title: Two-wave nanotherapy to target the stroma and optimize gemcitabine delivery to a human pancreatic cancer model in mice.
abstract: Pancreatic ductal adenocarcinoma (PDAC) elicits a dense stromal response that blocks vascular access because of pericyte coverage of vascular fenestrations. In this way, the PDAC stroma contributes to chemotherapy resistance in addition to causing other problems. In order to improve the delivery of gemcitabine, a first-line chemotherapeutic agent, a PEGylated drug-carrying liposome was developed, using a transmembrane ammonium sulfate gradient to encapsulate the protonated drug up to 20% w/w. However, because the liposome was precluded from entering the xenograft site due to the stromal interference, we developed a first-wave nanocarrier that decreases pericyte coverage of the vasculature through interference in the pericyte recruiting TGF-β signaling pathway. This was accomplished using a polyethyleneimine (PEI)/polyethylene glycol (PEG)-coated mesoporous silica nanoparticle (MSNP) for molecular complexation to a small molecule TGF-β inhibitor, LY364947. LY364947 contains a nitrogen atom that attaches, through H-bonding, to PEI amines with a high rate of efficiency. The copolymer coating also facilitates systemic biodistribution and retention at the tumor site. Because of the high loading capacity and pH-dependent LY364947 release from the MSNPs, we achieved rapid entry of IV-injected liposomes and MSNPs at the PDAC tumor site. This two-wave approach provided effective shrinkage of the tumor xenografts beyond 25 days, compared to the treatment with free drug or gemcitabine-loaded liposomes only. Not only does this approach overcome stromal resistance to drug delivery in PDAC, but it also introduces the concept of using a stepwise engineered approach to address a range of biological impediments that interfere in nanocancer therapy in a spectrum of cancers.
authors.affiliation: Division of NanoMedicine, Department of Medicine, ‡Department of Chemistry & Biochemistry, and §California NanoSystems Institute, University of California , Los Angeles, California 90095, United States.
authors.forename: Huan
authors.initials: H
authors.lastname: Meng
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Juyao
authors.initials: J
authors.lastname: Dong
authors.forename: Min
authors.initials: M
authors.lastname: Xue
authors.forename: Yu-Shen
authors.initials: YS
authors.lastname: Lin
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Ji
authors.forename: Wilson X
authors.initials: WX
authors.lastname: Mai
authors.forename: Haiyuan
authors.initials: H
authors.lastname: Zhang
authors.forename: Chong Hyun
authors.initials: CH
authors.lastname: Chang
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Brinker
authors.forename: Jeffrey I
authors.initials: JI
authors.lastname: Zink
authors.forename: Andre E
authors.initials: AE
authors.lastname: Nel
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003094:Collagen / Q000737:chemistry; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D004337:Drug Carriers; D004338:Drug Combinations; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D006801:Humans; D007797:Laminin / Q000737:chemistry; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D050997:Nanomedicine / Q000379:methods*; D053758:Nanoparticles / Q000737:chemistry; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D011092:Polyethylene Glycols / Q000737:chemistry; D011094:Polyethyleneimine / Q000737:chemistry; D011509:Proteoglycans / Q000737:chemistry; D015398:Signal Transduction; D012822:Silicon Dioxide / Q000737:chemistry; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D000093542:Gemcitabine
chemical_list: D004337:Drug Carriers; D004338:Drug Combinations; D007797:Laminin; D008081:Liposomes; D011509:Proteoglycans; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D003841:Deoxycytidine; C059485:matrigel; D011092:Polyethylene Glycols; D012822:Silicon Dioxide; D011094:Polyethyleneimine; D003094:Collagen; D000093542:Gemcitabine