CXCR4-Targeted and Redox Responsive Dextrin Nanogel for Metastatic Breast Cancer Therapy

The unsatisfied results of cancer therapy are caused by many issues and metastasis of cancer cells is one of the major challenge. It has been reported that inhibiting the SDF1/CXCR4 interaction can significantly reduce the metastasis of breast cancer cells to regional lymph nodes and lung. Herein, a nanogel system equipped with the FDA-approved CXCR4 antagonist AMD3100 was developed and evaluated for its combined antimetastatic and tumor targeting effects. Briefly, a bioreducible cross-linked dextrin nanogel (DNG) coated with AMD3100 was designed to possess multiple functions, including CXCR4 chemokine targeting, inhibition of tumor metastasis, and reduction-responsive intracellular release of doxorubicin (DOX) to reduce the cells proliferation. The in vitro results confirmed that the DOX-loaded AMD3100-coated dextrin nanogel (DOX-AMD-DNG) was more effectively taken up by 4T1 breast cancer cells than DOX-DNG and was significantly more cytotoxic to 4T1 cells than DOX-DNG. In biodistribution studies, the stronger fluorescence intensity of Cy7-AMD-DNG than Cy7-DNG further confirmed that AMD3100 mediated tumor targeting in vivo. AMD3100-coated DOX-DNG also exhibited a distinct antimetastatic effect and CXCR4 antagonistic activity by inhibiting CXCR4-mediated cell invasion in 4T1 and U2OS cells. Moreover, DOX-AMD-DNG displayed superior anticancer activity and antimetastatic effects in orthotopic breast cancer-bearing Balb/C mice. In summary, the multifunctional DOX-AMD-DNG can effectively target the tumor site and dually impede cancer progression and metastasis

Sesquiterpene-neolignans from <i>Manglietia hookeri</i>

<p>The comet assay-guided fractionation of the twigs of <i>Manglietia hookeri</i> resulted in the isolation of three sesquiterpene-neolignans, including a new one 5-allyl-2-(4-allyl-phenoxy)-3-[7-(1-hydroxy-1-methyl-ethyl)-1, 4a-dimethyl-decahydro-naphthalen-1-yloxy]-phenol (<b>1</b>), and eudesobovatol A (<b>2</b>) and eudesobovatol B (<b>3</b>), together with three lignans, obovatol (<b>4</b>), honokiol (<b>5</b>) and magnolol (<b>6</b>). Their structures were elucidated on the basis of spectral analysis and by comparison with related literature data. Compounds <b>1</b>, <b>4</b>–<b>6</b> showed a protective effect on UV inductive DNA damage in mice lymphocyte cells, while compound <b>1</b> indicated the smallest Olive Tail Moment 7.34 ± 2.09 at 6 × 10⁻⁶ μM.</p

Pyridinylquinazolines Selectively Inhibit Human Methionine Aminopeptidase‑1 in Cells

Methionine aminopeptidases (MetAPs), which remove the initiator methionine from nascent peptides, are essential in all organisms. While MetAP2 has been demonstrated to be a therapeutic target for inhibiting angiogenesis in mammals, MetAP1 seems to be vital for cell proliferation. Our earlier efforts identified two structural classes of human MetAP1 (<i>Hs</i>MetAP1)-selective inhibitors (<b>1</b>–<b>4</b>), but all of them failed to inhibit cellular <i>Hs</i>MetAP1. Using Mn­(II) or Zn­(II) to activate <i>Hs</i>MetAP1, we found that <b>1</b>–<b>4</b> could only effectively inhibit purified <i>Hs</i>MetAP1 in the presence of physiologically unachievable concentrations of Co­(II). In an effort to seek Co­(II)-independent inhibitors, a novel structural class containing a 2-(pyridin-2-yl)­quinazoline core has been discovered. Many compounds in this class potently and selectively inhibited <i>Hs</i>MetAP1 without Co­(II). Subsequently, we demonstrated that <b>11j</b>, an auxiliary metal-dependent inhibitor, effectively inhibited <i>Hs</i>MetAP1 in primary cells. This is the first report that an <i>Hs</i>MetAP1-selective inhibitor is effective against its target in cells