查看更多>>摘要：Chemotherapy is one of the major approaches for the treatment of metastatic lung cancer,although it is limited by the low tumor delivery efficacy of anticancer drugs.Bacterial therapy is emerging for cancer treatment due to its high immune stimulation effect;however,excessively generated immunogenicity will cause serious inflammatory response syndrome.Here,we prepared cancer cell membrane-coated liposomal paclitaxel-loaded bacterial ghosts(LP@BG@CCM)by layer-by-layer encapsulation for the treatment of metastatic lung cancer.The preparation processes were simple,only involving film formation,electroporation,and pore extrusion.LP@BG@CCM owned much higher 4T1 cancer cell toxicity than LP@BG due to its faster fusion with cancer cells.In the 4T1 breast cancer metastatic lung cancer mouse models,the remarkably higher lung targeting of intravenously injected LP@BG@CCM was observed with the almost normalized lung appearance,the reduced lung weight,the clear lung tissue structure,and the enhanced cancer cell apoptosis compared to its precursors.More-over,several major immune factors were improved after administration of LP@BG@CCM,including the CD4+/CD8a+T cells in the spleen and the TNF-α,IFN-γ,and IL-4 in the lung.LP@BG@CCM exhibits the optimal synergistic chemo-immunotherapy,which is a promising medication for the treatment of met-astatic lung cancer.
查看更多>>摘要：Gas therapy is emerging as a highly promising therapeutic strategy for cancer treatment.However,there are limitations,including the lack of targeted subcellular organelle accuracy and spatio-temporal release precision,associated with gas therapy.In this study,we developed a series of photoac-tivatable nitric oxide(NO)donors NRh-R-NO(R=Me,Et,Bn,iPr,and Ph)based on an N-nitrosated upconversion luminescent rhodamine scaffold.Under the irradiation of 808 nm light,only NRh-Ph-NO could effectively release NO and NRh-Ph with a significant turn-on frequency upconversion lumines-cence(FUCL)signal at 740 nm,ascribed to lower N-N bond dissociation energy.We also investigated the involved multistage near-infrared-controlled cascade release of gas therapy,including the NO released from NRh-Ph-NO along with one NRh-Ph molecule generation,the superoxide anion O2·-produced by the photodynamic therapy(PDT)effect of NRh-Ph,and highly toxic peroxynitrite anion(ONOO-)gener-ated from the co-existence of NO and O2·-.After mild nano-modification,the nanogenerator(NRh-Ph-NO NPs)empowered with superior biocompatibility could target mitochondria.Under an 808 nm laser irradiation,NRh-Ph-NO NPs could induce NO/ROS to generate RNS,causing a decrease in the mito-chondrial membrane potential and initiating apoptosis by caspase-3 activation,which further induced tu-mor immunogenic cell death(ICD).In vivo therapeutic results of NRh-Ph-NO NPs showed augmented RNS-potentiated gas therapy,demonstrating excellent biocompatibility and effective tumor inhibition guided by real-time FUCL imaging.Collectively,this versatile strategy defines the targeted RNS-mediated cancer therapy.
查看更多>>摘要：Nasal drug delivery efficiency is highly dependent on the position in which the drug is depos-ited in the nasal cavity.However,no reliable method is currently available to assess its impact on delivery performance.In this study,a biomimetic nasal model based on three-dimensional(3D)reconstruction and three-dimensional printing(3DP)technology was developed for visualizing the deposition of drug pow-ders in the nasal cavity.The results showed significant differences in cavity area and volume and powder distribution in the anterior part of the biomimetic nasal model of Chinese males and females.The nasal cavity model was modified with dimethicone and validated to be suitable for the deposition test.The experimental device produced the most satisfactory results with five spray times.Furthermore,particle sizes and spray angles were found to significantly affect the experimental device's performance and alter drug distribution,respectively.Additionally,mometasone furoate(MF)nasal spray(NS)distribution pat-terns were investigated in a goat nasal cavity model and three male goat noses,confirming the in vitro and in vivo correlation.In conclusion,the developed human nasal structure biomimetic device has the poten-tial to be a valuable tool for assessing nasal drug delivery system deposition and distribution.
查看更多>>摘要：Lignans are a powerful weapon for plants to resist stresses and have diverse bioactive func-tions to protect human health.Elucidating the mechanisms of stereoselective biosynthesis and response to stresses of lignans is important for the guidance of plant improvement.Here,we identified the complete pathway to stereoselectively synthesize antiviral(-)-lariciresinol glucosides in Isatis indigotica roots,which consists of three-step sequential stereoselective enzymes DIR1/2,PLR,and UGT71B2.DIR1 was further identified as the key gene in respoJanuary 2024nse to stresses and was able to trigger stress defenses by mediating the elevation in lignan content.Mechanistically,the phytohormone-responsive ERF transcription factor LTF1 colocalized with DIR1 in the cell periphery of the vascular regions in mature roots and helped resist biotic and abiotic stresses by directly regulating the expression of DIR1.These systematic results suggest that DIR1 as the first common step of the lignan pathway coop-erates with PLR and UGT71B2 to stereoselectively synthesize(-)-lariciresinol derived antiviral lignans in I.indigotica roots and is also a part of the LTF1-mediated regulatory network to resist stresses.In conclusion,the LTF1-DIR1 module is an ideal engineering target to improve plant Defenses while increasing the content of valuable lignans in plants.
查看更多>>摘要：A biosynthetic gene cluster for the bioactive fungal sesterterpenoids variecolin(1)and var-iecolactone(2)was identified in Aspergillus aculeatus ATCC 16872.Heterologous production of 1 and 2 was achieved in Aspergillus oryzae by expressing the sesterterpene synthase VrcA and the cytochrome P450 VrcB.Intriguingly,the replacement of VrcB with homologous P450s from other fungal terpenoid pathways yielded three new variecolin analogues(5-7).Analysis of the compounds'anticancer activity in vitro and in vivo revealed that although 5 and 1 had comparable activities,5 was associated with signif-icantly reduced toxic side effects in cancer-bearing mice,indicating its potentially broader therapeutic window.Our study describes the first tests of variecolin and its analogues in animals and demonstrates the utility of synthetic biology for creating molecules with improved biological activities.
万方数据
维普