Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer
Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer
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DOI：
10.1172/jci92284
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发表时间：
2017-05-01
影响因子：
15.9
通讯作者：
Meng, Huan
中科院分区：
文献类型：
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作者：
Liu, Xiangsheng;Lin, Paulina;Meng, Huan
胰腺导管腺癌(PDAC)几乎都是致命的；然而，随着伊立替康或紫杉醇纳米载体的引入，总体存活率得到了一定的改善。虽然一般认为纳米载体主要依赖异常的渗漏血管进入肿瘤，但最近报道了一种由神经粘连蛋白-1(NRP-1)调节的跨细胞转运途径。NRP-1介导的转运可被循环的肿瘤穿透肽IRGD触发。在KRAS诱导的原位PDAC模型中，IRGD共给药增强了伊立替康负载的硅酶体载体的摄取，这种摄取包括脂质双层包裹的介孔二氧化硅纳米颗粒(MSNPs)；这种摄取导致了提高存活率和显著减少转移。此外，经治疗的肿瘤的超微结构成像显示，IRGD联合给药诱导了一条囊泡运输路径，将金标记的硅腺体从血管腔运送到癌细胞内的核周位置。IRGD介导的硅酶体摄取在患者来源的异种移植物中也被观察到，与肿瘤血管上NRP-1的表达水平相称。这些结果表明，IRGD提高了伊立替康硅酶体基治疗的疗效，可能是一种合适的纳米粒治疗PDAC的佐剂。
Pancreatic ductal adenocarcinoma (PDAC) is almost uniformly fatal; however, some improvement in overall survival has been achieved with the introduction of nanocarriers that deliver irinotecan or paclitaxel. Although it is generally assumed that nanocarriers rely principally on abnormal leaky vasculature for tumor access, a transcytosis transport pathway that is regulated by neuropilin-1 (NRP-1) has recently been reported. NRP-1-mediated transport can be triggered by the cyclic tumor-penetrating peptide iRGD. In a KRAS-induced orthotopic PDAC model, coadministration of iRGD enhanced the uptake of an irinotecan-loaded silicasome carrier that comprises lipid bilayer-coated mesoporous silica nanoparticles (MSNPs); this uptake resulted in enhanced survival and markedly reduced metastasis. Further, ultrastructural imaging of the treated tumors revealed that iRGD coadministration induced a vesicular transport pathway that carried Au-labeled silicacomes from the blood vessel lumen to a perinuclear site within cancer cells. iRGD-mediated enhancement of silicasome uptake was also observed in patient-derived xenografts, commensurate with the level of NRP-1 expression on tumor blood vessels. These results demonstrate that iRGD enhances the efficacy of irinotecan-loaded silicasome-based therapy and may be a suitable adjuvant in nanoparticle-based treatments for PDAC.