酸受体（FR）介导的对FA-Ad-loaded PTX的摄取诱导高抗肿瘤活性。总的研究结果支持把经化学修饰的腺病毒载体作为有潜力的药载靶向肿瘤方式。
