Nano-composite hydrogels of Cu-Apa micelles for anti-vasculogenic mimicry

Abstract

Vasculogenic mimicry (VM) describes the phenomenon whereby fluid-conducting vessels are formed by highly invasive tumour cells, which supply blood to tumours during their early growth stages. Single antiangiogenic agents have limited inhibitory effects on VM, therefore, a multi-pathway anti-VM strategy is required. In this study, Apatinib (Apa) was coordinated with Cu²⁺ to form a Cu-Apa copper complex. The latter was loaded into oligo-hyaluronic acid (HA) polymeric micelles (HA-Chol) and subsequently embedded in Astragalus polysaccharide-based in situ hydrogels (APsGels) to generate Cu-Apa/HA-Chol@APsGels. In this system, Cu-Apa exerts the combined effects of Cu²⁺ and Apa to inhibit VM; HA-Chol micelles achieve targeted drug delivery and enhance endocytosis efficiency; APsGels realise sustained release of the drugs to ensure an anti-VM effect. This system demonstrated improved VM inhibition with low cytotoxicity and high biocompatibility, wound healing, and transwell invasion in three-dimensional cell cultured VM. Moreover, this system significantly inhibited VM formation and melanoma growth in a mouse tumour transplantation model. This study provides an effective strategy for inhibiting VM.

Keywords:

• Vasculogenic mimicry
• Apatinib
• copper complexes
• micelles
• nano-composite hydrogels

Disclosure statement

The authors report no conflicts of interest.

Ethical approval

The protocols and procedures were ethically reviewed and approved by Shanghai Ocean University (Lot number: SHOU-DW-2021-039). There was no human or animal testing in this study; therefore, ethics approval and consent to participate do not apply to this manuscript.

Additional information

Funding

This study was supported by the National Natural Science Foundation of China (82172796).