Int J Nanomedicine 2011 ;6 2337-49. [IF:4.976]
Multifunctional dendrimer/combretastatin A4 inclusion complexes enable in vitro targeted cancer therapy.
Zhang M , Guo R , Wang Y , Cao X , Shen M , Shi X .
State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, Donghua University, Shanghai, People's Republic of China.
上海东华大学纤维材料改性国家重点实验室
Abstract
We report here a unique approach to using multifunctional dendrimer/combretastatin A4 (CA4) inclusion complexes for targeted cancer therapeutics. Amine-terminated generation 5 polyamidoamine dendrimers were first partially acetylated to neutralize a significant portion of the terminal amines, and then the remaining dendrimer terminal amines were sequentially modified with fluorescein isothiocyanate as an imaging agent and folic acid as a targeting ligand. The multifunctional dendrimers formed (G5.NHAc-FI-FA) were utilized to encapsulate the anticancer drug, CA4, for targeted delivery into cancer cells overexpressing folic acid receptors. The inclusion complexes of G5.NHAc-FI-FA/CA4 formed were stable and are able to significantly improve the water solubility of CA4 from 11.8 to 240 μg/mL. In vitro release studies showed that the multifunctional dendrimers complexed with CA4 could be released in a sustained manner. Both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colorimetric assay and morphological cell observation showed that the inhibitory effect of the G5.NHAc-FI-FA/CA4 complexes was similar to that of free CA4 at the same selected drug concentration. More importantly, the complexes were able to target selectively and display specific therapeutic efficacy to cancer cells overexpressing high-affinity folic acid receptors. Multifunctional dendrimers may serve as a valuable carrier to form stable inclusion complexes with various hydrophobic anticancer drugs with improved water solubility, for targeting chemotherapy to different types of cancer.
摘要：
我们在此报告了一种使用多功能树形分子/考布他汀A4（CA4）包合络合物的独特的靶向肿瘤治疗方法。胺末端的5代聚酰胺树形分子首先被部分乙酰化以中和大部分的胺末端，接着借助异硫氰酸荧光素为显影剂，以叶酸为配体，保留下来的树形分子的末端胺被连续修饰。形成的多功能树形分子(G5.NHAc-FI-FA)用来封装抗癌药物CA4, 以靶向运送药物至过度表达叶酸受体的肿瘤细胞。形成的G5.NHAc-FI-FA/CA4络合物性质稳定且能将CA4的水溶性从11.8 μg/mL明显提高至 240 μg/mL。体外释放研究表明，结合了CA4的多功能树形分子可以恒定释放。溴化3-（4,5-二甲基-2-羟基）-2,5-二苯基四唑比色测定和形态学细胞观察显示相同选定药物浓度，G5.NHAc-FI-FA/CA4复合物的抑制功效与游离的CA4相似。更重要的是，该复合物具有靶向选择性，并且显示出对过度表达高亲和性叶酸受体的肿瘤细胞具有特异的治疗效果。在对不同种类肿瘤进行靶向化疗时，与各种疏水性抗肿瘤药形成稳定的包合络合物具有较高的水溶性，多功能树形分子可能在其中充当了重要载体的角色。
