title: The intracellular uptake of CD95 modified paclitaxel-loaded poly(lactic-co-glycolic acid) microparticles.
abstract: The CD95/CD95L receptor-ligand system is mainly recognised in the induction of apoptosis. However, it has also been shown that CD95L is over-expressed in many cancer types where it modulates immune-evasion and together with its receptor CD95 promotes tumour growth. Here, we show that CD95 surface modification of relatively large microparticles >0.5 μm in diameter, including those made from biodegradable polylactic-co-glycolic acid (PLGA), enhances intracellular uptake by a range of CD95L expressing cells in a process akin to phagocytosis. Using this approach we describe the intracellular uptake of microparticles and agent delivery in neurons, medulloblastoma, breast and ovarian cancer cells in vitro. CD95 modified paclitaxel-loaded PLGA microparticles are shown to be significantly more effective compared to conventional paclitaxel therapy (Taxol) at the same dose in subcutaneous medulloblastoma (∗∗∗P < 0.0001) and orthotopic ovarian cancer xenograft models where a >65-fold reduction in tumour bioluminescence was measured after treatment (∗P = 0.012). This drug delivery platform represents a new way of manipulating the normally advantageous tumour CD95L over-expression towards a therapeutic strategy. CD95 functionalised drug carriers could contribute to the improved function of cytotoxics in cancer, potentially increasing drug targeting and efficacy whilst reducing toxicity.
authors.affiliation: Pathology Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary, University of London, 4 Newark Street, London E1 2AT, UK. d.d.ateh@qmul.ac.uk
authors.forename: Davidson D
authors.initials: DD
authors.lastname: Ateh
authors.forename: Veronica H
authors.initials: VH
authors.lastname: Leinster
authors.forename: Sally R
authors.initials: SR
authors.lastname: Lambert
authors.forename: Afsha
authors.initials: A
authors.lastname: Shah
authors.forename: Ayub
authors.initials: A
authors.lastname: Khan
authors.forename: Hazel J
authors.initials: HJ
authors.lastname: Walklin
authors.forename: Jennifer V
authors.initials: JV
authors.lastname: Johnstone
authors.forename: Nader I
authors.initials: NI
authors.lastname: Ibrahim
authors.forename: Mustafa M
authors.initials: MM
authors.lastname: Kadam
authors.forename: Zain
authors.initials: Z
authors.lastname: Malik
authors.forename: Míriam
authors.initials: M
authors.lastname: Gironès
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Veldhuis
authors.forename: Gary
authors.initials: G
authors.lastname: Warnes
authors.forename: Silvia
authors.initials: S
authors.lastname: Marino
authors.forename: Iain A
authors.initials: IA
authors.lastname: McNeish
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Martin
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004337:Drug Carriers; D005434:Flow Cytometry; D006801:Humans; D019344:Lactic Acid; D008863:Microspheres; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D010587:Phagocytosis; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D019014:fas Receptor / Q000737:chemistry*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D019014:fas Receptor; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D017239:Paclitaxel