Lucero-Acuña Armando, Jeffery Justin J, Abril Edward R, Nagle Raymond B, Guzman Roberto, Pagel Mark D, Meuillet Emmanuelle J
Department of Chemical and Environmental Engineering, University of Arizona, Tucson, AZ, USA.
Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
Int J Nanomedicine. 2014 Dec 3;9:5653-65. doi: 10.2147/IJN.S68511. eCollection 2014.
The K-ras mutation in pancreatic cancer can inhibit drug delivery and increase drug resistance. This is exemplified by the therapeutic effect of PH-427, a small molecule inhibitor of AKT/PDK1, which has shown a good therapeutic effect against a BxPC3 pancreatic cancer model that has K-ras, but has a poor therapeutic effect against a MiaPaCa-2 pancreatic cancer model with mutant K-ras. To increase the therapeutic effect of PH-427 against the MiaPaCa-2 pancreatic cancer model with mutant K-ras, we encapsulated PH-427 into poly(lactic-co-glycolic acid) nanoparticles (PNP) to form drug-loaded PH-427-PNP. PH-427 showed a biphasic release from PH-427-PNP over 30 days during studies in sodium phosphate buffer, and in vitro studies revealed that the PNP was rapidly internalized into MiaPaCa-2 tumor cells, suggesting that PNP can improve PH-427 delivery into cells harboring mutant K-ras. In vivo studies of an orthotopic MiaPaCa-2 pancreatic cancer model showed reduced tumor load with PH-427-PNP as compared with treatment using PH-427 alone or with no treatment. Ex vivo studies confirmed the in vivo results, suggesting that PNP can improve drug delivery to pancreatic cancer harboring mutant K-ras.
胰腺癌中的K-ras突变可抑制药物递送并增加耐药性。这一点在PH-427（一种AKT/PDK1小分子抑制剂）的治疗效果中得到了体现，它对具有K-ras的BxPC3胰腺癌模型显示出良好的治疗效果，但对具有突变型K-ras的MiaPaCa-2胰腺癌模型的治疗效果较差。为了提高PH-427对具有突变型K-ras的MiaPaCa-2胰腺癌模型的治疗效果，我们将PH-427封装到聚乳酸-乙醇酸共聚物纳米颗粒（PNP）中，形成载药的PH-427-PNP。在磷酸钠缓冲液中的研究表明，PH-427在30天内从PH-427-PNP中呈现双相释放，体外研究显示PNP能迅速被MiaPaCa-2肿瘤细胞内化，这表明PNP可改善PH-427向携带突变型K-ras的细胞中的递送。对原位MiaPaCa-2胰腺癌模型的体内研究表明，与单独使用PH-427治疗或不治疗相比，PH-427-PNP治疗可降低肿瘤负荷。离体研究证实了体内研究结果，表明PNP可改善向携带突变型K-ras的胰腺癌的药物递送。
