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);

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Aqueous suspensions of dendronized iron oxide nanoparticles (NPs) have been obtained after functionalization, with two types of dendrons, of NPs synthesized either by coprecipitation (leading to naked NPs in water) or by thermal decomposition (NPs in situ coated by oleic acid in an organic solvent). Different grafting strategies have been optimized depending on the NPs synthetic method. The size distribution, the colloidal stability in isoosmolar media, the surface complex nature as well as the preliminary biokinetic studies performed with optical imaging, and the contrast enhancement properties evaluated through in vitro and in vivo MRI experiments, have been compared as a function of the nature of both dendrons and NPs. All functionalized NPs displayed good colloidal stability in water, however the ones bearing a peripheral carboxylic acid function gave the best results in isoosmolar media. Whereas the grafting rates were similar, the nature of the surface complex depended on the NPs synthetic method. The in vitro contrast enhancement properties were better than commercial products, with a better performance of the NPs synthesized by coprecipitation. On the other hand, the NPs synthesized by thermal decomposition were more efficient in vivo. Furthermore, they both displayed good biodistribution with renal and hepatobiliary elimination pathways and no consistent RES uptake.

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Integrin alphavbeta3 has been implicated in multiple aspects of tumor progression and metastasis. Many tumors have high expression of alphavbeta3 that correlates with tumor progression. Therefore, alphavbeta3 receptor is an excellent target for drug design and delivery. We have discovered a series of novel alphavbeta3 antagonists utilizing common feature pharmacophore models. Upon validation using a database of known alphavbeta3 receptor antagonists, a highly discriminative pharmacophore model was used as a 3D query. A search of a database of 600 000 compounds using the pharmacophore Hypo5 yielded 832 compounds. On the basis of structural novelty, 29 compounds were tested in alphavbeta3 receptor specific binding assay and four compounds showed excellent binding affinity. A limited SAR analysis on the active compound 26 resulted in the discovery of two compounds with nanomolar to subnanomolar binding affinity. These small-molecule compounds could be conjugated to paclitaxel for selective delivery to alphavbeta3 positive metastatic cancer cells.

During the last decades, a wide range of molecular and cellular imaging techniques have been developed and optimized, resulting in important progress in the understanding of diagnostic and biological processes. Among these techniques, magnetic resonance imaging (MRI) is certainly one of the most popular, because of its high spatial resolution and the fact that it does not require the use of radioisotopes. Although gadolinium has long been the most commonly used paramagnetic metal to design efficient MRI contrast agents, the discovery of its potential toxicity has driven researchers to give priority to other paramagnetic metals, as, for example, manganese. With this microreview we would like to highlight the state of the art of manganese‐based MRI contrast agents with a particular focus on the chemical structures of these agents and on their chronological evolution from simple chelates to complex nanohybrid systems.