CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. The SDF-1/CXCR4 axis is significantly associated with several diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis and lupus. For example, CXCR4 is one of the major co-receptors for HIV entry into target cells, while in cancer it plays an important role in tumor cell metastasis. Several promising CXCR4 antagonists have been developed to block SDF-1/CXCR4 interactions that are currently under different stages of development. The first in class CXCR4 antagonist, plerixafor, was approved by the FDA in 2008 for the mobilization of hematopoietic stem cells and several other drugs are currently in clinical trials for cancer, HIV, and WHIM syndrome. While the long-term safety data for the first generation CXCR4 antagonists are not yet available, several new compounds are under preclinical development in an attempt to provide safer and more efficient treatment options for HIV and cancer patients.

The current challenge in the field of nanomedicine is the design of multifunctional nano-objects effective both for the diagnosis and treatment of diseases. Here, dendronized FeO 1−x @Fe 3−x O 4 nanoparticles with spherical, cubic, and octopode shapes and oxidized Fe 3−x O 4 nanocubes have been synthesized and structurally and magnetically characterized. Strong exchange bias properties are highlighted in core−shell nanoparticles (NPs) due to magnetic interactions between their antiferromagnetic core and ferrimagnetic shell. Both in vitro relaxivity measurements and nuclear magnetic resonance (NMR) distribution profiles have confirmed the very good in vitro magnetic resonance imaging (MRI) properties of core−shell and cubic shape NPs, especially at low concentration. This might be related to the supplementary anisotropy introduced by the exchange bias properties and the cubic shape. The high heating values of core−shell NPs and oxidized nanocubes at low concentration are attributed to dipolar interactions inducing different clustering states, as a function of concentration. In vivo MRI studies have also evidenced a clustering effect at the injection point, depending on the concentration, and confirmed the very good in vivo MRI properties of core−shell NPs and oxidized nanocubes in particular at low concentration. These results show that these core−shell and cubic shape dendronized nano-objects are very suitable to combine MRI and hyperthermia properties at low injected doses.

Interleukin (IL)-6 and Stat3 play key roles in ovarian cancer progression. However, the role of glycoprotein 130 (gp130), the signal transducer of this signaling axis, is not well-established. Currently, there are no smallmolecule inhibitors of gp130 under clinical development. In this study, we show that gp130 is an attractive drug target in ovarian cancer due to its role in promoting cancer progression via the activation of its downstream Stat3 signaling. We also present preclinical studies of SC144, the first-in-class orally active small-molecule gp130 inhibitor. SC144 shows greater potency in human ovarian cancer cell lines than in normal epithelial cells. SC144 binds gp130, induces gp130 phosphorylation (S782) and deglycosylation, abrogates Stat3 phosphorylation and nuclear translocation, and further inhibits the expression of downstream target genes. In addition, SC144 shows potent inhibition of gp130 ligand-triggered signaling. Oral administration of SC144 delays tumor growth in a mouse xenograft model of human ovarian cancer without significant toxicity to normal tissues. Mol Cancer Ther; 12(6);