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GSH-responsive camptothecin prodrug-based hybrid micellar nanoparticles enable antitumor chemo-immunotherapy by PD-L1 knockdown

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Nano Research 2023年第1期16卷 834-848页

作者： Xi Tan Hong Zhou Chenhui Wang Xuhan Liu xiangliang yang Wei Liu College of Life Science and Technology Huazhong University of Science and TechnologyWuhan 430074China The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine Sichuan Provincial People’s HospitalUniversity of Electronic Science and Technology of ChinaChengdu 611731China Department of Emergency Medicine Shenzhen University General HospitalShenzhen University Clinical Medical AcademyShenzhen 518060China National Engineering Research Center for Nanomedicine Huazhong University of Science and TechnologyWuhan 430074China

The combinational chemo-immunotherapy as a novel treatment strategy has been widely studied and applied in clinic to enhance antitumor therapeutic efficacy and relieve side *** interference(RNAi)targeting PD-L1 via inhibiting novo production of PD-L1 will overcome the innate and adaptive PD-L1 expression during chemotherapy,thus enable sustained and efficient immune checkpoint blockade(ICB)to active antitumor immune ***,we designed a glutathione(GSH)-responsive camptothecin(CPT)prodrug-based hybrid micellar nanoparticles(siPD-L1@HM-CPT)to achieve synergistic antitumor chemoimmunotherapy by PD-L1 ***-L1@HM-CPT derived from the one-step loading PD-L1 siRNA(siPD-L1)into the CPT prodrug-based hybrid micelles(HM-CPT)which were co-assembled from biodegradable polyphosphoesters-based prodrug CPT-ss-PAEEP15 and stabilizer DSPE-PEG,showed high loading efficiency,GSH-responsive drug release,and excellent stability and ***-L1@HM-CPT achieved simultaneously the co-delivery of CPT and siPD-L1 in vitro and in vivo,high accumulation at the tumor sites,and rapid intracellular release to promote antitumor efficacy via sensitizing CPT chemotherapy,inducing strong immunogenic cell death(ICD)and sustained ICB to improve intratumoral CD8+T cells *** addition,the antitumor immunity response limited by the differentiated immunogenicity,intrinsic PD-L1 expression,and intracellular GSH level was facilitated by efficient ICD and ICB from silencing PD-L1 and synergistic CPT chemosensitization in our experimental B16-F10 and 4T1 tumor *** study might offer a perspective on designing novel co-delivery nanoparticles by convenient and controllable preparation for antitumor chemo-immunotherapy.

关键词： camptothecin prodrug hybrid micellar nanoparticles glutathione(GSH)-responsive PD-L1 knockdown chemoimmunotherapy

Hydroxyethyl starch and its derivatives as nanocarriers for delivery of diagnostic and therapeutic agents towards cancers

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Biomaterials Translational 2020年第1期1卷 46-57页

作者： Ronghua Tan Ying Wan xiangliang yang National Engineering Research Centre for Nanomedicine College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhanHubei ProvinceChina

Many types of drugs and agents used for cancer diagnosis and therapy often have low bioavailability and insufficient efficacy,as well as causing various side effects due to their nonspecific *** with purposely-designed compositions and structures have shown varying degrees of abilities to deliver these compounds towards cancers in passive or active *** the availability of a variety of materials for the construction of nanocarriers,natural polymers with good biocompatibility and biodegradability are preferable for such usage because of their high in vivo safety as well as easy removal of degradation *** the natural polymers intended for building nanocarriers,hydroxyethyl starch and its derivatives have gained tremendous attention in the field of drug delivery in the form of nanomedicines over the last *** is growing optimism that ever more hydroxyethyl starch-based nanomedicines will be a significant addition to the armoury currently used for cancer diagnosis and therapy.

关键词： anticancer treatment chemical modification diagnostic and therapeutic agents hydroxyethyl starch nanocarriers prodrug

Long-term exposure to titanium dioxide nanoparticles promotes diet-induced obesity through exacerbating intestinal mucus layer damage and microbiota dysbiosis

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Nano Research 2021年第5期14卷 1512-1522页

作者： Xiaoqiang Zhu Lijun Zhao Zhi Liu Qibing Zhou Yanhong Zhu Yuliang Zhao xiangliang yang National Engineering Research Center for Nanomedicine College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan430074China Department of Biotechnology College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan430074China CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety National Center for Nanoscience and Technology of ChinaBeijing100190China

Titanium dioxide nanoparticles (TiO2-NPs) are commonly used as food additives, including some high-fat foods that are risk factors for obesity. However, little is known about the effects of chronic TiO2-NPs digestion in the population on high fat diet (HFD). Herein, we reported that TiO2-NPs exacerbated HFD-induced obesity by disruption of mucus layer and alterations of gut microbiota. Oral intake of TiO2-NPs significantly increased body weight, liver weight, and amount of adipose tissues, especially in HFD-fed mice. Mechanistic studies revealed TiO2-NPs induced colonic mucus layer disruption and obesity-related microbiota dysbiosis. The damage on mucus was demonstrated through down-regulation of Muc2 gene and the absorption of mucin protein by TiO2-NPs. Consequently, mucus layer damage combined microbiota dysbiosis escalated the low-grade systemic inflammation, which exacerbated HFD-induced obesity. In contrast, gut microbiota depletion eliminated these effects, indicating gut microbiota were necessary for TiO2-NPs-induced inflammation and obesity. All the results stated the alarming role of TiO2-NPs in the HFD-driven obesity and emphasized the reevaluating the health impacts of nanoparticles commonly used in daily life, particularly, in susceptible population.

关键词： titanium dioxide nanoparticles nanosafety obesity mucus layer gut microbiota

The immune-chemo-embolization effect of temperature sensitive gold nanomedicines against liver cancer

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Nano Research 2023年第2期16卷 2749-2761页

作者： Yiming Liu Dingwen Shi Yanqiao Ren Ling Li Yanbing Zhao Chuansheng Zheng xiangliang yang Department of Radiology Union HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430022China National Engineering Research Center for Nanomedicine Key Laboratory of Molecular Biophysics of Ministry of EducationCollege of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China School of Biomedical Engineering Hubei University of Science and TechnologyXianning 437100China Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica Hubei Engineering Research Center for Biomaterials and Medical Protective MaterialsHuazhong University of Science and TechnologyWuhan 430074China GBA Research Innovation Institute for Nanotechnology Guangzhou 510530China Hubei Province Key Laboratory of Molecular Imaging Wuhan 430022China

Although transcatheter arterial chemo-embolization(TACE)plays a key role on clinical treatment of hepatocellular carcinoma(HCC),it was greatly limited by the poor synergistic effect between chemotherapeutics and physical embolization to tumor-feeding *** the present work,a temperature sensitive polymer poly(N-isopropylacrylamide-b-methacrylic acid)(PNA),which was modified with gold nanoparticles(AuNP@PNA),was successfully used to encapsulate doxorubicin(DOX)by electrostatic binding with their carboxyl *** resultant gold nanomedicines(AuNP@PNA/DOX)exhibited temperature responsive sol-gel phase transition,favorable shear thinning effect and X-ray *** in vivo evaluation of vascular embolization on VX2-tumor-bearing rabbits,AuNP@PNA/DOX exhibited far better antitumor efficacy than Lipiodol/DOX,on either tumor growth inhibition,proliferation,apoptosis,necrosis or *** to sufficient embolization to tumor vascular networks,AuNP@PNA/DOX down-regulated the expression levels of HIF-1α,VEGF and MMP-9,and prompted more efficient activation on CD3+/CD8+T cells and the related cytokines,suggesting the synergistic effect between AuNP@PNA and DOX on the improvement of post-operative tumor immunosuppressive *** their favorable pharmcokinetics and biocompatibility,AuNP@PNA/DOX is promising to be developed as a multi-functional artery-imaging/embolic agent with immune-chemo-embolization for enhancing TACE efficacy on HCC.

关键词： temperature sensitive nanogels gold nanoparticles transcatheter arterial chemo-embolization(TACE) antitumor immune response

Unimolecular Self-Assembled Hemicyanine-Oleic Acid Conjugate Acts as a Novel Succinate Dehydrogenase Inhibitor to Amplify Photodynamic Therapy and Eliminate Cancer Stem Cells

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Research 2024年第2期6卷 449-461页

作者： Qiang Wang Tian yang Shiyou Li Chen Xu Chong Wang Yuxuan Xiong Xing Wang Jiangling Wan xiangliang yang Zifu Li National Engineering Research Center for Nanomedicine College of Life Science and Technology.Huazhong University of Science and TechnologyWuhan 430074P.R.China Key Laboratory of Molecular Biophysics of Ministry of Education College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074P.R.China .3Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical Huazhong University of Science and TechnologyWuhan 430074P.R.China Hubei Engineering Research Center for Biomaterials and Medical Protective Materials Huazhong University of Science and TechnologyWuhan 430074P.R.China Hubei Bioinformatics and Molecular Imaging Key Laboratory College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074P.R.China

Photodynamic therapy with reactive oxygen species production is a prospective treatment to combat cancer stem cells(CSCs).However,the innate drawbacks,including short lifetime and diffusion distance of reactive oxygen species and hypoxia within solid tumors,have become bottlenecks for clinical applications of photodynamic ***,we develop a mitochondria-targeting hemicyanine-oleic acid conjugate(CyOA),which can self-assemble into supramolecular nanoparticles(NPs)without any exogenous *** is also shown for targeting the mitochondrial complex II protein succinate dehydrogenase to inhibit oxidative phosphorylation and reverse tumor hypoxia,resulting in 50.4-fold higher phototoxicity against breast cancer stem cells(BCSCs)compared to SO_(3)-CyOA NPs that cannot target to *** 4T1 and BCSC tumor models,CyOA NPs achieve higher tumor inhibition and less lung metastasis nodules compared to the clinically used photosensitizer *** study develops a self-assembled small molecule that can serve as both oxidative phosphorylation inhibitor and photosensitizer for eradication of CSCs and treatment of solid tumors.

关键词： cyanine oxidative treatment

Targeting cancer-associated fibroblasts with hydroxyethyl starch nanomedicine boosts cancer therapy

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Nano Research 2023年第5期16卷 7323-7336页

作者： Chong Wang Huimin Wang Hai yang Chen Xu Qiang Wang Zheng Li Zhijie Zhang Jiankun Guan Ximiao Yu Xiaoquan yang xiangliang yang Zifu Li National Engineering Research Center for Nanomedicine College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China GBA Research Innovation Institute for Nanotechnology Guangzhou 510530China Key Laboratory of Biomedical Photonics(HUST) Ministry of EducationHuazhong University of Science and TechnologyWuhan 430074China Key Laboratory of Molecular Biophysics of Ministry of Education College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical Huazhong University of Science and TechnologyWuhan 430074China Hubei Engineering Research Center for Biomaterials and Medical Protective Materials Huazhong University of Science and TechnologyWuhan 430074China Hubei Bioinformatics and Molecular Imaging Key Laboratory College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China

Cancer-associated fibroblasts(CAFs)play an important role in facilitating the progression of triple-negative breast cancer(TNBC)by deteriorating the tumor mechanical microenvironment(TMME).Herein,we designed a CAFs-targeting nanomedicine by conjugating doxorubicin(DOX)-loaded hydroxyethyl starch-IR780 nanoparticles(NPs)with Cys-Arg-Glu-Lys-Ala(CREKA)peptide,which had a special affinity for fibronectin overexpressed on *** systemic administration,the NPs efficiently targeted CAFs and generated hyperthermia upon light irradiation,decreasing CAFs through the combination of chemo-and ***,a series of changes in TMME were achieved by reducing CAFs,which further disrupted the niche of cancer stem cells(CSCs)to affect their *** a result,the tumor growth was significantly inhibited in 4T1 *** strategy of TMME modulation and CSCs elimination through targeting and depleting CAFs provides a novel therapeutic treatment for desmoplastic solid tumors.

关键词： hydroxyethyl starch cancer-associated fibroblasts tumor mechanical microenvironment cancer stem cells combination therapy

Tumor-repopulating cell-derived microparticles elicit cascade amplification of chemotherapy-induced antitumor immunity to boost anti-PD-1 therapy

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Signal Transduction and Targeted Therapy 2023年第11期8卷 5539-5555页

作者： Nana Bie Tuying Yong Zhaohan Wei Qingle Liang Xiaoqiong Zhang Shiyu Li Xin Li Jianye Li Lu Gan xiangliang yang National Engineering Research Center for Nanomedicine College of Life Science and TechnologyHuazhong University of Science and Technology430074WuhanChina Key Laboratory of Molecular Biophysics of the Ministry of Education College of Life Science and TechnologyHuazhong University of Science and Technology430074WuhanChina Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medica Huazhong University of Science and Technology430074WuhanChina

Immune checkpoint blockade(ICB)therapy,particularly antibodies targeting the programmed death receptor 1(PD-1)and its ligand(PD-L1),has revolutionized cancer ***,its efficacy as a standalone therapy remains *** ICB therapy in combination with chemotherapy shows promising therapeutic responses,the challenge lies in amplifying chemotherapy-induced antitumor immunity *** relies on efficient drug delivery to tumor cells and robust antigen presentation by dendritic cells(DCs).Here,we developed tumor-repopulating cell(TRC)-derived microparticles with exceptional tumor targeting to deliver doxorubicin(DOX@3D-MPs)for improve anti-PD-1 ***@3D-MPs effectively elicit immunogenic tumor cell death to release sufficient tumor *** shock protein 70(HSP70)overexpressed in DOX@3D-MPs contributes to capturing tumor antigens,promoting their phagocytosis by DCs,and facilitating DCs maturation,leading to the activation of CD8+T ***@3D-MPs significantly enhance the curative response of anti-PD-1 treatment in large subcutaneous H22 hepatoma,orthotopic 4T1 breast tumor and Panc02 pancreatic tumor *** results demonstrate that DOX@3D-MPs hold promise as agents to improve the response rate to ICB therapy and generate long-lasting immune memory to prevent tumor relapse.

关键词： immunity chemotherapy boost

Mechanisms of peroxynitrite-induced [Ca^(2+)]_i increase in single neuronal cell

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Chinese Science Bulletin 1998年第20期43卷 1727-1732页

作者： YI Yong CAI Dong GAO Zhonghong yang xiangliang QU Anlian XU Huibi WANG Xiaomin HAN Songping Institute of Biophysics and Biochemistry Huazhong University of Science and TechnologyWuhan 430074China Neurosscience Research Centes Beijing Medical University Beijing 100083.China Department of Phammacol and Phyaiol Sci.St Louis Univ School of Mec St Louis MO 63104 USA.

The mechanism of peroxynitrite (ONOO -)induced [Ca 2+ ] i increase in single MN9D cell (Dopaminergic neuroblastoma cell line) was studied by using Fura2 microfluorometric technique. The results show that ONOO - caused a rapid increase of [Ca 2+ ] i when ONOO - was puffed to the cell. Removing Ca 2+ from the bath or using calcium channel antagonist (CdCl 2, Nifedipine) greatly inhibited the [Ca 2+ ] i increase induced by ONOO -, suggesting that the opening of LCa 2+ channel makes a great contribution to the [Ca 2+ ]\-i increase. The effect of sulfhydryl reductive agent (DTT) on ONOO -induced [Ca 2+ ]\-i increase suggests that ONOO -activating LCa 2+ channel is partly related to its oxidative speciality.

关键词： peroxynitrite(ONOO-) intracellular calcium concentration([Ca2+]i) MN9D cells.

Hydroxyethyl starch conjugates co-assembled nanoparticles promote photodynamic therapy and antitumor immunity by inhibiting antioxidant systems

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Asian Journal of Pharmaceutical Sciences 2024年第5期19卷 166-181页

作者： Xiang Chen Zhengtao Yong Yuxuan Xiong Hai yang Chen Xu Xing Wang Qingyuan Deng Jiayuan Li xiangliang yang Zifu Li Key Laboratory of Molecular Biophysics of Ministry of Education Huazhong University of Science and TechnologyWuhan 430074China Department of Nanomedicine and Biopharmaceuticals College of Life Science and TechnologyHuazhong University of Science and TechnologyWuhan 430074China National Engineering Research Center for Nanomedicine Huazhong University of Science and TechnologyWuhan 430074China Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical Huazhong University of Science and TechnologyWuhan 430074China Hubei Engineering Research Center for Biomaterials and Medical Protective Materials Huazhong University of Science and TechnologyWuhan 430074China Hubei Bioinformatics and Molecular Imaging Key Laboratory Huazhong University of Science and TechnologyWuhan 430074China

Photodynamic therapy(PDT)can produce high levels of reactive oxygen species(ROS)to kill tumor cells and induce antitumor ***,intracellular antioxidant systems,including glutathione(GSH)system and thioredoxin(Trx)system,limit the accumulation of ROS,resulting in compromised PDT and insufficient immune ***,we designed a nanomedicine PtHPs co-loading photosensitizer pyropheophorbide a(PPa)and cisplatin prodrug Pt-COOH(IV)(Pt(IV))based on hydroxyethyl starch(HES)to inhibit both GSH and Trx antioxidant systems and achieve potent PDT as well as antitumor immune ***,HES-PPa and HES-Pt were obtained by coupling HES with PPa and Pt(IV),and assembled into nanoparticle PtHPs by emulsification method to achieve the purpose of co-delivery of PPa and Pt(IV).PtHPs improved PPa photostability while retaining PPa photodynamic *** vitro experiments showed that PtHPs reduced GSH,inhibited Trx system and had better cell-killing effect and ROS generation *** tumormodels showed that PtHPs had good safety and tumor inhibition *** tumor models suggested that PtHPs promoted the release of damage-associated molecular patterns and the maturation of dendritic cells,induced T cell-mediated immune responses,and thus suppressed the growth of both primary and distal *** study reports a novel platinum-based nanomedicine and provides a newstrategy for boosting PDT therapy-mediated antitumor immunity by overcoming intrinsic antioxidant systems.

关键词： Hydroxyethyl starch smart nanomedicine Photodynamic therapy Antioxidant systems Immunogenic cell death