The intracellular uptake of CD95 modified paclitaxel-loaded poly(lactic-co-glycolic acid) microparticles

• Published in: Biomaterials 2011-11, Vol.32 (33), p.8538-8547
• Main Authors: Ateh, Davidson D, Leinster, Veronica H, Lambert, Sally R, Shah, Afsha, Khan, Ayub, Walklin, Hazel J, Johnstone, Jennifer V, Ibrahim, Nader I, Kadam, Mustafa M, Malik, Zain, Gironès, Míriam, Veldhuis, Gert J, Warnes, Gary, Marino, Silvia, McNeish, Iain A, Martin, Joanne E
• Format: Article
• Language: English
• Subjects: Advanced Basic Science; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - chemistry; Antineoplastic Agents, Phytogenic - pharmacokinetics; Cancer; CD95; CD95L; Cell Line, Tumor; Dentistry; Drug Carriers; Drug delivery systems; Drugs; fas Receptor - chemistry; Flow Cytometry; Humans; Lactic Acid; Microparticles; Microspheres; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - chemistry; Paclitaxel - pharmacokinetics; Phagocytosis; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer; Polylactic-co-glycolic acid; Toxicity; Tumours; Uptakes
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2011.07.060

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  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.