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A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation,apoptosis and M2 macrophages polarization

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2658-2671页

作者： Tingting Yang Yuzhu Hu Junming Miao Jing Chen Jiagang Liu Yongzhong Cheng Xiang Gao department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China department of Medical Oncology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China

Glioma is a primary aggressive brain tumor with high recurrence rate.The poor efficiency of chemotherapeutic drugs crossing the blood-brain barrier(BBB) is well-known as one of the main challenges for anti-glioma therapy.Moreover,massive infiltrated tumor-associated macrophages(TAMs) in glioma further thwart the drug efficacy.Herein,a therapeutic nanosystem(SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera(PROTAC) ARV-825 into the complex micelle(SPP) composed of substance P(SP) peptide-modified poly(ethylene glycol)-poly(D,L-lactic acid)(SP-PEG-PDLL A) and methoxy poly(ethylene glycol)-poly(D,L-lac tic acid)(mPEG-PDLL A,PP),which could penetrate BBB and target brain tumor.Subsequently,released drug engenders antitumor effect via attenuating cells proliferation,inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6,STAT3 and AKT.Taken together,our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma,which may provide a novel strategy for glioma therapy in future.

关键词： Glioma BRD4 ARV-825 Micelle M2 macrophage

Tau Modulates Neurovascular Coupling

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Neuroscience Bulletin 2021年第3期37卷 433-435页

作者： Fei Tang Qing Wang Jun Guo Peng Lei department of Neurology and State Key Laboratory of biotherapy Collaborative Innovation Center for BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

The microtubule-associated protein tau was identified in the neurofibrillary tangles(NFTs)of Alzheimer's disease(AD)more than 30 years ago,and its mutation can directly cause neurodegeneration.As implied by its purification from microtubules,tau was thought to stabilize microtubules and therefore to be of crucial importance in the brain.However,the physiological function of tau is still in debate since there is no detectable deficit in tau-knockout mice until they are 12 months old[1].Recently.

关键词： tau Alzheimer purification

Monkeypox:epidemiology,pathogenesis,treatment and prevention

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Signal Transduction and Targeted Therapy 2022年第12期7卷 4261-4282页

作者： Yong Huang Li Mu Wei Wang Department of Biotherapy State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduChina

Monkeypox is a zoonotic disease that was once endemic in west and central Africa caused by monkeypox virus.However,cases recently have been confirmed in many nonendemic countries outside of Africa.WHO declared the ongoing monkeypox outbreak to be a public health emergency of international concern on July 23,2022,in the context of the COVID-19 pandemic.The rapidly increasing number of confirmed cases could pose a threat to the international community.Here,we review the epidemiology of monkeypox,monkeypox virus reservoirs,novel transmission patterns,mutations and mechanisms of viral infection,clinical characteristics,laboratory diagnosis and treatment measures.In addition,strategies for the prevention,such as vaccination of smallpox vaccine,is also included.Current epidemiological data indicate that high frequency of human-to-human transmission could lead to further outbreaks,especially among men who have sex with men.The development of antiviral drugs and vaccines against monkeypox virus is urgently needed,despite some therapeutic effects of currently used drugs in the clinic.We provide useful information to improve the understanding of monkeypox virus and give guidance for the government and relative agency to prevent and control the further spread of monkeypox virus.

关键词： epidemiology prevention drugs treatment

Development of small-molecule tropomyosin receptor kinase(TRK) inhibitors for NTRK fusion cancers

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Acta Pharmaceutica Sinica B 2021年第2期11卷 355-372页

作者： Tingting Jiang Guan Wang Yao Liu Lu Feng Meng Wang Jie Liu Yi Chen Liang Ouyang State Key Laboratory of biotherapy and Cancer Center West China Hospitaland Collaborative Innovation Center of BiotherapySichuan UniversityChengdu 610041China State Key Laboratory of biotherapy and Cancer Center and department of Gastrointestinal Surgery West China HospitalSichuan Universityand Collaborative Innovation Center for BiotherapyChengdu 610041China

Tropomyosin receptor kinase A,B and C(TRKA,TRKB and TRKC),which are well-known members of the cell surface receptor tyrosine kinase(RTK)family,are encoded by the neurotrophic receptor tyrosine kinase 1,2 and 3(NTRK1,NTRK2 and NTRK3)genes,respectively.TRKs can regulate cell proliferation,differentiation and even apoptosis through the RAS/MAPKs,PI3 K/AKT and PLCγtyrosine kinase fusions;Small-molecule inhibitor;NTRK fusion cancer pathways.Gene fusions involving NTRK act as oncogenic drivers of a broad diversity of adult and pediatric tumors,and TRKs have become promising antitumor targets.Therefore,achieving a comprehensive understanding of TRKs and relevant TRK inhibitors should be urgently pursued for the further development of novel TRK inhibitors for potential clinical applications.This review focuses on summarizing the biological functions of TRKs and NTRK fusion proteins,the development of small-molecule TRK inhibitors with different chemotypes and their activity and selectivity,and the potential therapeutic applications of these inhibitors for future cancer drug discovery efforts.

关键词： Tropomyosin receptor kinase Neurotrophic receptor tyrosine kinase fusions Small-molecule inhibitor NTRK fusion cancer

Self-sufficient nanoparticles with dual-enzyme activity trigger radical storms and activate cascade-amplified antitumor immunologic responses

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Acta Pharmaceutica Sinica B 2024年第2期14卷 821-835页

作者： Liping Bai Jin Yang Siting Yu Zhongzheng Xiang Yuanyuan Zeng Meiling Shen Xiaorong Kou Qinjie Wu Changyang Gong Department of Biotherapy Cancer Center and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Radiotherapy(RT) can potentially induce systemic immune responses by initiating immunogenic cell death(ICD) of tumor cells.However,RT-induced antitumor immunologic responses are sporadic and insufficient against cancer metastases.Herein,we construct multifunctional self-sufficient nanoparticles(MARS) with dual-enzyme activity(GOx and peroxidase-like) to trigger radical storms and activate the cascade-amplified systemic immune responses to suppress both local tumors and metastatic relapse.In addition to limiting the Warburg effect to actualize starvation therapy,MARS catalyzes glucose to produce hydrogen peroxide(H_(2)O_(2)),which is then used in the Cu^(+)-mediated Fenton-like reaction and RT sensitization.RT and chemodynamic therapy produce reactive oxygen species in the form of radical storms,which have a robust ICD impact on mobilizing the immune system.Thus,when MARS is combined with RT,potent systemic antitumor immunity can be generated by activating antigen-presenting cells,promoting dendritic cells maturation,increasing the infiltration of cytotoxic T lymphocytes,and reprogramming the immuno suppre ssive tumor microenvironment.Furthermore,the synergistic therapy of RT and MARS effectively suppresses local tumor growth,increases mouse longevity,and results in a 90% reduction in lung metastasis and postoperative recurrence.Overall,we provide a viable approach to treating cancer by inducing radical storms and activating cascade-amplified systemic immunity.

关键词： Dual-enzyme activity Radiotherapy Chemodynamic therapy Fenton-likereaction Radical storms Immunogeniccell death Tumormicroenvironment Systemicimmunity

Co-delivery of doxorubicin and curcumin via cRGD-peptide modified PEG-PLA self-assembly nanomicelles for lung cancer therapy

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Chinese Chemical Letters 2022年第5期33卷 2507-2511页

作者： Yunchu Zhang Tingting Li Yuzhu Hu Jing Chen Yihong He Xiang Gao Yan Zhang department of Thoracic Oncology Cancer CenterState Key Laboratory of BiotherapyWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China

Lung cancer is the most common malignancy in the world, with a high mortality rate. Nevertheless,therapies to act effectively against lung cancer remain elusive. So far, chemotherapy is still the frontline treatment of lung cancer. Doxorubicin(DOX) is a broad-spectrum anti-tumor drug. However, DOX often has serious side effects and causes multi-drug resistance, which greatly limits its clinical application.In this work, biodegradable methoxy poly(ethylene glycol)-poly(lactic acid)(MPEG-PLA) and cyclo(ArgGly-Asp-D-Phe-Lys)(c RGD) polypeptide modified PEG-PLA(c RGD-PEG-PLA) copolymers were used for the co-delivery of curcumin(CUR) and DOX(CUR-DOX/c RGD-M). The particle size of the self-assembled drugloaded nanomicelle approximately was 27.4 nm and the zeta potential was -2.7mV. Interestingly, CUR can enhance the uptake of DOX by Lewis lung carcinoma(LL/2) cells. The experimental results in vivo and in vitro showed that CUR-DOX/c RGD-M combination therapy could promote apoptosis of lung cancer cells, and conspicuously inhibit the tumor growth. Our data indicate that CUR-DOX/c RGD-M will be biodegradable and sustainable, which may have potential clinical application value in the treatment of lung cancer.

关键词： Doxorubicin Curcumin Lung cancer Nanomicelle Co-delivery

Blossom of CRISPR technologies and applications in disease treatment

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Synthetic and Systems Biotechnology 2018年第4期3卷 217-228页

作者： Huayi Liu Lian Wang Yunzi Luo department of Gastroenterology State Key Laboratory of BiotherapyWest China HospitalSichuan University and Collaborative Innovation Center of BiotherapyChengdu610041PR China

Since 2013,the CRISPR-based bacterial antiviral defense systems have revolutionized the genome editing field.In addition to genome editing,CRISPR has been developed as a variety of tools for gene expression regulations,live cell chromatin imaging,base editing,epigenome editing,and nucleic acid detection.Moreover,in the context of further boosting the usability and feasibility of CRISPR systems,novel CRISPR systems and engineered CRISPR protein mutants have been explored and studied actively.With the flourish of CRISPR technologies,they have been applied in disease treatment recently,as in gene therapy,cell therapy,immunotherapy,and antimicrobial therapy.Here we present the developments of CRISPR technologies and describe the applications of these CRISPR-based technologies in disease treatment.

关键词： CRISPR technologies CRISPR-based tools CRISPR-based therapy

Author correction to“Development of small-molecule tropomyosin receptor kinase(TRK)inhibitors for NTRK fusion cancers”[Acta Pharmaceutica Sinica B 11(2021)355e372]

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Acta Pharmaceutica Sinica B 2022年第6期12卷 2963-2964页

The authors regret that there are some compound structure errors and misplacement of Ref.Nos.in the article due to the mistake of copying and pasting in the process of assembling figures and negligence in the proofreading.Although it does not affect the conclusion,it is obvious errors.The authors have now modified as below.The authors apologize for any inconvenience caused to the journal and readers.1.Ref.23 should be replaced with‘Cabozantinib in patients with RET fusion-positive advanced non-small cell lung cancer and those with other genotypes:ROS1 or NTRK fusions or increased MET or AXL activity.ClinicalTrails.

关键词： lung correction journal

Fc receptor-like 5(FCRL5)-directed CAR-T cells exhibit antitumor activity against multiple myeloma

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Signal Transduction and Targeted Therapy 2024年第2期9卷 724-737页

作者： Zhengyu Yu Hexian Li Qizhong Lu Zongliang Zhang Aiping Tong Ting Niu department of Hematology State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengdu 610041China

Multiple myeloma(MM)remains a challenging hematologic malignancy despite advancements in chimeric antigen receptor T-cell(CAR-T)therapy.Current targets of CAR-T cells used in MM immunotherapy have limitations,with a subset of patients experiencing antigen loss resulting in relapse.Therefore,novel targets for enhancing CAR-T cell therapy in MM remain needed.Fc receptor-like 5(FCRL5)is a protein marker with considerably upregulated expression in MM and has emerged as a promising target for CAR-T cell therapeutic interventions,offering an alternative treatment for MM.To further explore this option,we designed FCRL5-directed CAR-T cells and assessed their cytotoxicity in vitro using a co-culture system and in vivo using MM cell-derived xenograft models,specifically focusing on MM with gain of chromosome 1q21.Given the challenges in CAR-T therapies arising from limited T cell persistence,our approach incorporates interleukin-15(IL-15),which enhances the functionality of central memory T(TCM)cells,into the design of FCRL5-directed CAR-T cells,to improve cytotoxicity and reduce T-cell dysfunction,thereby promoting greater CAR-T cell survival and efficacy.Both in vitro and xenograft models displayed that FCRL5 CAR-T cells incorporating IL-15 exhibited potent antitumor efficacy,effectively inhibiting the proliferation of MM cells and leading to remarkable tumor suppression.Our results highlight the capacity of FCRL5-specific CAR-T cells with the integration of IL-15 to improve the therapeutic potency,suggesting a potential novel immunotherapeutic strategy for MM treatment.

关键词： directed thereby offering