The oxidation of alcohols into the corresponding aldehydes or ketones is one of the most important functional group transformations in organic synthesis. 1 Recently, the use of molecular oxygen as terminal oxidant has received great attention for both economic and environmental benefits, and many highly efficient systems have been developed for catalytic aerobic alcohol oxidation using copper, 2 palladium, 3 or ruthenium catalysts. 4 Of particular interest are the catalysis systems involving both transition metals and nitroxyl radicals (e.g., 2,2,6,6-tetramethyl-piperidyl-1-oxy TEMPO). 5,6 However, only a few catalyst systems, for example, small amounts of cheap metal salts, together with TEMPO, provided an efficient catalyst for aerobic oxidation of alcohols under mild conditions. 6c,h Therefore, attempting to obtain more efficient processes, chemists have paid much attention to screening various transition metals and designing new ligands while largely ignoring the advantages inherent in a nonmetal catalytic system. We are particularly interested in exploring the potential of such a transition-metal-free catalyst system for aerobic alcohol oxidations.Our research was inspired by the results of the TEMPO-Cl 2 oxidation system by Bjørsvik et al. 7a and the TEMPO-Br 2 /I 2 system by Miller et al. 7b In their procedures, NaHCO 3 or Na 2 CO 3 was used to neutralize the coproduct HX (X ) Cl, Br, I). We reasoned that if HX can be oxidized to regenerate X 2 in situ by molecular oxygen rather than being scavenged by inorganic base, a TEMPO-catalyzed process with a catalytic amount of X 2 could be established. In this communication, we report a highly efficient catalytic system without transition metal for the aerobic oxidation of a variety of alcohols.Initial investigation of TEMPO-catalyzed (1 mol %) aerobic oxidation was carried out using benzyl alcohol as substrate with 4 mol % of Br 2 and 0.5 MPa of oxygen under 100°C for 1 h. The preliminary result (8.36% of conversion) clearly indicated the role of Br 2 as an active catalyst. Prolonging the reaction time to 5 h increased the conversion to 20.4%. 8 Recognizing that the first incorporation of molecular oxygen into the reaction system has been the keystone for successful aerobic oxidations, we sought to find a cocatalyst to bridge the gap between O 2 activation and HBr reoxidation. The ready availability and unique redox property of NaNO 2 as a source of NO under acidic conditions attracted our attention. 9 Although NaNO 2 alone showed almost no activity in TEMPO-catalyzed aerobic oxidation, when 4 mol % of Br 2 and 8 mol % of NaNO 2 were both employed in TEMPO-catalyzed aerobic oxidation, a highly efficient catalyst system emerged (eq 1). 8 The quantitative oxidation of benzyl alcohol can be achieved without acid either under 0.5 MPa of oxygen at 100°C or under 0.2 MPa of oxygen at 60°C. 8 Indeed, the transition-metal-free catalyst system for aerobic alcohol oxidations exhibited extremely high selectivities and are remarkably easy to control. After systematic op...

In biomedical applications, polyethylene glycol (PEG) functionalization has been a major approach to modify nanocarriers such as nano-graphene oxide for particular biological requirements. However, incorporation of a PEG shell poses a significant diffusion barrier that adversely affects the release of the loaded drugs. This study addresses this critical issue by employing a redox-responsive PEG detachment mechanism. A PEGylated nano-graphene oxide (NGO-SS-mPEG) with redox-responsive detachable PEG shell is developed that can rapidly release an encapsulated payload at tumor-relevant glutathione (GSH) levels. The PEG shell grafted onto NGO sheets gives the nanocomposite high physiological solubility and stability in circulation. It can selectively detach from NGO upon intracellular GSH stimulation. The surface-engineered structures are shown to accelerate the release of doxorubicin hydrochloride (DXR) from NGO-SS-mPEG 1.55 times faster than in the absence of GSH. Confocal microscopy shows clear evidence of NGO-SS-mPEG endocytosis in HeLa cells, mainly accumulated in cytoplasm. Furthermore, upon internalization of DXR-loaded NGO with a disulfide-linked PEG shell into HeLa cells, DXR is effectively released in the presence of an elevated GSH reducing environment, as observed in confocal microscopy and flow cytometric experiments. Importantly, inhibition of cell proliferation is directly correlated with increased intracellular GSH concentrations due to rapid DXR release.

Cancer immunotherapy has achieved promising clinical responses in recent years owing to the potential of controlling metastatic disease. However, there is a limited research to prove the superior therapeutic efficacy of immunotherapy on breast cancer compared with melanoma and non‐small‐cell lung cancer because of its limited expression of PD‐L1, low infiltration of cytotoxic T lymphocytes (CTLs), and high level of myeloid‐derived suppressor cells (MDSCs). Herein, a multifunctional nanoplatform (FA‐CuS/DTX@PEI‐PpIX‐CpG nanocomposites, denoted as FA‐CD@PP‐CpG) for synergistic phototherapy (photodynamic therapy (PDT), photothermal therapy (PTT) included) and docetaxel (DTX)‐enhanced immunotherapy is successfully developed. The nanocomposites exhibit excellent PDT efficacy and photothermal conversion capability under 650 and 808 nm irradiation, respectively. More significantly, FA‐CD@PP‐CpG with no obvious side effects can remarkably inhibit the tumor growth in vivo based on a 4T1‐tumor‐bearing mice modal. A low dosage of loaded DTX in FA‐CD@PP‐CpG can promote infiltration of CTLs to improve efficacy of anti‐PD‐L1 antibody (aPD‐L1), suppress MDSCs, and effectively polarize MDSCs toward M1 phenotype to reduce tumor burden, further to enhance the antitumor efficacy. Taken together, FA‐CD@PP‐CpG nanocomposites offer an efficient synergistic therapeutic modality in docetaxel‐enhanced immunotherapy for clinical application of breast cancer.

Background An in-depth understanding of immune evasion mechanisms in tumors is crucial to overcome resistance and enable innovative advances in immunotherapy. Circular RNAs (circRNAs) have been implicated in cancer progression. However, much remains unknown regarding whether circRNAs impact immune escape in non-small-cell lung carcinoma (NSCLC). Methods We performed bioinformatics analysis to profile and identify the circRNAs mediating immune evasion in NSCLC. A luciferase reporter assay, RNA immunoprecipitation (RIP), RNA pulldown assays and fluorescence in situ hybridization were performed to identify the interactions among circIGF2BP3, miR-328-3p, miR-3173-5p and plakophilin 3 (PKP3). In vitro T cell-mediated killing assays and in vivo syngeneic mouse models were used to investigate the functional roles of circIGF2BP3 and its downstream target PKP3 in antitumor immunity in NSCLC. The molecular mechanism of PKP3-induced PD-L1 upregulation was explored by immunoprecipitation, RIP, and ubiquitination assays. Results We demonstrated that circIGF2BP3 (hsa_circ_0079587) expression was increased in NSCLC and negatively correlated with CD8+ T cell infiltration. Functionally, elevated circIGF2BP3 inactivated cocultured T cells in vitro and compromised antitumor immunity in an immunocompetent mouse model, and this effect was dependent on CD8+ T cells. Mechanistically, METTL3 mediates the N6-methyladenosine (m6A) modification of circIGF2BP3 and promotes its circularization in a manner dependent on the m6A reader protein YTHDC1. circIGF2BP3 competitively upregulates PKP3 expression by sponging miR-328-3p and miR-3173-5p to compromise the cancer immune response. Furthermore, PKP3 engages with the RNA-binding protein FXR1 to stabilize OTUB1 mRNA, and OTUB1 elevates PD-L1 abundance by facilitating its deubiquitination. Tumor PD-L1 deletion completely blocked the impact of the circIGF2BP3/PKP3 axis on the CD8+ T cell response. The inhibition of circIGF2BP3/PKP3 enhanced the treatment efficacy of anti-PD-1 therapy in a Lewis lung carcinoma mouse model. Collectively, the PKP3/PD-L1 signature and the infiltrating CD8+ T cell status stratified NSCLC patients into different risk groups. Conclusion Our results reveal the function of circIGF2BP3 in causing immune escape from CD8+ T cell-mediated killing through a decrease in PD-L1 ubiquitination and subsequent proteasomal degradation by stabilizing OTUB1 mRNA in a PKP3-dependent manner. This work sheds light on a novel mechanism of PD-L1 regulation in NSCLC and provides a rationale to enhance the efficacy of anti-PD-1 treatment in NSCLC.