SDF-1-loaded PLGA nanoparticles for the targeted photoacoustic imaging and photothermal therapy of metastatic lymph nodes in tongue squamous cell carcinoma.

The combination of photothermal therapy and targeted chemotherapy can produce much greater cytotoxicity than chemotherapy. Herein, we developed multifunctional targeted polymeric nanoparticles (NPs) loaded with indocyanine green (ICG) and doxorubicin (DOX) for the targeted photoacoustic imaging and photothermal ablation of oral cancer cells. The chemokine SDF-1, a specific antibody, was conjugated to NPs by the carbodiimide method. The NPs were automatically targeted to tumour tissue in vitro and in vivo through CXCR4-SDF-1 interactions. The results of in vivo and in vitro photoacoustic imaging and photothermal therapy experiments showed that the multifunctional NPs had excellent photoacoustic imaging characteristics and photothermal therapy capabilities. The photothermal material heated rapidly after laser irradiation, and the resulting heat increased cell metabolism and membrane permeability, which increased cellular NP uptake. The encapsulated drug (DOX) was released immediately after the liquid core was transformed into a gas via laser effects, which killed tumour cells while producing strong photoacoustic signals in vitro and in vivo. Thus, we concluded that the chemokine SDF-1 can be applied for the targeted chemotherapy of metastatic lymph nodes of oral squamous cell carcinoma (OSCC) and is more effective for treating oral cancer when combined with photothermal therapy than when used alone.

Pancreatic Cancer Cell Migration and Metastasis Is Regulated by Chemokine-Biased Agonism and Bioenergetic Signaling.

Patients with pancreatic ductal adenocarcinoma (PDAC) invariably succumb to metastatic disease, but the underlying mechanisms that regulate PDAC cell movement and metastasis remain little understood. In this study, we investigated the effects of the chemokine gene CXCL12, which is silenced in PDAC tumors, yet is sufficient to suppress growth and metastasis when re-expressed. Chemokines like CXCL12 regulate cell movement in a biphasic pattern, with peak migration typically in the low nanomolar concentration range. Herein, we tested the hypothesis that the biphasic cell migration pattern induced by CXCL12 reflected a biased agonist bioenergetic signaling that might be exploited to interfere with PDAC metastasis. In human and murine PDAC cell models, we observed that nonmigratory doses of CXCL12 were sufficient to decrease oxidative phosphorylation and glycolytic capacity and to increase levels of phosphorylated forms of the master metabolic kinase AMPK. Those same doses of CXCL12 locked myosin light chain into a phosphorylated state, thereby decreasing F-actin polymerization and preventing cell migration in a manner dependent upon AMPK and the calcium-dependent kinase CAMKII. Notably, at elevated concentrations of CXCL12 that were insufficient to trigger chemotaxis of PDAC cells, AMPK blockade resulted in increased cell movement. In two preclinical mouse models of PDAC, administration of CXCL12 decreased tumor dissemination, supporting our hypothesis that chemokine-biased agonist signaling may offer a useful therapeutic strategy. Our results offer a mechanistic rationale for further investigation of CXCL12 as a potential therapy to prevent or treat PDAC metastasis.

Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach.

Phosphoinositide 3-kinases (PI3Ks) are among the most frequently activated signaling pathways in cancer. In chronic lymphocytic leukemia (CLL), signals from the microenvironment are critical for expansion of the malignant B cells, and cause constitutive activation of PI3Ks. CXCR4 is a key receptor for CLL cell migration and adhesion to marrow stromal cells (MSCs). Because of the importance of CXCR4 and PI3Ks for CLL-microenvironment cross-talk, we investigated the activity of novel, isoform-selective PI3K inhibitors that target different isoforms of the p110-kDa subunit. Inhibition with p110alpha inhibitors (PIK-90 and PI-103) resulted in a significant reduction of chemotaxis and actin polymerization to CXCL12 and reduced migration beneath MSC (pseudoemperipolesis). Western blot and reverse phase protein array analyses consistently demonstrated that PIK-90 and PI-103 inhibited phosphorylation of Akt and S6, whereas p110delta or p110beta/p110delta inhibitors were less effective. In suspension and MSC cocultures, PI-103 and PIK-90 were potent inducers of CLL cell apoptosis. Moreover, these p110alpha inhibitors enhanced the cytotoxicity of fludarabine and reversed the protective effect of MSC on fludarabine-induced apoptosis. Collectively, our data demonstrate that p110alpha inhibitors antagonize stromal cell-derived migration, survival, and drug-resistance signals and therefore provide a rational to explore the therapeutic activity of these promising agents in CLL.