title: The effect of multistage nanovector targeting of VEGFR2 positive tumor endothelia on cell adhesion and local payload accumulation.
abstract: Nanovectors are a viable solution to the formulation of poorly soluble anticancer drugs. Their bioaccumulation in the tumor parenchyma is mainly achieved exploiting the enhanced permeability and retention (EPR) effect of the leaky neovasculature. In this paper we demonstrate that multistage nanovectors (MSV) exhibit rapid tumoritropic homing independent of EPR, relying on particle geometry and surface adhesion. By studying endothelial cells overexpressing vascular endothelial growth factor receptor-2 (VEGFR2), we developed MSV able to preferentially target VEGFR2 expressing tumor-associated vessels. Static and dynamic targeting revealed that MSV conjugated with anti-VEGFR2 antibodies displayed greater than a 4-fold increase in targeting efficiency towards VEGFR2 expressing cells while exhibiting minimal adherence to control cells. Additionally, VEGFR2 conjugation bestowed MSV with a significant increase in breast tumor targeting and in the delivery of a model payload while decreasing their accumulation in the liver. Surface functionalization with an anti-VEGFR2 antibody provided enhanced affinity towards the tumor vascular endothelium, which promoted enhanced adhesion and tumoritropic accumulation of a reporter molecule released by the MSV.
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA; Graduate School of Biomedical Sciences, University of Texas Health Science Center, 6767 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Jonathan O
authors.initials: JO
authors.lastname: Martinez
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Evangelopoulos
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Karun
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Evan
authors.initials: E
authors.lastname: Shegog
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Wang
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA; Escuela de Medicina y Ciencias de la Salud, Tecnológico de Monterrey, 3000 Ave. Morones Prieto Esquina Con Dr. Cantú, Monterrey, Nuevo León, México.
authors.forename: Christian
authors.initials: C
authors.lastname: Boada
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Xuewu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA.
authors.forename: Mauro
authors.initials: M
authors.lastname: Ferrari
authors.affiliation: Department of Nanomedicine, Houston Methodist Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA. Electronic address: etasciotti@HoustonMethodist.org.
authors.forename: Ennio
authors.initials: E
authors.lastname: Tasciotti
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D008819:Mice, Nude; D012821:Silanes / Q000737:chemistry / Q000493:pharmacokinetics; D013552:Swine; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D004337:Drug Carriers; D012821:Silanes; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Drug delivery; Multi-stage nanovectors; Nanoparticles; Tumor vascular targeting; Vascular endothelial growth factor receptor