Irinotecan Delivery by Lipid-Coated Mesoporous Silica Nanoparticles Shows Improved Efficacy and Safety over Liposomes for Pancreatic Cancer

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 f...

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Bibliographic Details
Published in:ACS nano 2016-02, Vol.10 (2), p.2702-2715
Main Authors: Liu, Xiangsheng, Situ, Allen, Kang, Yanan, Villabroza, Katie Rose, Liao, Yupei, Chang, Chong Hyun, Donahue, Timothy, Nel, Andre E, Meng, Huan
Format: Article
Language:English
Subjects:
Adenocarcinoma - drug therapy
Animals
Antineoplastic Agents, Phytogenic - administration & dosage
Antineoplastic Agents, Phytogenic - adverse effects
Antineoplastic Agents, Phytogenic - pharmacokinetics
Camptothecin - administration & dosage
Camptothecin - adverse effects
Camptothecin - analogs & derivatives
Camptothecin - pharmacokinetics
Cell Line, Tumor
Drug Liberation
Female
Lipid Bilayers - chemistry
Liposomes - adverse effects
Liposomes - chemistry
Mice
Nanoparticles - adverse effects
Nanoparticles - chemistry
Pancreatic Neoplasms - drug therapy
Silicon Dioxide - chemistry
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Summary: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.
ISSN:1936-0851
1936-086X
DOI:10.1021/acsnano.5b07781