The unprecedented oxidative dearomatization-induced [5+2] cycloaddition/pinacol-type 1,2-acyl migration cascade efficiently generates a quaternary carbon center and assembles the highly oxygenated bicyclo[3.2.1]octane framework of ent-kaurene diterpenoids. By incorporation of the subsequent retro-aldol/aldol process and singlet oxygen ene reaction, this concise and convergent approach has enabled the first asymmetric total syntheses of pharicin A, pharicinin B, 7-O-acetylpseurata C, and pseurata C.

Protein therapeutics is playing an increasingly critical role in treatment of human diseases. However, current vectors are captured by the digestive endo-lysosomal system, which results in an extremely low fraction (<2%) of protein being released in the cytoplasm. This paper reports a drug-delivering-drug platform (HA-PNPplex, 200 nm) for potent intracellular delivery of protein and combined treatment of cancer.Methods: The platform was prepared by loading functional protein on pure drug nanoparticles (PNPs) followed by hyaluronic acid coating and was characterized by dynamic light scattering, transmission electron microscopy, and gel electrophoresis. In vitro, cellular uptake, trafficking, and cytotoxicity were evaluated by flow cytometry and confocal laser microscopy. Protein expression was assayed by western blot. In vivo, blood circulation and biodistribution were studied using a fluorescence imaging system, antitumor efficacy was assessed in a caspase 3-deficient tumor model, and biocompatibility was determined by comparison of hemolytic activity and proinflammatory cytokines and tissue histology.Results: HA-PNPplex delivered the functional protein, caspase 3, to cells via bypassing endo-lysosomes and raised the caspase-3 level 6.5-fold in caspase 3-deficient cells. Promoted tumor accumulation (1.5-fold) and penetration were exhibited, demonstrating a high tumor-targeting ability of HA-PNPplex. HA-PNPplex rendered a 7-fold increase in caspase 3 in tumor and allowed for a 100% tumor growth inhibition and >60% apoptosis, implying significant antitumor activities.Conclusions: This platform gains cellular entry without entrapment in the endo-lysosomes and enables efficient intracellular protein delivery and resultant profound cancer treatment. This platform, with extremely high drug-loading, is a valuable platform for combined cancer therapy with small-molecule drugs and proteins. More importantly, this work offers a robust and safe approach for protein therapeutics and intracellular delivery of other functional peptides, as well as gene-based therapy.

Background Postoperative recurrence of cancers is responsible for a large portion of deaths in cancer patients. Our study investigated the involvement of lncRNA AWPPH in recurrence of resected non-small cell lung cancer (NSCLC). Material/Methods A total of 128 patients were followed up for 3 years. Blood was extracted from each patient on the day of discharge, the day of the diagnosis of recurrence, or at the end of follow-up. Blood from 30 healthy controls was used as a control group. Patient were divided into 3 groups – a non-recurrence group (NR, n=54), a local recurrence group (LR, n=42), and a distant recurrence (DR, n=32) group – according to the follow-up results. Blood AWPPP was detected by qRT-PCR. AWPPH expression vectors were transfected into cells of human NSCLC cell lines. Cell migration and invasion were detected by Transwell migration and invasion assay, respectively. TGF-β1 expression was detected by Western blot analysis. Results Blood AWPPH levels were the highest in the DR group, followed by the LR and NR groups. The lowest blood AWPPH levels were observed in the control group. Blood AWPPH levels increased significantly in the DR group but not in the NR and LR groups during follow-up. Blood AWPPH levels were positively correlated with TGF-β1 mRNA levels in the DR group but not in the NR and LR groups during follow-up. AWPPH overexpression promoted cell migration and invasion and upregulated TGF-β1 expression. Conclusions lncRNA AWPPH can promote postoperative distant recurrence in resected NSCLC by upregulating TGF-β1.

miR-30d suppressed cell migration and invasion by directly targeting NFIB in NSCLC, and NFIB could partially abrogated the inhibition of biological functions by miR-30d.

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