Targeted nanoparticles that deliver a sustained, specific release of Paclitaxel to irradiated tumors.
Targeted nanoparticles that deliver a sustained, specific release of Paclitaxel to irradiated tumors.
复制标题
DOI：
10.1158/0008-5472.can-10-0339
复制
发表时间：
2010-06-01
期刊：
影响因子：
11.2
通讯作者：
Diaz R
中科院分区：
文献类型：
--
作者：
Passarella RJ;Spratt DE;van der Ende AE;Phillips JG;Wu H;Sathiyakumar V;Zhou L;Hallahan DE;Harth E;Diaz R
为了利用肿瘤细胞对电离辐射的反应，我们开发了一种控释纳米颗粒药物递送系统，该系统使用识别辐射诱导的细胞表面受体的靶向肽。噬菌体展示生物淘选将 Gly-Ile-Arg-Leu-Arg-Gly (GIRLRG) 鉴定为一种肽，可选择性识别对电离辐射有反应的肿瘤。经辐照的神经胶质瘤细胞的膜蛋白提取物鉴定出葡萄糖调节蛋白 GRP78 作为 GILRRG 的受体靶点。 GRP78 抗体在体外和体内阻断 GIRLRG 的结合。将 GIRLRG 与缓释纳米颗粒药物递送系统结合，可在长达三周的时间内增加受辐射乳腺癌中紫杉醇的浓度和细胞凋亡。与对照组相比，在MDA-MB-231中单次向受辐射肿瘤施用GIRLRG靶向纳米颗粒药物递送系统可将体内肿瘤三倍化时间延迟55天（P=0.0001），在GL261中延迟12天（P<0.005）。这种靶向剂将新型重组肽与紫杉醇封装纳米颗粒相结合，专门针对受辐射的肿瘤，以优于已知化疗方法的方式增加细胞凋亡和延迟肿瘤生长。
To capitalize on the response of tumor cells to ionizing radiation, we developed a controlled-release nanoparticle drug delivery system using a targeting peptide that recognizes a radiation-induced cell surface receptor. Phage display biopanning identified Gly-Ile-Arg-Leu-Arg-Gly (GIRLRG) as a peptide that selectively recognizes tumors responding to ionizing radiation. Membrane protein extracts of irradiated glioma cells identified glucose-regulated protein GRP78 as the receptor target for GIRLRG. Antibodies to GRP78 blocked the binding of GIRLRG in vitro and in vivo. Conjugation of GIRLRG to a sustained-release nanoparticle drug delivery system yielded increased paclitaxel concentration and apoptosis in irradiated breast carcinomas for up to three weeks. Compared to controls, a single administration of the GIRLRG-targeted nanoparticle drug delivery system to irradiated tumors delayed the in vivo tumor tripling time by 55 days (P=0.0001) in MDA-MB-231, and 12 days in GL261 (P<0.005). This targeting agent combines a novel recombinant peptide with a paclitaxel encapsulating nanoparticle that specifically targets irradiated tumors, increasing apoptosis and tumor growth delay in a manner superior to known chemotherapy approaches.