Metformin, a widely implemented anti-diabetic drug, exhibits potent anticancer efficacies. Herein a polymeric construction of Metformin, PolyMetformin (PolyMet) is successfully synthesized through conjugation of linear polyethylenimine (PEI) with dicyandiamide. The delocalization of cationic charges in the biguanide groups of PolyMet reduces the toxicity of PEI both in vitro and in vivo. Furthermore, the polycationic properties of PolyMet permits capture of siRNA into a core-membrane structured lipid-polycation-hyaluronic acid (LPH) nanoparticle for systemic gene delivery. Advances herein permit LPH-PolyMet nanoparticles to facilitate VEGF siRNA delivery for VEGF knockdown in a human lung cancer xenograft, leading to enhanced tumour suppressive efficacy. Even in the absence of RNAi, LPH-PolyMet nanoparticles act similarly to Metformin and induce antitumour efficacy through activation of the AMPK and inhibition of the mTOR. In essence, PolyMet successfully combines the intrinsic anticancer efficacy of Metformin with the capacity to carry siRNA to enhance the therapeutic activity of an anticancer gene therapy.

The tumor microenvironment (TME) serves as an innate resistance niche for chemotherapy assault and a physiological barrier against therapeutic nanoparticles (NP) penetration. Previous studies have indicated that therapeutic NP can distribute to and deplete tumor associated fibroblasts (TAF) for improved therapeutic outcome. However, resistance develops after repeated chemotherapeutic NP exposure. In this study, we explored NP-delivered cisplatin induced resistance in the TME by investigating the effects of NP damaged TAF on neighboring naïve cells and comparing the stroma structure of single and multiple dose NP treatments. Our study suggested that although off-targeted NP damaged TAF initially inhibited tumor growth, chronic exposure of TAF to cisplatin NP led to elevated secretion of Wnt16 in a paracrine manner that supported tumor cell resistance and stroma reconstruction. Our study demonstrates that knockdown of Wnt16 in the damaged TAF could be a promising combinatory strategy to improve efficacy of NP delivered cisplatin in a stroma-rich bladder cancer model.

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As the most common malignant brain tumors, glioblastoma multiforme (GBM) was characterized by angiogenesis and tumor cells proliferation. Dual targeting to neovasculature and GBM cells could deliver cargoes to these two kinds of cells, leading to a combination treatment. In this study, polymeric nanoparticles were functionalized with RGD and interleukin-13 peptide (IRNPs) to construct a neovasculature and tumor cell dual targeting delivery system in which RGD could target αvβ3 on neovasculature and interleukin-13 peptide could target IL13Rα2 on GBM cells. In vitro, interleukin-13 peptide and RGD could enhance the uptake by corresponding cells (C6 and human umbilical vein endothelial cells). Due to the expression of both receptors on C6 cells, RGD also could enhance the uptake by C6 cells. Through receptor labeling, it clearly showed that αvβ3 could mediate the internalization of RGD modified nanoparticles and IL13Rα2 could mediate the internalization of interleukin-13 peptide modified nanoparticles. The ligand functionalization also resulted in a modification on endocytosis pathways, which changed the main endocytosis pathways from macropinocytosis for unmodified nanoparticles to clathrin-mediated endocytosis for IRNPs. IRNPs also displayed the strongest penetration ability according to tumor spheroid analysis. In vivo, IRNPs could effectively deliver cargoes to GBM with higher intensity than monomodified nanoparticles. After CD31-staining, it demonstrated IRNPs could target both neovasculature and GBM cells. In conclusion, IRNPs showed promising ability in dual targeting both neovasculature and GBM cells.

SummaryThe TruView EVO2 laryngoscope was compared with the traditional Macintosh laryngoscope in 200 patients who required tracheal intubation for elective surgery. Mallampati score determined prior to laryngoscopy was significantly related to the view of the glottis during laryngoscopy for both laryngoscopes. The view of the larynx was better with the TruView EVO2 laryngoscope than with the Macintosh laryngoscope in patients with a Cormack and Lehane grade greater than 1 (p < 0.01). The mean time to intubate was significantly shorter with the Macintosh laryngoscope (34 s) than with the TruView laryngoscope (51 s) (p < 0.01). Many cases of difficult intubation are unanticipated and are frequently not recognised during pre-operative assessment [1]. Many different designs of laryngoscopes have been developed in an effort to reduce the incidence of this problem [2][3][4].The TruView EVO2 laryngoscope (Truphatek International Ltd, Netanya, Israel) is a recently introduced device with a unique blade that provides an optical view 'around the corner'. The blade is a modified laryngoscope blade incorporating an unmagnified optic side port with anterior fraction of 35% in the line of sight allowing indirect tracheal intubation [5].The aim of this study was to compare the TruView EVO2 laryngoscope with the direct Macintosh laryngoscope. We wished to determine whether the TruView EVO2 laryngoscope provided an improved view at laryngoscopy compared to that provided by the Macintosh laryngoscope and to also to assess the time taken for intubation with these two devices. MethodsApproval for the study was obtained from the hospital research ethics committee and written informed consent was obtained from each patient participating. Patients were considered appropriate for recruitment if they were undergoing elective surgery for which tracheal intubation was planned. Exclusion criteria included the presence of raised intracranial pressure, cervical spine injury, risk factors for pulmonary aspiration of gastric contents and the presence of any pathology of the head and neck. Preoperatively, patients' demographics and characteristics were reported. The Mallampati score and thyromental distance in mouth opening were also recorded.In the operating room, standard monitoring was employed on all patients and, after pre-oxygenation, anaesthesia was induced with midazolam 0.02-0.04 lg.kg )1 , fentanyl 2-4 lg.kg, and propofol 1-2 mg.kg )1 . Neuromuscular blockade was achieved using rocuronium in a dose of 0.6 mg.kg )1 and an adequacy of neuromuscular block confirmed using a peripheral nerve stimulator. Patients were placed in the 'sniffing' position with their head on a pillow. If ventilation via face mask was considered inadequate by the anaesthesiologist, the patient was withdrawn from the study. Anaesthesia was maintained with either propofol or sevoflurane in oxygen during the study and analgesics agents administered according to preference. A standard Macintosh laryngoscope and TruView EVO2 laryngoscope were used throughout the study...

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P2X receptors on dorsal root ganglion (DRG) neurons have been strongly implicated in pathological nociception after peripheral nerve injuries or inflammation. However, nothing is known of a role for purinergic receptors in neuropathic pain produced by a chronic compression of DRG (CCD) -an injury that may accompany an intraforaminal stenosis, a laterally herniated disc or other disorders of the spine leading to radicular pain. In a rat model of DRG compression, hyperexcitable neurons retain functioning axonal connections with their peripheral targets. It is unknown whether such hyperexcitability might enhance chemically mediated nociceptive stimulation of the skin. In this study, CCD facilitated the nocifensive behavior and mechanical hyperalgesia-induced by the P2X 3 agonist, α,β-methylene ATP (α,β-meATP). An injection of α,β-meATP into the hind paw of CCD rats resulted in a significantly greater decrease in the mean threshold to von Frey stimuli and a greater duration of paw lifts than in sham-operated control rats. CCD also increased the levels of P2X 3 receptor protein and the number of P2X 3 immunoreactive, small diameter DRG neurons in the compressed ganglion. P2X 3 receptors were co-labeled with the isolectin IB4, consistent with a role in nociception. In addition, a α,β-meATP induced significantly larger fast-inactivating currents in CCD-than in sham-operated acutely dissociated DRG neurons. These currents were accompanied by the generation of action potentials -but only in the CCD neurons. U0126, a specific inhibitor of the MEK1/2, greatly down-regulated the enhanced current. Taken together, these observations suggest that enhanced purinergic responses after CCD are mediated by P2X 3 receptors.

Clinically, combined therapy of cisplatin (CDDP) and metformin is an effective treatment for non-small cell lung cancer (NSCLC). The success is attributed to synergistic effects between the two drugs. Therefore, we hypothesize that co-encapsulation of CDDP and metformin will avoid the prominent toxicity of CDDP while maintaining the synergy between the regimens. CDDP was first conjugated to polyglutamic acid (PGA) to form anionic PGA-CDDP which was electrostatically complexed with the cationic polymeric metformin (polymet). The nano-sized complex was then stabilized with cationic liposomes composed of DOTAP (2, 3-Dioleoyloxy-propyl)-trimethylammonium/Cholesterol/DSPE-PEG-anisamide aminoethyl. Both in vitro and in vivo experiments confirmed the synergy between polymet and CDDP. CDDP delivered with nanoparticles (NPs) exhibited significantly increased tumor accumulation over free CDDP and suppressed tumor growth through apoptosis in NSCLC H460 tumor-bearing mice without nephrotoxicity. The synergistic effect of polymet alongside CDDP demonstrates that polymet-CDDP NPs can activate the AMP-activated protein kinase α (AMPKα) pathway and inhibit mammalian target rapamycin (mTOR) activity to enhance growth suppression. In all, this platform is the first to successfully co-load polymet, a polymeric metformin, and CDDP into the same nanoparticle for successful treatment of NSCLC.