title: Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration.
abstract: Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75% smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics.
authors.affiliation: Molecular Immunology Unit, UCL Institute of Child Health, University College London, London, UK.
authors.forename: Aristides D
authors.initials: AD
authors.lastname: Tagalakis
authors.forename: Stephanie M
authors.initials: SM
authors.lastname: Grosse
authors.forename: Qing-Hai
authors.initials: QH
authors.lastname: Meng
authors.forename: M Firouz Mohd
authors.initials: MF
authors.lastname: Mustapa
authors.forename: Albert
authors.initials: A
authors.lastname: Kwok
authors.forename: Shahla E
authors.initials: SE
authors.lastname: Salehi
authors.forename: Alethea B
authors.initials: AB
authors.lastname: Tabor
authors.forename: Helen C
authors.initials: HC
authors.lastname: Hailes
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Hart
mesh_terms: D000279:Administration, Cutaneous; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D016023:Integrins / Q000235:genetics*; D018664:Interleukin-12 / Q000235:genetics / Q000502:physiology; D007376:Interleukin-2 / Q000235:genetics / Q000502:physiology; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry*; D009369:Neoplasms / Q000628:therapy*; D016133:Polymerase Chain Reaction; D014162:Transfection
chemical_list: D016023:Integrins; D007376:Interleukin-2; D018664:Interleukin-12