Abstract
BackgroundInhibition of tumor angiogenesis through simultaneous targeting of vascular endothelial growth factor receptor (VEGFR)-1 and -2 is highly efficacious. An antagonist peptide of VEGFA/VEGFB, referred to as VGB3, can recognize and neutralize both VEGFR1 and VEGFR2 on the endothelial and tumoral cells, thereby inhibits angiogenesis and tumor growth. However, improved efficacy and extending injection intervals is required for its clinical translation. Given that gold nanoparticles (GNPs) can enhance the efficacy of biotherapeutics, we conjugated VGB3 to GNPs to enhance its efficacy and extends the intervals between treatments without adverse effects.ResultsGNP–VGB3 bound to VEGFR1 and VEGFR2 in human umbilical vein endothelial (HUVE) and 4T1 mammary carcinoma cells. GNP–VGB3 induced cell cycle arrest, ROS overproduction and apoptosis and inhibited proliferation and migration of endothelial and tumor cells more effectively than unconjugated VGB3 or GNP. In a murine 4T1 mammary carcinoma tumor model, GNP–VGB3 more strongly than VGB3 and GNP inhibited tumor growth and metastasis, and increased animal survival without causing weight loss. The superior antitumor effects were associated with durable targeting of VEGFR1 and VEGFR2, thereby inhibiting signaling pathways of proliferation, migration, differentiation, epithelial-to-mesenchymal transition, and survival in tumor tissues. MicroCT imaging and inductively coupled plasma mass spectrometry showed that GNP–VGB3 specifically target tumors and exhibit greater accumulation within tumors than the free GNPs.ConclusionConjugation to GNPs not only improved the efficacy of VGB3 peptide but also extended the intervals between treatments without adverse effects. These results suggest that GNP–VGB3 is a promising candidate for clinical translation.Graphical
Highlights
Inhibition of tumor angiogenesis through simultaneous targeting of vascular endothelial growth factor receptor (VEGFR)-1 and -2 is highly efficacious
Based on mechanism-based analyses of tumor tissues, the superior anticancer properties of gold nanoparticles (GNPs)–VGB3 over free peptide is due to retaining the VEGFR1/R2-binding property, followed by suppression of signaling pathways of proliferation, migration and metastasis in tumor-bearing animals
These data open a new window to understand how antiangiogenic, antitumor and antimetastatic properties arising from the dual blockade of VEGFR1 and VEGFR2 can be potentiated by the positive therapeutic effects of gold nanoparticles
Summary
Inhibition of tumor angiogenesis through simultaneous targeting of vascular endothelial growth factor receptor (VEGFR)-1 and -2 is highly efficacious. An antagonist peptide of VEGFA/VEGFB, referred to as VGB3, can recognize and neutralize both VEGFR1 and VEGFR2 on the endothelial and tumoral cells, thereby inhibits angiogenesis and tumor growth. Different types of signaling molecules so far have identified as inducers of tumor angiogenesis, among which the vascular endothelial growth factorA (VEGF-A), referred to as VEGF, and its receptor VEGF receptor-2 (VEGFR-2) are major activators of tumor angiogenesis [1, 2]. Binding of VEGF-B to VEGFR-1 plays important roles in tumor angiogenesis and metastasis mainly through promotion of PI3K/AKT/mTOR signaling pathway [4]. The common approach for antiangiogenic therapy has been based on the blockade of VEGF/VEGFR-2 signaling pathway [10]. Peptides have emerged as new generation of therapeutics, as they combine the advantages of small molecules, such as stability and bioavailability, with those of proteins, such as high specificity and potency
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
