title: Hitchhiking nanoparticles: Reversible coupling of lipid-based nanoparticles to cytotoxic T lymphocytes.
abstract: Following intravenous injection of anti-cancer nanomedicines, many barriers need to be overcome en route to the tumor. Cell-mediated delivery of nanoparticles (NPs) is promising in terms of overcoming several of these barriers based on the tumoritropic migratory properties of particular cell types. This guided transport aims to enhance the NP accumulation in the tumor and moreover enhance the infiltration of regions that are typically inaccessible for free NPs. Within this study, cytotoxic CD8(+) T cells were selected as carriers based on both their ability to migrate to the tumor and their intrinsic cytolytic activity against tumor cells. Many anti-cancer nanomedicines require tumor cell internalization to mediate cytosolic drug delivery and enhance the anti-cancer effect. This proof-of-concept therefore reports on the reversible attachment of liposomes to the surface of cytotoxic T lymphocytes via a reduction sensitive coupling. The activation status of the T cells and the liposome composition are shown to strongly influence the loading efficiency. Loading the cells with liposomes does not compromise T cell functionalities like proliferation and cytolytic function. Additionally, the triggered liposome release is demonstrated upon the addition of glutathione. Based on this optimization using liposomes as model NPs, a small interfering RNA (siRNA)-loaded NP was developed that can be coupled to the surface of CD8(+) T cells.
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Wayteck
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Heleen
authors.initials: H
authors.lastname: Dewitte
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Lynn
authors.initials: L
authors.lastname: De Backer
authors.affiliation: Laboratory of Molecular and Cellular Therapy, Department of Biomedical Sciences, Vrije Universiteit Brussel, Laarbeeklaan 103/E, 1090 Brussels, Belgium.
authors.forename: Karine
authors.initials: K
authors.lastname: Breckpot
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Demeester
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium. Electronic address: Stefaan.Desmedt@Ugent.be.
authors.forename: Stefaan C
authors.initials: SC
authors.lastname: De Smedt
authors.affiliation: Laboratory of General Biochemistry and Physical Pharmacy, Faculty of Pharmaceutical Sciences, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Raemdonck
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D003602:Cytotoxicity, Immunologic; D003911:Dextrans / Q000008:administration & dosage; D004220:Disulfides / Q000737:chemistry; D016503:Drug Delivery Systems; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005978:Glutathione / Q000494:pharmacology; D020100:Hydrogels; D016219:Immunotherapy, Adoptive; D008081:Liposomes / Q000008:administration & dosage* / Q000737:chemistry; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000737:chemistry / Q000166:cytology / Q000637:transplantation; D008689:Methacrylates / Q000008:administration & dosage; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D010047:Ovalbumin / Q000276:immunology; D010713:Phosphatidylcholines / Q000008:administration & dosage*; D010714:Phosphatidylethanolamines / Q000008:administration & dosage*; D010715:Phosphatidylglycerols / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D034741:RNA, Small Interfering / Q000008:administration & dosage*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000737:chemistry / Q000166:cytology / Q000637:transplantation; D013945:Thymoma / Q000276:immunology / Q000473:pathology / Q000628:therapy
chemical_list: C112318:1,2-dioleoyl-sn-glycero-3--phosphatidylethanolamine-N-(3-(2-pyridyldithio)propionate); C120889:2-(trimethylammonio)ethyl methacrylate; D003911:Dextrans; D004220:Disulfides; D020100:Hydrogels; D008081:Liposomes; D008689:Methacrylates; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010715:Phosphatidylglycerols; D011725:Pyridines; D034741:RNA, Small Interfering; D011948:Receptors, Antigen, T-Cell; C508284:dextran hydroxyethyl methacrylate; D010047:Ovalbumin; C017251:1,2-oleoylphosphatidylcholine; D005978:Glutathione
keywords: Cell-mediated drug delivery; Cytotoxic T lymphocytes; Liposomes; Nanoparticles; Tumor targeting