Targeted lipid-coated nanoparticles: delivery of tumor necrosis factor-functionalized particles to tumor cells

J Control Release. 2009 Jul 1;137(1):69-77. doi: 10.1016/j.jconrel.2009.03.010. Epub 2009 Mar 21.

Abstract

Polymeric nanoparticles displaying tumor necrosis factor on their surface (TNF nanocytes) are useful carrier systems capable of mimicking the bioactivity of membrane-bound TNF. Thus, TNF nanocytes are potent activators of TNF receptor 1 and 2 leading to a striking enhancement of apoptosis. However, in vivo applications are hampered by potential systemic toxicity. Here, using TNF nanocytes as a model system, we developed a procedure to generate targeted lipid-coated particles (TLP) in which TNF activity is shielded. The TLPs generated here are composed of an inner single-chain TNF (scTNF)-functionalized, polymeric nanoparticle core surrounded by a lipid coat endowed with polyethylene glycol (PEG) for sterical stabilization and a single-chain Fv (scFv) fragment for targeting. Using a scFv directed against the tumor stroma marker fibroblast activation protein (FAP) we show that TLP and scTNF-TLP specifically bind to FAP-expressing, but not to FAP-negative cells. Lipid coating strongly reduced nonspecific binding of particles and scTNF-mediated cytotoxicity towards FAP-negative cells. In contrast, an increased cytotoxicity of TLP was observed for FAP-positive cells. Thus, through liposome encapsulation, nanoparticles carrying bioactive molecules, which are subject to nonselective uptake and activity towards various cells and tissues, can be converted into target cell-specific composite particles exhibiting a selective activity towards antigen-positive target cells. Besides safe and targeted delivery of death ligands such as TNF, TLP should be suitable for various diagnostic and therapeutic applications, which benefit from a targeted delivery of reagents embedded into the particle core or displayed on the core particle surface.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / immunology*
  • Biomarkers, Tumor / metabolism
  • Cell Line, Tumor
  • Cholesterol / chemistry
  • Coated Materials, Biocompatible / chemistry
  • Cytotoxicity, Immunologic / immunology
  • Drug Carriers / chemistry
  • Fibrosarcoma / metabolism
  • Fibrosarcoma / pathology
  • Gelatinases
  • Humans
  • Immunoglobulin Fragments / chemistry*
  • Immunoglobulin Fragments / genetics
  • Immunoglobulin Fragments / metabolism
  • Lipids / chemistry*
  • Liposomes / chemistry
  • Membrane Proteins / metabolism
  • Mice
  • Models, Biological
  • Nanoparticles / chemistry*
  • Phospholipids / chemistry
  • Polyethylene Glycols / chemistry
  • Polystyrenes / chemistry
  • Protein Binding / immunology
  • Rhabdomyosarcoma / metabolism
  • Rhabdomyosarcoma / pathology
  • Serine Endopeptidases / metabolism
  • Tumor Necrosis Factor-alpha / immunology
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Biomarkers, Tumor
  • Coated Materials, Biocompatible
  • Drug Carriers
  • Immunoglobulin Fragments
  • Lipids
  • Liposomes
  • Membrane Proteins
  • Phospholipids
  • Polystyrenes
  • Tumor Necrosis Factor-alpha
  • immunoglobulin Fv
  • Polyethylene Glycols
  • Cholesterol
  • Serine Endopeptidases
  • fibroblast activation protein alpha
  • Gelatinases