title: Nanobody-albumin nanoparticles (NANAPs) for the delivery of a multikinase inhibitor 17864 to EGFR overexpressing tumor cells.
abstract: A novel, EGFR-targeted nanomedicine has been developed in the current study. Glutaraldehyde crosslinked albumin nanoparticles with a size of approximately 100nm were loaded with the multikinase inhibitor 17864-L(x)-a platinum-bound sunitinib analogue-which couples the drug to methionine residues of albumin and is released in a reductive environment. Albumin nanoparticles were surface-coated with bifunctional polyethylene glycol 3500 (PEG) and a nanobody-the single variable domain of an antibody-(Ega1) against the epidermal growth factor receptor (EGFR). EGa1-PEG functionalized nanoparticles showed a 40-fold higher binding to EGFR-positive 14C squamous head and neck cancer cells in comparison to PEGylated nanoparticles. 17864-L(x) loaded EGa1-PEG nanoparticles were internalized by clathrin-mediated endocytosis and ultimately digested in lysosomes. The intracellular routing of EGa1 targeted nanoparticles leads to a successful release of the kinase inhibitor in the cell and inhibition of proliferation whereas the non-targeted formulations had no antiproliferative effects on 14C cells. The drug loaded targeted nanoparticles were as effective as the free drug in vitro. These results demonstrate that multikinase inhibitor loaded nanoparticles are interesting nanomedicines for the treatment of EGFR-positive cancers.
authors.affiliation: Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
authors.forename: Isil
authors.initials: I
authors.lastname: Altintas
authors.forename: Raimond
authors.initials: R
authors.lastname: Heukers
authors.forename: Roy
authors.initials: R
authors.lastname: van der Meel
authors.forename: Marie
authors.initials: M
authors.lastname: Lacombe
authors.forename: Maryam
authors.initials: M
authors.lastname: Amidi
authors.forename: Paul M P
authors.initials: PM
authors.lastname: van Bergen En Henegouwen
authors.forename: Wim E
authors.initials: WE
authors.lastname: Hennink
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Schiffelers
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: Kok
mesh_terms: D055910:Antibodies, Immobilized / Q000276:immunology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004337:Drug Carriers / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D053758:Nanoparticles / Q000737:chemistry* / Q000648:ultrastructure; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D055910:Antibodies, Immobilized; D004337:Drug Carriers; D047428:Protein Kinase Inhibitors; D012709:Serum Albumin; D066246:ErbB Receptors