Use of a lipid-coated mesoporous silica nanoparticle platform for synergistic gemcitabine and paclitaxel delivery to human pancreatic cancer in mice.
Use of a lipid-coated mesoporous silica nanoparticle platform for synergistic gemcitabine and paclitaxel delivery to human pancreatic cancer in mice.
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使用脂质包被的介孔二氧化硅纳米颗粒平台协同吉西他滨和紫杉醇递送至小鼠的人类胰腺癌。
DOI：
10.1021/acsnano.5b00510
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发表时间：
2015
期刊：
影响因子：
17.1
通讯作者：
Nel, Andre E.
中科院分区：
文献类型：
--
作者：
Meng, Huan;Wang, Meiying;Liu, Huiyu;Liu, Xiangsheng;Situ, Allen;Wu, Bobby;Ji, Zhaoxia;Chang, Chong Hyun;Nel, Andre E.
关键词：
最近，商业白蛋白结合紫杉醇（PTX）纳米载体（Abraxane）被批准为近十年来第一个治疗胰腺导管腺癌的新药。 PTX 通过抑制肿瘤基质和抑制 GEM 失活酶胞苷脱氨酶 (CDA) 的表达，提高一线胰腺癌药物吉西他滨 (GEM) 的药效。因此，我们询问是否有可能开发一种用于胰腺癌的介孔二氧化硅纳米颗粒 (MSNP) 载体，以共同提供协同的 GEM/PTX 组合。通过定制设计的包被脂质膜技术实现高载药量，通过使用支持的脂质双层 (LB) 封装计算剂量的 GEM (40 wt%)。 65 nm 纳米颗粒被脂质膜均匀包裹，可以掺入亚致死量的疏水性 PTX，它可以与 GEM 共同递送到胰腺细胞和肿瘤中。我们证明，LB-MSNP 比例 PTX 掺入和递送可以抑制 CDA 表达，同时诱导氧化应激作为 PTX 协同作用的操作原理。为了证明体内功效，携带皮下 PANC-1 异种移植物的小鼠接受静脉 (IV) 注射 PTX/GEM 负载的 LB-MSNP。与负载 GEM 的 LB-MSNP、游离 GEM 或游离 GEM 加 Abraxane 相比，药物共同递送提供了更有效的肿瘤缩小效果。类似的肿瘤缩小需要同时施用 12 倍量的游离 Abraxane。对肿瘤相关 GEM 代谢物的高效液相色谱分析证实，与游离 GEM 相比，MSNP 共递送将磷酸化 DNA 相互作用的 GEM 代谢物增加了 13 倍，并将灭活和脱氨基代谢物减少了 4 倍。在 PANC-1 原位模型中静脉注射 MSNP 递送的 PTX/GEM 可有效抑制原发肿瘤生长并消除转移灶。双重递送载体的体内功效增强，且没有局部或全身毒性的证据。总之，我们展示了一种有效的 LB-MSNP 纳米载体的开发，用于在胰腺癌中协同 PTX/GEM 递送。
Recently, a commercial albumin-bound paclitaxel (PTX) nanocarrier (Abraxane) was approved as the first new drug for pancreatic ductal adenocarcinoma in almost a decade. PTX improves the pharmaceutical efficacy of the first-line pancreatic cancer drug, gemcitabine (GEM), through suppression of the tumor stroma and inhibiting the expression of the GEM-inactivating enzyme, cytidine deaminase (CDA). We asked, therefore, whether it was possible to develop a mesoporous silica nanoparticle (MSNP) carrier for pancreatic cancer to co-deliver a synergistic GEM/PTX combination. High drug loading was achieved by a custom-designed coated lipid film technique to encapsulate a calculated dose of GEM (40 wt %) by using a supported lipid bilayer (LB). The uniform coating of the 65 nm nanoparticles by a lipid membrane allowed incorporation of a sublethal amount of hydrophobic PTX, which could be co-delivered with GEM in pancreatic cells and tumors. We demonstrate that ratiometric PTX incorporation and delivery by our LB-MSNP could suppress CDA expression, contemporaneous with induction of oxidative stress as the operating principle for PTX synergy. To demonstrate the in vivo efficacy, mice carrying subcutaneous PANC-1 xenografts received intravenous (IV) injection of PTX/GEM-loaded LB-MSNP. Drug co-delivery provided more effective tumor shrinkage than GEM-loaded LB-MSNP, free GEM, or free GEM plus Abraxane. Comparable tumor shrinkage required coadministration of 12 times the amount of free Abraxane. High-performance liquid chromatography analysis of tumor-associated GEM metabolites confirmed that, compared to free GEM, MSNP co-delivery increased the phosphorylated DNA-interactive GEM metabolite 13-fold and decreased the inactivated and deaminated metabolite 4-fold. IV injection of MSNP-delivered PTX/GEM in a PANC-1 orthotopic model effectively inhibited primary tumor growth and eliminated metastatic foci. The enhanced in vivo efficacy of the dual delivery carrier could be achieved with no evidence of local or systemic toxicity. In summary, we demonstrate the development of an effective LB-MSNP nanocarrier for synergistic PTX/GEM delivery in pancreatic cancer.
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影响因子：
17.1
作者：
Ashley CE;Carnes EC;Epler KE;Padilla DP;Phillips GK;Castillo RE;Wilkinson DC;Wilkinson BS;Burgard CA;Kalinich RM;Townson JL;Chackerian B;Willman CL;Peabody DS;Wharton W;Brinker CJ
通讯作者：
Brinker CJ
影响因子：
3.4
作者：
BAYERL, TM;BLOOM, M
通讯作者：
BLOOM, M
影响因子：
10.8
作者：
Cauda, Valentina;Engelke, Hanna;Bein, Thomas
通讯作者：
Bein, Thomas
影响因子：
11.5
作者：
Batist, Gerald;Gelmon, Karen A.;Louie, Arthur C.
通讯作者：
Louie, Arthur C.
影响因子：
3.9
作者：
Baker, Jessica A. Roseberry;Wickremsinhe, Enaksha R.;Guo, Yingying
通讯作者：
Guo, Yingying