RNA interference (RNAi) represents a promising strategy for identification and validation of putative therapeutic targets and for treatment of a myriad of important human diseases including cancer. However, the effective systemic in vivo delivery of small interfering RNA (siRNA) to tumors remains a formidable challenge. Using a robust self-assembly strategy, we develop a unique nanoparticle (NP) platform composed of a solid polymer/cationic lipid hybrid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell for systemic siRNA delivery. The new generation lipid-polymer hybrid NPs are small and uniform, and can efficiently encapsulate siRNA and control its sustained release. They exhibit long blood circulation (t 1/2 ∼8 h), high tumor accumulation, effective gene silencing, and negligible in vivo side effects. With this RNAi NP, we delineate and validate the therapeutic role of Prohibitin1 (PHB1), a target protein that has not been systemically evaluated in vivo due to the lack of specific and effective inhibitors, in treating non-small cell lung cancer (NSCLC) as evidenced by the drastic inhibition of tumor growth upon PHB1 silencing. Human tissue microarray analysis also reveals that high PHB1 tumor expression is associated with poorer overall survival in patients with NSCLC, further suggesting PHB1 as a therapeutic target. We expect this long-circulating RNAi NP platform to be of high interest for validating potential cancer targets in vivo and for the development of new cancer therapies.siRNA delivery | nanoparticle | Prohibitin1 | non-small cell lung cancer W ith the capability to silence any gene of interest, RNA interference (RNAi) technology has demonstrated enormous potential in medical research and applications (1, 2). RNAi-mediated gene silencing has revealed the functionality of specific genetic alterations in cancers (3-5). Many of these genes and pathways are considered "undruggable" targets or require complex and time-consuming development of effective inhibitors. The ubiquitous application of RNAi in cancer research and therapy is nevertheless hindered by the challenge of effective systemic in vivo delivery of siRNA to tumors, which requires overcoming of multiple physiological barriers, such as enzymatic degradation, rapid elimination by renal excretion or by the mononuclear phagocyte system (MPS), and poor cellular uptake and endosomal escape (2, 6, 7). To this end, a great number of cationic lipid/polymer-based nanoparticles (NPs) have been developed to protect siRNA from serum nucleases and facilitate its cytosolic delivery (8). Surface PEGylation has also been applied extensively to improve NP stability and reduce MPS recognition (9, 10). Several RNAi nanotherapeutics are now in clinical trial in cancer patients. However, the clinical stage anticancer RNAi NPs have shown relatively rapid clearance in blood (11,12), which may reduce their extravasation into tumor tissue through the enhanced permeability and retention (EPR) effect (13). This could result in decreased in vivo silencing efficacy...

Highly stretchable neural interface of concurrent robust electrical and mechanical properties is developed with a conducting polymer film as the sole conductor for both electrodes and leads. This neural interface offers benefits of conducting polymer electrodes in a demanding stretchable format, including low electrode impedance and high charge injection capacity, due to large electroactive surface area of the electrode.

The paucity of microspheres trapped within the brain indicates that retrograde cerebral perfusion, either alone or combined with inferior vena caval occlusion, does not provide sufficient cerebral capillary perfusion to confer any metabolic benefit. The slightly improved outcome previously reported with retrograde cerebral perfusion during prolonged circulatory arrest in this model may be a consequence of enhanced cooling resulting from perfusion of nonbrain capillaries and from venoarterial and venovenous shunting.

No abstract