title: Large-Pore Functionalized Mesoporous Silica Nanoparticles as Drug Delivery Vector for a Highly Cytotoxic Hybrid Platinum-Acridine Anticancer Agent.
abstract: Large-pore mesoporous silica nanoparticles (MSN) were prepared and functionalized to serve as a highly robust and biocompatible delivery platform for platinum-acridine (PA) anticancer agents. The material showed a high loading capacity for the dicationic, hydrophilic hybrid agent [PtCl(en)(N-[acridin-9-ylaminoethyl]-N-methylpropionamidine)] dinitrate salt (P1A1) and virtually complete retention of payload at neutral pH in a high-chloride buffer. In acidic media mimicking the pH inside the cell lysosomes, rapid, burst-like release of P1A1 from the nanoparticles is observed. Coating of the materials in phospholipid bilayers resulted in nanoparticles with greatly improved colloidal stability. The lipid and carboxylate-modified nanoparticles containing 40 wt % drug caused S-phase arrest and inhibited cell proliferation in pancreatic cancer cells at submicromolar concentrations similar to carrier-free P1A1. The most striking feature of nanoparticle-delivered P1A1 was that the payload did not escape from the acidified lysosomal vesicles into the cytoplasm, but was shuttled to the nuclear membrane and released into the nucleus.
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC, 27109, USA.
authors.forename: Ye
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Cale D
authors.initials: CD
authors.lastname: Fahrenholtz
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC, 27109, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Hackett
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC, 27109, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Ding
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC, 27109, USA.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Day
authors.affiliation: Analytical Instrumentation Facility, Monteith Research Center, North Carolina State University, Raleigh, NC, 27695, USA.
authors.forename: Rohan
authors.initials: R
authors.lastname: Dhall
authors.affiliation: Department of Biology, Wake Forest University, Winston-Salem, NC, 27109, USA.
authors.forename: Glen S
authors.initials: GS
authors.lastname: Marrs
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC, 27109, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Gross
authors.affiliation: Department of Cancer Biology, Wake Forest School of Medicine, Winston-Salem, NC, 27157, USA.
authors.forename: Ravi
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Chemistry, Wake Forest University, Winston-Salem, NC, 27109, USA.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bierbach
mesh_terms: D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry* / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D046529:Microscopy, Electron, Transmission / Q000379:methods; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010743:Phospholipids / Q000737:chemistry; D010984:Platinum; D011092:Polyethylene Glycols / Q000737:chemistry; D016062:Porosity; D012822:Silicon Dioxide / Q000737:chemistry*; D013499:Surface Properties
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004337:Drug Carriers; D010743:Phospholipids; D011092:Polyethylene Glycols; D010984:Platinum; D012822:Silicon Dioxide
keywords: anticancer drug delivery; mesoporous materials; nanoparticles; platinum acridines; vesicular transport