Department of Materials Engineering, Graduate School of Engineering, The University of Tokyo , 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
ACS Nano. 2013 Oct 22;7(10):8583-92. doi: 10.1021/nn402662d. Epub 2013 Sep 18.
Ligand-mediated drug delivery systems have enormous potential for improving the efficacy of cancer treatment. In particular, Arg-Gly-Asp peptides are promising ligand molecules for targeting αvβ3/αvβ5 integrins, which are overexpressed in angiogenic sites and tumors, such as intractable human glioblastoma (U87MG). We here achieved highly efficient drug delivery to U87MG tumors by using a platinum anticancer drug-incorporating polymeric micelle (PM) with cyclic Arg-Gly-Asp (cRGD) ligand molecules. Intravital confocal laser scanning microscopy revealed that the cRGD-linked polymeric micelles (cRGD/m) accumulated rapidly and had high permeability from vessels into the tumor parenchyma compared with the PM having nontargeted ligand, "cyclic-Arg-Ala-Asp" (cRAD). As both cRGD/m- and cRAD-linked polymeric micelles have similar characteristics, including their size, surface charge, and the amount of incorporated drugs, it is likely that the selective and accelerated accumulation of cRGD/m into tumors occurred via an active internalization pathway, possibly transcytosis, thereby producing significant antitumor effects in an orthotopic mouse model of U87MG human glioblastoma.
配体介导的药物传递系统在提高癌症治疗效果方面具有巨大的潜力。特别是 Arg-Gly-Asp 肽是靶向 αvβ3/αvβ5 整合素的有前途的配体分子，αvβ3/αvβ5 整合素在血管生成部位和肿瘤中过度表达，如难治性人类脑胶质瘤（U87MG）。我们通过使用含有环 Arg-Gly-Asp（cRGD）配体分子的铂类抗癌药物结合聚合物胶束（PM），实现了对 U87MG 肿瘤的高效药物传递。活体共聚焦激光扫描显微镜显示，与具有非靶向配体“环 Arg-Ala-Asp”（cRAD）的 PM 相比，cRGD 连接的聚合物胶束（cRGD/m）从血管快速积累并具有高通透性进入肿瘤实质。由于 cRGD/m 和 cRAD 连接的聚合物胶束具有相似的特征，包括其大小、表面电荷和结合的药物量，因此 cRGD/m 选择性和加速进入肿瘤可能是通过主动内化途径发生的，可能是转胞吞作用，从而在 U87MG 人脑胶质瘤的原位小鼠模型中产生显著的抗肿瘤作用。
