title: PEGylated squalenoyl-gemcitabine nanoparticles for the treatment of glioblastoma.
abstract: New treatments for glioblastoma multiforme (GBM) are desperately needed, as GBM prognosis remains poor, mainly due to treatment resistance, poor distribution of therapeutics in the tumor tissue, and fast metabolism of chemotherapeutic drugs in the brain extracellular space. Convection-enhanced delivery (CED) of nanoparticles (NPs) has been shown to improve the delivery of chemotherapeutic drugs to the tumor bed, providing sustained release, and enhancing survival of animals with intracranial tumors. Here we administered gemcitabine, a nucleoside analog used as a first line treatment for a wide variety of extracranial solid tumors, within squalene-based NPs using CED, to overcome the above-mentioned challenges of GBM treatment. Small percentages of poly(ethylene) glycol (PEG) dramatically enhanced the distribution of squalene-gemcitabine nanoparticles (SQ-Gem NPs) in healthy animals and tumor-bearing animals after administration by CED. When tested in an orthotopic model of GBM, SQ-Gem-PEG NPs demonstrated significantly improved therapeutic efficacy compared to free gemcitabine, both as a chemotherapeutic drug and as a radiosensitizer. Furthermore, MR contrast agents were incorporated into the SQ-Gem-PEG NP formulation, providing a way to non-invasively track the NPs during infusion.
authors: Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
authors: Alice
authors: A
authors: Gaudin
authors: Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
authors: Eric
authors: E
authors: Song
authors: Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
authors: Amanda R
authors: AR
authors: King
authors: Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
authors: Jennifer K
authors: JK
authors: Saucier-Sawyer
authors: Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT, 06511, USA.
authors: Ranjit
authors: R
authors: Bindra
authors: Institut Galien Paris-Sud, UMR CNRS 8612, University Paris-Sud XI, Châtenay-Malabry, 92290, France.
authors: Didier
authors: D
authors: Desmaële
authors: Institut Galien Paris-Sud, UMR CNRS 8612, University Paris-Sud XI, Châtenay-Malabry, 92290, France.
authors: Patrick
authors: P
authors: Couvreur
authors: Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA. Electronic address: mark.saltzman@yale.edu.
authors: W Mark
authors: WM
authors: Saltzman
mesh_terms: D065966:Absorption, Physicochemical; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D001932:Brain Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000737:chemistry* / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D057054:Molecular Imaging / Q000379:methods; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry*; D051381:Rats; D013185:Squalene / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D016896:Treatment Outcome; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D053769:Nanocapsules; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D013185:Squalene; D000093542:Gemcitabine
keywords: Convection-enhanced delivery; Gemcitabine; Glioblastoma; Nanoparticles; Squalene