Conventional treatment fails to completely eliminate highly invasive breast cancer cells, and most surviving breast cancer cells tend to reproliferate and metastasize by forming vasculogenic mimicry (VM) channels. Thus, a type of targeted liposomes was developed by modification with Arginine₈-Glycine-Aspartic acid (R₈GD) to encapsulate daunorubicin and emodin separately. A combination of the two targeted liposomes was then developed to destroy VM channels and inhibit tumor metastasis. MDA-MB-435S cells, a highly invasive breast cancer, were then evaluated in vitro and in mice. The experiments indicated that R₈GD modified daunorubicin liposomes plus R₈GD modified emodin liposomes had small particle size, uniform particle size distribution and high drug encapsulation rate. The combination of the two targeted liposomes exerted strong toxicity on the MDA-MB-435S cells and effectively inhibited the formation of VM channels and the metastasis of tumor cells. Action mechanism studies showed that the R₈GD modified daunorubicin liposomes plus R₈GD modified emodin liposomes could downregulate some metastasis-related proteins, including MMP-2, VE-cad, TGF-β1, and HIF-1α. These studies also demonstrated that the targeted liposomes allowed the chemotherapeutic drug to selectively accumulate at tumor site, thus exhibiting a distinct antitumor effect. Therefore, the combination of targeted daunorubicin liposomes and targeted emodin liposomes can provide a potential treatment for invasive breast cancer.

Presently, there are no few anticancer drugs that have been used clinically due to their poor targeting ability, short half-life period, non-selective distributions, generation of vasculogenic mimicry (VM) channels, high metastasis, and high recurrence rate. This study aimed to explore the effects of R₈ modified epirubicin–dihydroartemisinin liposomes that could target non-small-cell lung cancer (NSCLC) cells, destroy VM channels, inhibit tumor metastasis, and explain the possible underlying mechanism. In vitro assays indicated that R₈ modified epirubicin–dihydroartemisinin liposomes with ideal physicochemical characteristics could exhibit not only powerful cytotoxicity on A549 cells, but also the effective suppression of VM channels and tumor metastasis. Mechanistic studies manifested that R₈ modified epirubicin–dihydroartemisinin liposomes could down-regulate the levels of VE-Cad, TGF-β1, MMP-2, and HIF-1α. In vivo assays indicated that R₈ modified epirubicin–dihydroartemisinin liposomes could both increase the selective accumulation of chemotherapeutic drugs at tumor sites and show a targeting conspicuous of antitumor efficacy. In conclusion, the R₈ modified epirubicin–dihydroartemisinin liposomes prepared in this study provide a treatment strategy with high efficiency for NSCLC.

Background: Non-small cell lung cancer (NSCLC) is one of the most lethal types of cancer with highly infiltrating. Chemotherapy is far from satisfactory, vasculogenic mimicry (VM) and angiogenesis results in invasion, migration and relapse. Purpose: The objective of this study was to construct a novel CPP _(mmp) modified vinorelbine and dioscin liposomes by two new functional materials, DSPE-PEG₂₀₀₀-MAL and CPP-PVGLIG-PEG₅₀₀₀, to destroy VM channels, angiogenesis, EMT and inhibit invasion and migration. Methods and Results: The targeting liposomes could be enriched in tumor sites through passive targeting, and the positively charged CPP was exposed and enhanced active targeting via electrostatic adsorption after being hydrolyzed by MMP2 enzymes overexpressed in the tumor microenvironment. We found that CPP _(mmp) modified vinorelbine and dioscin liposomes with the ideal physicochemical properties and exhibited enhanced cellular uptake. In vitro and in vivo results showed that CPP _(mmp) modified vinorelbine and dioscin liposomes could inhibit migration and invasion of A549 cells, destroy VM channels formation and angiogenesis, and block the EMT process. Pharmacodynamic studies showed that the targeting liposomes had obvious accumulations in tumor sites and magnificent antitumor efficiency. Conclusion: CPP _(mmp) modified vinorelbine plus dioscin liposomes could provide a new strategy for NSCLC.

Chemotherapy for non‐small cell lung cancer (NSCLC) is far from satisfactory, mainly due to poor targeting of antitumor drugs and self‐adaptations of the tumors. Angiogenesis, vasculogenic mimicry (VM) channels, migration, and invasion are the main ways for tumors to get nutrition. Herein, RPV‐modified Epirubicin and dioscin co‐delivery liposomes were successfully prepared. These liposomes exhibited ideal physicochemical properties, enhanced tumor targeting and accumulation in tumor sites, and inhibited VM channels formation, tumor angiogenesis, migration and invasion. The liposomes also down‐regulated VM‐related and angiogenesis‐related proteins in vitro. Furthermore, when tested in vivo, the targeted co‐delivery liposomes increased the selective accumulation of drugs in tumor sites and exhibited extended stability in blood circulation. In conclusion, the RPV‐modified Epirubicin and dioscin co‐delivery liposomes exhibited strong antitumor efficacy in vivo and could thus be considered a promising strategy for NSCLC treatment.