Despite standard treatment for non-small cell lung cancer(NSCLC)being surgical resection,cancer recurrence and complications,such as induction of malignant pleural effusion(MPE)and significant postoperative pain,usual...Despite standard treatment for non-small cell lung cancer(NSCLC)being surgical resection,cancer recurrence and complications,such as induction of malignant pleural effusion(MPE)and significant postoperative pain,usually result in treatment failure.In this study,an alginate-based hybrid hydrogel(SOG)is developed that can be injected into the resection surface of the lungs during surgery.Briefly,endoplasmic reticulum-modified liposomes(MSLs)pre-loaded with the signal transducer and activator of transcription 3(STAT3)small interfering RNA and lidocaine hydrochloride are encapsulated in SOG.Once applied,MSLs strongly downregulated STAT3 expression in the tumor microenvironment,resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype.Meanwhile,the release of lidocaine hydrochloride(LID)was beneficial for pain relief and natural killer cell activation.Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life,including reduced MPE volume and pain relief in orthotopic NSCLC mouse models,even with a single administration.MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC,and may alter the treatment paradigms for other cancers.展开更多
Patients with an influenza virus infection can be complicated by acute encephalopathy and encephalitis. To investigate the immune reactions involved in the neurocomplication, mouse microglia and astrocytes were isolat...Patients with an influenza virus infection can be complicated by acute encephalopathy and encephalitis. To investigate the immune reactions involved in the neurocomplication, mouse microglia and astrocytes were isolated, infected with human H1N1 and avian H5N1 influenza viruses, and examined for their immune responses. We observed homogeneously distributed viral receptors, sialic acid （SA）-a2,3-Galactose （Gal） and SA-a2,6-Gal, on microglia and astrocytes. Both viruses were replicative and productive in microglia and astrocytes. Virus-induced apoptosis and cytopathy in infected cells were observed at 24 h post-infection （p.i.）. Expression of IL-1β, IL-6 and TNF-a mRNA examined at 6 h and 24 h p.i. was up-regulated, and their expression levels were considerably higher in H5N1 infection. The amounts of secreted proinflammatory IL-1β, IL-6 and TNF-a at 6 h and 24 h p.i. were also induced, with greater induction by H5N1 infection. This study is the first demonstration that both human H1N1 and avian H5N1 influenza viruses can infect mouse microglia and astrocytes and induce apoptosis, cytopathy, and proinflammatory cytokine production in them in vitro. Our results suggest that the direct cellular damage and the consequences of immunopathological injury in the CNS contribute to the influenza viral pathogenesis. Cellular ＆ Molecular Immunology.展开更多
The combination of paclitaxel(PTX)and doxorubicin(DOX)has been widely used in the clinic.However,it remains unsatisfied due to the generation of severe toxicity.Previously,we have successfully synthesized a prodrug PT...The combination of paclitaxel(PTX)and doxorubicin(DOX)has been widely used in the clinic.However,it remains unsatisfied due to the generation of severe toxicity.Previously,we have successfully synthesized a prodrug PTX-S-DOX(PSD).The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX.Thus,we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation.Due to the fact that copper ions(Cu2+)could coordinate with the anthracene nucleus of DOX,we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+gradient.Hence,we designed a remote loading liposomal formulation of PSD(PSD LPs)for combination chemotherapy.The prepared PSD LPs displayed extended blood circulation,improved tumor accumulation,and more significant anti-tumor efficacy compared with PSD NPs.Furthermore,PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil,indicating better safety.Therefore,this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.展开更多
Liposomes have made remarkable achievements as drug delivery vehicles in the clinic.Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs,but seem...Liposomes have made remarkable achievements as drug delivery vehicles in the clinic.Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs,but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents,thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy.In this study,a series of weak acid drug derivatives were designed by a simplistic one step synthesis,which could be remotely loaded into liposomes by p H gradient method.Cabazitaxel(CTX)weak acid derivatives were selected to evaluate regarding its safety profiles,pharmacodynamics,and pharmacokinetics.CTX weak acid derivative liposomes were superior to Jevtanaa in terms of safety profiles,including systemic toxicity,hematological toxicity,and potential central nerve toxicity.Specifically,it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons.Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.展开更多
Therapeutic efficacy against cancer relies heavily on the ability of the therapeutic agents to reach their final targets.The optimal targets of most cancer therapeutic agents are usually biological macromolecules at t...Therapeutic efficacy against cancer relies heavily on the ability of the therapeutic agents to reach their final targets.The optimal targets of most cancer therapeutic agents are usually biological macromolecules at the subcellular level,which play a key role in carcinogenesis.Therefore,to improve the therapeutic efficiency of drugs,researchers need to focus on delivering not only the therapeutic agents to the target tissues and cells but also the drugs to the relevant subcellular structures.In this review,we discuss the most recent construction strategies and release patterns of various cancer cell subcellular-targeting nanoformulations,aiming at providing guidance in the overall design of precise nanomedicine.Additionally,future challenges and potential perspectives are illustrated in the hope of enhancing anticancer efficacy and accelerating the translational progress of precise nanomedicine.展开更多
To increase the efficiency and accuracy of clinical tumor detection,we explored multiple imaging by preparing carbon quantum dot(CQD)-loaded nanobubbles for ultrasonic fluorescence dual detection.In this experiment,we...To increase the efficiency and accuracy of clinical tumor detection,we explored multiple imaging by preparing carbon quantum dot(CQD)-loaded nanobubbles for ultrasonic fluorescence dual detection.In this experiment,we prepared 1,2-dioleoyl-3-trimethylammonium-propane chloride(DOTAP)cationic liposomes using the film dispersion method and chose perfluoropentane as the core gas material of the nanobubbles.The nanobubbles were coupled with the negatively charged CQDs through the charge effect to prepare the testing agent for two-way diagnosis with ultrasound contrast and fluorescence detection.The formulation and preparation of the loaded CQD liposome nanobubbles were screened.In vivo experiments showed that nanobubbles can be enriched to the tumor site within 5 min,which enables clearer ultrasound imaging and is conducive to tumor detection.We expect CQD-loaded liposome(Lip-CQD)nanobubbles to become a new ultrasonic contrast agent for clinical applications that can provide a basis for early tumor diagnosis and thus earlier treatment.展开更多
基金supported by the National Natural Science Foundation of China[grant numbers 21873057,22373059]the Natural Science Foundation of Shandong Province[grant numbers ZR2023MB082]。
文摘Despite standard treatment for non-small cell lung cancer(NSCLC)being surgical resection,cancer recurrence and complications,such as induction of malignant pleural effusion(MPE)and significant postoperative pain,usually result in treatment failure.In this study,an alginate-based hybrid hydrogel(SOG)is developed that can be injected into the resection surface of the lungs during surgery.Briefly,endoplasmic reticulum-modified liposomes(MSLs)pre-loaded with the signal transducer and activator of transcription 3(STAT3)small interfering RNA and lidocaine hydrochloride are encapsulated in SOG.Once applied,MSLs strongly downregulated STAT3 expression in the tumor microenvironment,resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype.Meanwhile,the release of lidocaine hydrochloride(LID)was beneficial for pain relief and natural killer cell activation.Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life,including reduced MPE volume and pain relief in orthotopic NSCLC mouse models,even with a single administration.MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC,and may alter the treatment paradigms for other cancers.
基金supported by grants from National Natural Science Foundation of China(No.30571674 and No.30771988)Guangdong Natural Science Foundation(No.05008347 and No.04020239).
文摘Patients with an influenza virus infection can be complicated by acute encephalopathy and encephalitis. To investigate the immune reactions involved in the neurocomplication, mouse microglia and astrocytes were isolated, infected with human H1N1 and avian H5N1 influenza viruses, and examined for their immune responses. We observed homogeneously distributed viral receptors, sialic acid （SA）-a2,3-Galactose （Gal） and SA-a2,6-Gal, on microglia and astrocytes. Both viruses were replicative and productive in microglia and astrocytes. Virus-induced apoptosis and cytopathy in infected cells were observed at 24 h post-infection （p.i.）. Expression of IL-1β, IL-6 and TNF-a mRNA examined at 6 h and 24 h p.i. was up-regulated, and their expression levels were considerably higher in H5N1 infection. The amounts of secreted proinflammatory IL-1β, IL-6 and TNF-a at 6 h and 24 h p.i. were also induced, with greater induction by H5N1 infection. This study is the first demonstration that both human H1N1 and avian H5N1 influenza viruses can infect mouse microglia and astrocytes and induce apoptosis, cytopathy, and proinflammatory cytokine production in them in vitro. Our results suggest that the direct cellular damage and the consequences of immunopathological injury in the CNS contribute to the influenza viral pathogenesis. Cellular ＆ Molecular Immunology.
基金supported by National Science and Technology Major Projects for Major New Drugs Innovation and Development(No.2017ZX09101-001-005,Beijing,China)Science and Technology Plan Project of Shenyang(No.18-400-4-08,Z17-5-064,China)the Career Development Program for Young and Middle-aged Teachers in Shenyang Pharmaceutical University(Shenyang,China)
文摘The combination of paclitaxel(PTX)and doxorubicin(DOX)has been widely used in the clinic.However,it remains unsatisfied due to the generation of severe toxicity.Previously,we have successfully synthesized a prodrug PTX-S-DOX(PSD).The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX.Thus,we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation.Due to the fact that copper ions(Cu2+)could coordinate with the anthracene nucleus of DOX,we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+gradient.Hence,we designed a remote loading liposomal formulation of PSD(PSD LPs)for combination chemotherapy.The prepared PSD LPs displayed extended blood circulation,improved tumor accumulation,and more significant anti-tumor efficacy compared with PSD NPs.Furthermore,PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil,indicating better safety.Therefore,this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.
基金financially supported by the National Nature Science Foundation of China(U1608283)the Career Development Program for Young and Middle-aged Teachers in Shenyang Pharmaceutical University
文摘Liposomes have made remarkable achievements as drug delivery vehicles in the clinic.Liposomal products mostly benefited from remote drug loading techniques that succeeded in amphipathic and/or ionizable drugs,but seemed impracticable for nonionizable and poorly water-soluble therapeutic agents,thereby impeding extensive promising drugs to hitchhike liposomal vehicles for disease therapy.In this study,a series of weak acid drug derivatives were designed by a simplistic one step synthesis,which could be remotely loaded into liposomes by p H gradient method.Cabazitaxel(CTX)weak acid derivatives were selected to evaluate regarding its safety profiles,pharmacodynamics,and pharmacokinetics.CTX weak acid derivative liposomes were superior to Jevtanaa in terms of safety profiles,including systemic toxicity,hematological toxicity,and potential central nerve toxicity.Specifically,it was demonstrated that liposomes had capacity to weaken potential toxicity of CTX on cortex and hippocampus neurons.Significant advantages of CTX weak acid derivative-loaded liposomes were achieved in prostate cancer and metastatic cancer therapy resulting from higher safety and elevated tolerated doses.
基金supported by the National Natural Science Foundation of China(Grant No.21873057)Shandong Provincial Natural Science Foundation of China(Grant No.ZR2019MB041)+1 种基金the Major Basic Research Project of Shandong Natural Science Foundation,P.R.China(Grant No.ZR2018ZC0232)the Fundamental Research Funds of Shandong University(Grant No.2018JC006).
文摘Therapeutic efficacy against cancer relies heavily on the ability of the therapeutic agents to reach their final targets.The optimal targets of most cancer therapeutic agents are usually biological macromolecules at the subcellular level,which play a key role in carcinogenesis.Therefore,to improve the therapeutic efficiency of drugs,researchers need to focus on delivering not only the therapeutic agents to the target tissues and cells but also the drugs to the relevant subcellular structures.In this review,we discuss the most recent construction strategies and release patterns of various cancer cell subcellular-targeting nanoformulations,aiming at providing guidance in the overall design of precise nanomedicine.Additionally,future challenges and potential perspectives are illustrated in the hope of enhancing anticancer efficacy and accelerating the translational progress of precise nanomedicine.
基金supported by the National Natural Science Foundation of China(No.21873057)the Shandong Provincial Natural Science Foundation of China(No.ZR2019MB041)the Fundamental Research Funds of Shandong University(No.2018JC006),China。
文摘To increase the efficiency and accuracy of clinical tumor detection,we explored multiple imaging by preparing carbon quantum dot(CQD)-loaded nanobubbles for ultrasonic fluorescence dual detection.In this experiment,we prepared 1,2-dioleoyl-3-trimethylammonium-propane chloride(DOTAP)cationic liposomes using the film dispersion method and chose perfluoropentane as the core gas material of the nanobubbles.The nanobubbles were coupled with the negatively charged CQDs through the charge effect to prepare the testing agent for two-way diagnosis with ultrasound contrast and fluorescence detection.The formulation and preparation of the loaded CQD liposome nanobubbles were screened.In vivo experiments showed that nanobubbles can be enriched to the tumor site within 5 min,which enables clearer ultrasound imaging and is conducive to tumor detection.We expect CQD-loaded liposome(Lip-CQD)nanobubbles to become a new ultrasonic contrast agent for clinical applications that can provide a basis for early tumor diagnosis and thus earlier treatment.
