Suppression of pancreatic tumor growth by targeted arsenic delivery with anti-CD44v6 single chain antibody conjugated nanoparticles.
Suppression of pancreatic tumor growth by targeted arsenic delivery with anti-CD44v6 single chain antibody conjugated nanoparticles.
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DOI：
10.1016/j.biomaterials.2013.04.056
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发表时间：
2013-08
期刊：
影响因子：
14
通讯作者：
Chenchen Qian;Yong Wang;Yinting Chen;L. Zeng;Qiu-bo Zhang;X. Shuai;Kaihong Huang
中科院分区：
文献类型：
--
作者：
Chenchen Qian;Yong Wang;Yinting Chen;L. Zeng;Qiu-bo Zhang;X. Shuai;Kaihong Huang
三氧化二砷（As_2O_3）是一种很有前途的抗实体瘤药物。然而，由于缺乏肿瘤特异性而导致的对正常组织的高毒性仍然是其全身应用的巨大挑战。靶向载体能够将药物递送到特定的癌细胞，从而在癌症治疗中带来更好的治疗效果和低副作用的巨大潜力。我们的前期工作已经证明，从人源噬菌体展示单链抗体库中筛选出的抗CD 44 v6单链抗体（scFvCD 44 v6）对胰腺癌、肝细胞癌、结直肠癌和胃癌等上皮源性肿瘤中过表达的膜抗原CD 44 v6具有高度的特异性和亲和力。本文合成了马来酰亚胺官能化的聚乙二醇和聚丙交酯两亲性嵌段共聚物（mal-PEG-PDLLA），并组装成亚砷酸根离子（As）包封在其核中的囊泡（As-NPs）。将scFvCD 44 v6与mal-PEG-PDLLA偶联（scFv-As-NPs）能够更有效地递送As，并且在人胰腺癌细胞PANC-1中表现出比非靶向的As-NPs更高的细胞毒活性。此外，靶向递送的As诱导更显着的基因抑制的抗凋亡Bcl-2蛋白的表达。因此，作为细胞凋亡的分子指标的切割的半胱天冬酶-3的表达水平显著升高。在动物实验中，发现scFv-As-NPs极大地增加了药物在肿瘤部位的积聚，并且由于增强了细胞凋亡而增强了As抑制肿瘤生长的功效。这些结果意味着我们的肿瘤特异性纳米载体为胰腺癌治疗提供了一个高效和安全的平台。
Arsenic trioxide (As2O3) is a promising anticancer agent for solid tumors. However, the high toxicity to normal tissues resulting from the lack of tumor specificity remains a huge challenge in its systemic application. Targeted vectors enabling drug delivery to specific cancer cells bring about great potential for better therapeutic efficacy whereas low side effects in cancer treatments. Our previous work has demonstrated that the anti-CD44v6 single chain variable fragment (scFvCD44v6) screened out from the human phage-displayed scFv library possesses high specificity and affinity to membrane antigen CD44v6 over-expressing in a subset of epithelium-derived cancers, such as pancreatic, hepatocellular, colorectal and gastric cancers. Herein, a maleimide-functionalized amphiphilic diblock copolymer of poly (ethylene glycol) and poly (d, l-lactide) (mal-PEG-PDLLA) was synthesized and assembled to vesicles with arsenite ion (As) encapsulated in their cores (As-NPs). Conjugation of scFvCD44v6with mal-PEG-PDLLA (scFv-As-NPs) enabled more efficient delivery of As and exhibited higher cytotoxic activity than non-targeted ones (As-NPs) in human pancreatic cancer cells PANC-1. Furthermore, the targeted delivery of As induced more significant gene suppression in terms of the expression of anti-apoptotic Bcl-2 protein. Consequently, the expression level of cleaved caspase-3 which is a molecular indicator of cell apoptosis was remarkably elevated. In animal tests, scFv-As-NPs were found to greatly increase accumulation of drug in tumor site and potentiate the efficacy of As in inhibiting tumor growth owing to the enhanced cell apoptosis. These results imply that our tumor specific nanocarriers provide a highly efficient and safe platform for pancreatic cancer therapy.