Lipopolyplex-Mediated Co-Delivery of Doxorubicin and FAK siRNA to Enhance Therapeutic Efficiency of Treating Colorectal Cancer.

Tumor metastasis is a major concern in cancer therapy. In this context, focal adhesion kinase (FAK) gene overexpression, which mediates cancer cell migration and invasion, has been reported in several human tumors and is considered a potential therapeutic target. However, gene-based treatment has certain limitations, including a lack of stability and low transfection ability. In this study, a biocompatible lipopolyplex was synthesized to overcome the aforementioned limitations. First, polyplexes were prepared using poly(2-Hydroxypropyl methacrylamide-co-methylacrylate-hydrazone-pyridoxal) (P(HPMA-co-MA-hyd-VB6)) copolymers, which bore positive charges at low pH value owing to protonation of pyridoxal groups and facilitated electrostatic interactions with negatively charged FAK siRNA. These polyplexes were then encapsulated into methoxy polyethylene glycol (mPEG)-modified liposomes to form lipopolyplexes. Doxorubicin (DOX) was also loaded into lipopolyplexes for combination therapy with siRNA. Experimental results revealed that lipopolyplexes successfully released DOX at low pH to kill cancer cells and induced siRNA out of endosomes to inhibit the translation of FAK proteins. Furthermore, the efficient accumulation of lipopolyplexes in the tumors led to excellent cancer therapeutic efficacy. Overall, the synthesized lipopolyplex is a suitable nanocarrier for the co-delivery of chemotherapeutic agents and genes to treat cancers.

Specific Cancer Cytosolic Drug Delivery Triggered by Reactive Oxygen Species-Responsive Micelles.

Cytosolic drug delivery, a major route in cancer therapy, is limited by the lack of efficient and safe endosomal escape techniques. Herein, we demonstrate a reactive oxygen species (ROS)-responsive micelle composed of methoxy polyethylene glycol-b-poly(diethyl sulfide) (mPEG-PS) copolymers which can induce specific endosome escape in cancer cells by changes in the hydrophobicity of copolymers. Owing to the more ROS levels in cancer cells than normal cells, the copolymers can be converted into more hydrophilic and insert into and destabilize the cancer intracellular endosome membrane after cellular uptake. More importantly, we show that acid-intolerant drugs successfully maintain their bioactivity and cause selective cytotoxicity for cancer cells over normal cells. Our results suggest that the endosomal escape induced by hydrophobic-hydrophilic exchange of copolymers has great potential to locally and efficiently deliver biological agents (e.g., proteins and genes) in the cancer cell cytosol.

Axl is a prognostic marker in oral squamous cell carcinoma.

BACKGROUND: Overexpression of the receptor tyrosine kinase Axl is implicated in several diseases. The present study was conducted to determine the biologic and clinical significance of Axl in oral squamous cell carcinoma (OSCC). METHODS: The expression of Axl was examined in a panel of OSCC cell lines. Activation of Axl by Gas6 treatment and silencing of Axl via Axl shRNA were used to examine the effect of Axl on OSCC cell line. Expression of Axl in cancer tissues were examined by immunohistochemical staining. The associations between Axl expression and clinicopathologic features and prognosis were analyzed. RESULTS: Varied Axl expression was noted in OSCC cell lines. Compared with control cells, modulated Axl signal affected epithelial-mesenchymal gene expression and cell invasion and migration. The immunoreactivity of Axl was low in normal epithelium, and a progressively increased positive percentage was noted, from normal/hyperplastic epithelium (10.9%) to dysplasia (30.8%) to cancer tissue (54.5%). Axl expression correlated with lymph node status (P = .001) and clinical stage (P = .014) of OSCC. Patients with high expression of Axl showed poor prognosis compared with those with low Axl expression patients (P < .001). In multivariate prognostic analysis according to the Cox proportional hazard regression model, Axl expression remained as an independent prognostic factor (P = .037; CI, 1.042-3.839). CONCLUSIONS: Our data indicated that Axl signal promotes OSCC carcinogenesis and progression. The expression of Axl is a valuable marker for OSCC aggressiveness and clinical outcome.