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Zoledronic acid (ZOL) has been used as an adjuvant therapy for breast cancer. It is suggested that ZOL might be associated with inhibition of macrophages, which in turn reduces tumor growth, metastasis and tumor angiogenesis. Moreover, metronomic therapy can inhibit tumor angiogenesis and tumor immune cells. Previously we developed ZOL based cationic liposomes that allowed a higher intratumor delivery of drug compared with free ZOL in vivo . Therefore, in this study, Asn-Gly-Arg (NGR) and PEG2000 were used as ligands to modify the surface of liposomes (NGR-PEG-LP-ZOL) in metronomic therapy to clear the tumor-associated macrophages (TAMs) and inhibit the formation of tumor angiogenesis, achieving the purpose of anti-tumor growth. Our data showed that NGR-PEG-LP-ZOL metronomic therapy has the strongest inhibitory effect on tumor growth. Further, NGR-PEG-LP-ZOL metronomic therapy could significantly impair TAMs by inhibiting the expression of CD206 antibody in tumor tissues, decreasing the expression of cytokine related gene expression of TAMs, as well as reducing the percentage of TAMs in tumor tissues. In addition, NGR-PEG-LP-ZOL metronomic therapy could significantly inhibit the expression of tumor neovascular specific antibody CD31 and reduce the microvessel density. In conclusion, our study demonstrated that NGR-PEG-LP-ZOL metronomic therapy could impair TAMs by inhibiting tumor angiogenesis and enhance the antitumor effect of ZOL., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interests.

Blood-tumor barrier (BTB) reduce the permeability for drugs into tumor tissues. We found that histamine might serve as an essential regulator of BTB function. Further, we aim to determine the role of H2 receptor expression in BTB permeability, and elucidate the underlying mechanisms thereof. Transmission electron microscopy showed that histamine disrupted the integrity of tight junctions (TJ) and increased the number of pinosomes in the cytoplasm. Horseradish peroxidase (HRP) and trans-endothelial resistance detection (TEER) assays revealed that histamine could open BTB and this action was inhibited by cimetidine. Western blot and immunofluorescence assays showed that histamine decreased the expression of tight junction proteins zonula occluden-1(ZO-1), occludin, and claudin-5. Further, quantitative RT-PCR assay showed that the expression of H2 receptor could represent and predicted histamine-induced BTB permeability. In conclusion, histamine opened BTB by down-regulating the TJ-associated proteins. The levels of H2 receptor expression was correlated with the histamine-induced BTB permeability., Competing Interests: The authors have no potential conflicts of interest.