title: Targeting hepatocyte growth factor receptor (Met) positive tumor cells using internalizing nanobody-decorated albumin nanoparticles.
abstract: The hepatocyte growth factor receptor (HGFR, c-Met or Met) is a receptor tyrosine kinase that is involved in embryogenesis, tissue regeneration and wound healing. Abnormal activation of this proto-oncogene product is implicated in the development, progression and metastasis of many cancers. Current therapies directed against Met, such as ligand- or, dimerization-blocking antibodies or kinase inhibitors, reduce tumor growth but hardly eradicate the tumor. In order to improve anti-Met therapy, we have designed a drug delivery system consisting of crosslinked albumin nanoparticles decorated with newly selected anti-Met nanobodies (anti-Met-NANAPs). The anti-Met NANAPs bound specifically to and were specifically taken up by Met-expressing cells and transported to lysosomes for degradation. Treatment of tumor cells with anti-Met NANAPs also resulted in downregulation of the total Met protein. This study shows that anti-Met NANAPs offer a potential system for lysosomal delivery of drugs into Met-positive tumor cells.
authors.affiliation: Cell Biology, Department of Biology, Science Faculty, Utrecht University, 3584 CH Utrecht, The Netherlands.
authors.forename: Raimond
authors.initials: R
authors.lastname: Heukers
authors.forename: Isil
authors.initials: I
authors.lastname: Altintas
authors.forename: Smiriti
authors.initials: S
authors.lastname: Raghoenath
authors.forename: Erica
authors.initials: E
authors.lastname: De Zan
authors.forename: Richard
authors.initials: R
authors.lastname: Pepermans
authors.forename: Rob C
authors.initials: RC
authors.lastname: Roovers
authors.forename: Rob
authors.initials: R
authors.lastname: Haselberg
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
authors.forename: Paul M P
authors.initials: PM
authors.lastname: van Bergen en Henegouwen
mesh_terms: D000418:Albumins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004705:Endocytosis; D005260:Female; D006801:Humans; D053758:Nanoparticles; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D019859:Proto-Oncogene Proteins c-met / Q000276:immunology / Q000378:metabolism*; D061905:Single-Domain Antibodies / Q000276:immunology*
chemical_list: D000418:Albumins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D061905:Single-Domain Antibodies; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
keywords: Albumin nanoparticles; Intracellular delivery; Met; Nanobody; Receptor down regulation; VHH