Casitas b cell lymphoma­B (Cbl-b): A new therapeutic avenue for small-molecule immunotherapy.

Immunotherapy has revolutionized the area of cancer treatment. Although most immunotherapies now are antibodies targeting membrane checkpoint molecules, there is an increasing demand for small-molecule drugs that address intracellular pathways. The E3 ubiquitin ligase Casitas B cell lymphoma­b (Cbl-b) has been regarded as a promising intracellular immunotherapy target. Cbl-b regulates the downstream proteins of multiple membrane receptors and co-receptors, restricting the activation of the innate and adaptive immune system. Recently, Cbl-b inhibitors have been reported with promising effects on immune surveillance activation and anti-tumor efficacy. Several molecules have entered phase Ⅰ clinical trials. In this review, the biological rationale of Cbl-b as a promising target for cancer immunotherapy and the latest research progress of Cbl-b are summarized, with special emphasis on the allosteric small-molecule inhibitors of Cbl-b.

Design, synthesis and biological evaluation of novel 2,4-disubstituted quinazoline derivatives targeting H1975 cells via EGFR-PI3K signaling pathway.

In order to find new and highly effective anti-tumor drugs with targeted therapeutic effects, a series of novel 4-aminoquinazoline derivatives containing N-phenylacetamide structure were designed, synthesized and evaluated for antitumor activity against four human cancer cell lines (H1975, PC-3, MDA-MB-231 and MGC-803) using MTT assay. The results showed that the compound 19e had the most potent antiproliferative activity against H1975, PC-3, MDA-MB-231 and MGC-803 cell lines. At the same time, compound 19e could significantly inhibit the colony formation and migration of H1975 cells. Compound 19e also arrested the H1975 cell cycle in the G1 phase and mediated cell apoptosis, promoted the accumulation of ROS in H1975 cells. Furthermore, compound 19e exerted antitumor effect in vitro by reducing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 19e could significantly decreased the phosphorylation of EGFR and its downstream protein PI3K in H1975 cells. Which indicated that compound 19e targeted H1975 cell via interfering with EGFR-PI3K signaling pathway. Molecular docking showed that compound 19e could bind into the active pocket of EGFR. Those work suggested that compound 19e would have remarkable implications for further design of anti-tumor agents.

2,4-Disubstituted quinazolines targeting breast cancer cells via EGFR-PI3K.

A series of novel 2,4-disubstituted quinazolines were synthesized and evaluated for their anti-tumor activity against five human cancer cells (MDA-MB-231, MCF-7, PC-3, HGC-27 and MGC-803) using MTT assay. Among them, compound 9n showed the most potent cytotoxicity against breast cancer cells. Compound 9n also significantly inhibited the colony formation and migration of MDA-MB-231 and MCF-7 cells. Meanwhile, compound 9n induced cell cycle arrest at G1 phase and cell apoptosis, as well as increased accumulation of intracellular ROS. Furthermore, compound 9n exerted anti-tumor effects in vitro via decreasing the expression of anti-apoptotic protein Bcl-2 and increasing the pro-apoptotic protein Bax and p53. Mechanistically, compound 9n markedly decreased p-EGFR and p-PI3K expression, which revealed that compound 9n targeted breast cancer cells via interfering with EGFR-PI3K signaling pathway. Molecular docking suggested that compound 9n could indeed bind into the active pocket of EGFR. All the findings suggest that compound 9n might be a valuable lead compound for anti-tumor agents targeting breast cancer cells.

Multifunctional Magnetic Mesoporous Silica Nanoagents for in vivo Enzyme-Responsive Drug Delivery and MR Imaging.

In this study, we report novel multifunctional nanoagents for in vivo enzyme-responsive anticancer drug delivery and magnetic resonance imaging (MRI), based on mesoporous silica coated iron oxide nanoparticles (Fe3O4@MSNs). The anticancer drug, DOX, was encapsulated in the porous cavities with a MMP-2 enzyme responsive peptide being covalently linked to the nanoparticles surface. The in vitro experiment results indicated that the enzyme responsive nanoagents own high specificity for controlled drug release in the cell line with high MMP-2 expression. Furthermore, the targeted delivery of the nanoagents to the tumor site purpose has been successfully achieved through magnet-guided nanocarrier accumulation by utilizing the magnetic properties of the Fe3O4 nanocores, which resulted in efficient inhibition of the tumor growth. Additionally, these novel nanoagents can also be used as MRI agent for the real-time diagnosis the tumor treatment process of living animals. Taking the advantages of high specificity, controllable drug release and real-time MRI imaging, we believe these multifunctional nanoagents could also be used as a general platform for the design of stimulus-responsive multifunctional nanomaterials for the aim of accurate diagnosis and efficient treatment of other diseases.

Fabrication of PEGylated Fe@Bi2S3 nanocomposites for dual-mode imaging and synergistic thermoradiotherapy.

Nanocomposites for integrating imaging and therapy have attracted tremendous attention for biomedical applications. Herein, Fe@Bi2S3 nanocomposites modified with polyethylene glycol (PEG) molecules are fabricated for synergistic thermoradiotherapy. For such nanocomposites, Bi2S3 exhibits a strong absorbance in the near-infrared (NIR) region, which allows Bi2S3 to convert energy from light into heat for effective photothermal therapy (PTT), whereas Bi can also significantly enhance radio-mediated cell death induction as a radiotherapy sensitizer due to its high atomic number (high-Z). Most importantly, it is found that the combination of PTT and radiation therapy (RT), using PEGylated Fe@Bi2S3 nanocomposites, can bring a strong synergistic effect for the tumor treatment in in vitro and in vivo experiments. Besides, the magnetic Fe core and the Bi2S3 shell components endow this nanocomposite with an ability to serve as both a magnetic resonance imaging (MRI) and computed tomography (CT) contrast agent. Therefore, our work presents a new type of multifunctional nanocomposite with the potential for synergistic thermoradiotherapy and simultaneously MRI/CT imaging.

Facile preparation of hybrid core-shell nanorods for photothermal and radiation combined therapy.

The hybrid platinum@iron oxide core-shell nanorods with high biocompatibility were synthesized and applied for combined therapy. These hybrid nanorods exhibit a good photothermal effect on cancer cells upon irradiation with a NIR laser. Furthermore, due to the presence of a high atomic number element (platinum core), the hybrid nanorods show a synergistic effect between photothermal and radiation therapy. Therefore, the as-prepared core-shell nanorods could play an important role in facilitating synergistic therapy between photothermal and radiation therapy to achieve better therapeutic efficacy.

Preparation and characterization of rare-earth bulks with controllable nanostructures.

The preparation and characterization of pure rare-earth-metal bulks with controllable nanostructures are reported in this paper. A novel 'oxygen-free' in situ synthesis technique that combines inert-gas condensation with spark plasma sintering (SPS) technology is proposed. Taking into account the special mechanisms of SPS consolidation and the scale effects of nanoparticles, we introduced practical procedures for preparing rare-earth bulks of amorphous, mixed amorphous and nanocrystals, and nanocrystalline microstructures, respectively. Compared with the conventional polycrystalline bulk, these nanostructured bulks exhibit substantially improved physical and mechanical properties. This technique enables comprehensive studies on the microstructures and properties of a large variety of nanostructured metallic materials that are highly reactive in the air.