Liu Xiangsheng, Situ Allen, Kang Yanan, Villabroza Katie Rose, Liao Yupei, Chang Chong Hyun, Donahue Timothy, Nel Andre E, Meng Huan
Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.
Departments of Surgery, Division of General Surgery, and Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA , Los Angeles, California 90095, United States.
ACS Nano. 2016 Feb 23;10(2):2702-15. doi: 10.1021/acsnano.5b07781. Epub 2016 Feb 9.
Urgent intervention is required to improve the 5 year survival rate of pancreatic ductal adenocarcinoma (PDAC). While the four-drug regimen, FOLFIRINOX (comprising irinotecan, 5-fluorouracil, oxaliplatin, and leucovorin), has a better survival outcome than the more frequently used gemcitabine, the former treatment platform is highly toxic and restricted for use in patients with good performance status. Since irinotecan contributes significantly to FOLFIRINOX toxicity (bone marrow and gastrointestinal tract), our aim was to reduce the toxicity of this drug by a custom-designed mesoporous silica nanoparticle (MSNP) platform, which uses a proton gradient for high-dose irinotecan loading across a coated lipid bilayer (LB). The improved stability of the LB-coated MSNP (LB-MSNP) carrier allowed less drug leakage systemically with increased drug concentrations at the tumor sites of an orthotopic Kras-derived PDAC model compared to liposomes. The LB-MSNP nanocarrier was also more efficient for treating tumor metastases. Equally important, the reduced leakage and slower rate of drug release by the LB-MSNP carrier dramatically reduced the rate of bone marrow, gastrointestinal, and liver toxicity compared to the liposomal carrier. We propose that the combination of high efficacy and reduced toxicity by the LB-MSNP carrier could facilitate the use of irinotecan as a first-line therapeutic to improve PDAC survival.
需要采取紧急干预措施来提高胰腺导管腺癌（PDAC）的5年生存率。虽然四药方案FOLFIRINOX（由伊立替康、5-氟尿嘧啶、奥沙利铂和亚叶酸组成）的生存结果优于更常用的吉西他滨，但前一种治疗方案毒性很大，仅适用于身体状况良好的患者。由于伊立替康是FOLFIRINOX毒性（骨髓和胃肠道）的主要来源，我们的目标是通过定制设计的介孔二氧化硅纳米颗粒（MSNP）平台降低该药物的毒性，该平台利用质子梯度在包被脂质双层（LB）上高剂量加载伊立替康。与脂质体相比，LB包被的MSNP（LB-MSNP）载体稳定性提高，全身药物泄漏减少，原位Kras衍生的PDAC模型肿瘤部位的药物浓度增加。LB-MSNP纳米载体在治疗肿瘤转移方面也更有效。同样重要的是，与脂质体载体相比，LB-MSNP载体减少的泄漏和较慢的药物释放速率显著降低了骨髓、胃肠道和肝脏的毒性发生率。我们认为，LB-MSNP载体兼具高效和低毒的特性，有助于将伊立替康用作一线治疗药物，以提高PDAC患者的生存率。
