Simultaneous targeting of VEGF-receptors 2 and 3 with immunoliposomes enhances therapeutic efficacy

Abstract

Background: Tumor progression depends on angiogenesis. Vascular endothelial growth factor (VEGF) receptors (VEGFRs) are the main signal transducers that stimulate endothelial cell migration and vessel sprouting. At present, only VEGFR2 is targeted in the clinical practice.

Purpose: To develop new, anti-angiogenic nanoparticles (immunoliposomes, ILs), that redirect cytotoxic compounds to tumor-associated vascular cells.

Methods: Pegylated liposomal doxorubicin (PLD) was targeted against VEGFR2- and VEGFR3-expressing cells by inserting anti-VEGFR2 and/or anti-VEGFR3 antibody fragments into the lipid bilayer membrane of PLD. These constructs were tested in vitro, and in vivo in the Rip1Tag2 mouse model of human cancer.

Results: The combination treatment with anti-VEGFR2-ILs-dox and anti-VEGFR3-ILs-dox was superior to targeting only VEGFR2 cells and provides a highly efficient approach of depleting tumor-associated vasculature. This leads to tumor starvation and pronounced reduction of tumor burden.

Conclusion: Nanoparticles against VEGFR2 and −3 expressing tumor-associated endothelial cells represent a promising and novel anti-cancer strategy.

• Anti-angiogenic therapy
• nanoparticle
• targeted drug delivery
• VEGFR2
• VEGFR3

Declaration of interest

This work was supported by the Gebert-Rüf Stiftung (GRS-038/07) (to AW and CM), the Desiree and Niels Yde Foundation (to AW), the Schoenmakers-Müller Foundation (to AW and CM), the Science Fund of the University of Basel (to AW), the Swiss Cancer League (CCRP OCS-01812-12-2005), the Nora van Meeuwen-Haefliger Foundation and the EU-FP7 TuMIC HEALTH-F2-2008-201662 (to GC).

The authors have no conflicts of interest to declare.

Supplementary material available online

Supplementary File S1 and Supplementary Figures S1 and S2.