Development of quercetin-loaded PVCL-PVA-PEG micelles and application in inhibiting tumor angiogenesis through the PI3K/Akt/VEGF pathway.

Quercetin (Que) exhibits excellent biological activity; however, its clinical development is hindered owing to the poor water solubility. In this study, Que. was loaded on polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PVCL-PVA-PEG, Soluplus) micelles through a thin-film hydration process, and their tumor angiogenesis inhibition ability was investigated. The particle size of Soluplus-Que micelles was 55.3 ± 1.8 nm, and the micelles stayed stability within 9 months. Soluplus-Que micelles can enhance the cell uptake of Que. and transport the micelles to intracellular lysosomes and mitochondria. The MTT assay results revealed that Soluplus-Que micelles enhanced the cytotoxicity of Que. on HUVEC cells. Furthermore, Soluplus-Que micelles inhibited migration and invasion of HUVEC cells, as well as inhibited the neovascularization of chick embryo allantoic membrane (CAM). The in vivo study revealed that Soluplus-Que micelles significantly inhibit the growth of H22 solid tumors, with low toxic side effects. Soluplus-Que inhibited the expression of CD31 (a marker of angiogenesis) and the PI3K/Akt/VEGF pathway in tumor tissues, indicating its potential to hold back tumor growth via the inhibition of angiogenesis. Our findings indicated that as a delivery system, Soluplus micelles demonstrate potential for the delivery of poorly soluble drugs for tumor treatment.

EGPI-1, a novel eIF4E/eIF4G interaction inhibitor, inhibits lung cancer cell growth and angiogenesis through Ras/MNK/ERK/eIF4E signaling pathway.

eIF4E plays an important role in regulating tumor growth and angiogenesis, and eIF4E is highly expressed in a variety of lung cancer cell lines. siRNA eIF4E can significantly inhibit the proliferation of lung cancer cells, indicating that inhibition of eIF4E may become a novel anti-tumor target. In the previous study, we synthesized a series of small molecule compounds with the potential to inhibit eIF4E. Among them, the compound EGPI-1 significantly inhibited the proliferation of a variety of lung cancer cells such as A549, NCI-H460, NCI-H1650 and 95D without inhibiting the proliferation of HUVEC cells. Further studies found that EGPI-1 interfered with the eIF4E/eIF4G interaction and inhibited the phosphorylation of eIF4E in NCI-H460 cells. The results of flow cytometry showed that EGPI-1 induced apoptosis and G0/G1 cycle arrest in NCI-H460 cell. Interestingly, we also found that EGPI-1 induced autophagy and DNA damage in NCI-H460 cells. The mechanism results showed that EGPI-1 inhibited the Ras/MNK/ERK/eIF4E signaling pathway. Moreover, EGPI-1 inhibited tube formation of HUVECs, as well as inhibited the neovascularization of CAM, proving the anti-angiogenesis activity of EGPI-1. The NCI-H460 xenograft studies showed that EGPI-1 inhibited tumor growth and angiogenesis in vivo by regulating Ras/MNK/ERK/eIF4E pathway. Our studies proved that eIF4E was a novel target for regulating tumor growth, and the eIF4E/eIF4G interaction inhibitor EGPI-1 was promising to develop into a novel anti-lung cancer drug.

Improved anticancer activity of betulinic acid on breast cancer through a grafted copolymer-based micelles system.

Betulinic acid (3ß-Hydroxy-20(29)-lupaene-28-oic acid, BA) has excellent anti-cancer activity but poor solubility and low bioavailability. To improve the antitumor activity of BA, a polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol (PVCL-PVA-PEG) graft copolymer (Soluplus) encapsulated BA micelle (Soluplus-BA) was fabricated. The Soluplus-BA micelles presented a mean size of 54.77 ± 1.26 nm and a polydispersity index (PDI) of 0.083. The MTT assay results showed that Soluplus-BA micelles increased the inhibitory effect of BA on MDA-MB-231 cells, mainly due to the enhanced accumulation of reactive oxygen species (ROS) and the destruction of mitochondrial membrane potential (MMP). Soluplus-BA micelles induced the DNA double-strand breaks (DSBs) as the γH2AX foci increased. Moreover, Soluplus-BA also inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVECs), and inhibited the neovascularization of the chicken chorioallantoic membrane (CAM). This angiogenesis inhibitory effect may be accomplished by regulating the HIF-1/VEGF-FAK signaling pathway. The in vivo study confirmed the improved anti-tumor effect of Soluplus-BA and its inhibitory effect on angiogenesis, demonstrating the possibility of Soluplus-BA as an effective anti-breast cancer drug delivery system.