Conjugation of VEGFR1/R2-targeting peptide with gold nanoparticles to enhance antiangiogenic and antitumoral activity

Abstract

Background 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. 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. Results GNP–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. Conclusion Conjugation 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 Abstract

Vascular endothelial growth factor and its receptors regulation in gestational diabetes mellitus and eclampsia

“…The specific mechanisms of antagonistic action have multiple explanations. For example, VEGFR-1 and VEGF-2 can be recognized by VGB-3 (VEGF-A/B antagonist peptide) [ 18 ], thus inhibiting the growth of blood vessels. It can be inferred that VEGF-R indirectly regulates vascular growth and differentiation.…”

“…This can be used clinically to treat diseases by regulating cell migration or apoptosis. Currently,, relevant studies can use the mutual regulatory characteristics of VEGF and VEGF-R Bolatai et al Journal of Translational Medicine (2022) 20:400 to inhibit the growth and metastasis of tumor cells [18], as well as relieve complications in the fundus and kidney. It is therefore crucial to ensure the stability of VEGF and homeostasis in the body.…”

A VEGFB-Based Peptidomimetic Inhibits VEGFR2-Mediated PI3K/Akt/mTOR and PLCγ/ERK Signaling and Elicits Apoptotic, Antiangiogenic, and Antitumor Activities

“…Results of the current study confirm that VEGF promotes EMT in VEGFR2-expressing tumor cells, and suppression of the VEGF/VEGFR2 system may attenuate this process in favor of metastasis inhibition. On the other hand, FAK/Paxillin signaling axis is involved in VEGF-driven metastasis-related responses [25]. We indicated that VGB3 could efficiently suppress cell detachment by the marked inhibition of the FAK/Paxillin signaling axis, which is an initial step in the metastatic transformation.…”

“…The FAK/Paxillin signaling cascade is implicated in cell adhesion, migration, proliferation, and survival. Therefore, the downregulation of this axis is a marker of metastasis inhibition [25]. Analysis of 4T1 cell lysates indicated that VGB3 substantially inhibited FAK (P = 0.001), p-FAK (P = 0.001), paxillin (P < 0.0001), and p-paxillin (P = 0.0001) compared to controls.…”

The Refined Application and Evolution of Nanotechnology in Enhancing Radiosensitivity During Radiotherapy: Transitioning from Gold Nanoparticles to Multifunctional Nanomaterials

“…The results proved that conjugation with GNPs not only improved the efficacy of VGB3 but also enhanced anti-angiogenic and anti-tumor activity, extended the interval between treatments without increasing side effects, indicating that GNP-VGB3 provides a new direction for clinical anti-tumor treatment. 104 …”