title: Irinotecan Delivery by Lipid-Coated Mesoporous Silica Nanoparticles Shows Improved Efficacy and Safety over Liposomes for Pancreatic Cancer.
abstract: 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.
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.
authors.forename: Xiangsheng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.
authors.forename: Allen
authors.initials: A
authors.lastname: Situ
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.
authors.forename: Katie Rose
authors.initials: KR
authors.lastname: Villabroza
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.
authors.forename: Yupei
authors.initials: Y
authors.lastname: Liao
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.
authors.forename: Chong Hyun
authors.initials: CH
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Timothy
authors.initials: T
authors.lastname: Donahue
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.|California NanoSystems Institute, University of California , Los Angeles, California 90095, United States.
authors.forename: Andre E
authors.initials: AE
authors.lastname: Nel
authors.affiliation: Division of NanoMedicine, Department of Medicine, University of California , Los Angeles, California 90095, United States.
authors.forename: Huan
authors.initials: H
authors.lastname: Meng
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D065546:Drug Liberation; D005260:Female; D000077146:Irinotecan; D008051:Lipid Bilayers / Q000737:chemistry; D008081:Liposomes / Q000009:adverse effects* / Q000737:chemistry; D051379:Mice; D053758:Nanoparticles / Q000009:adverse effects* / Q000737:chemistry; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D012822:Silicon Dioxide / Q000737:chemistry
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008051:Lipid Bilayers; D008081:Liposomes; D012822:Silicon Dioxide; D000077146:Irinotecan; D002166:Camptothecin
keywords: FOLFIRINOX; irinotecan; lipid bilayer; mesoporous silica nanoparticle; pancreatic cancer; proton gradient; toxicity reduction
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