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Harnessing bacteria for tumor therapy:Current advances and challenges

Chinese Chemical Letters 2024年第2期35卷 97-106页

作者： Lina Guo Jinsong Ding wenhu zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Changsha Medical University Academician WorkstationChangsha 410219China Key Laboratory of Biological Nanotechnology of National Health Commission Changsha 410008China

After a century of standstill,bacteria-based tumor therapy has resurged recently benefiting from the revolution of tumor immunotherapy,which provides unique solutions to tackle the obstacles of traditional tumor *** and facultative anaerobes with active tropism can selectively colonize at tumor sites and suppress tumor growth via different mechanisms,serving as attractive tools for tumor treatment either as a monotherapy or combining with other therapies for synergistic anti-tumor *** this critical review,we introduce the recent advances of bacteria-based tumor therapy from the following ***,the general properties of bacteria are reviewed emphasizing on their structural components related to tumor immunotherapy,and the main bacteria that have been used in tumor therapy are ***,the benefits of bacteria for tumor therapy are illustrated,such as tumor targetability,deep penetration,and facile genetic engineering for attenuation,enhanced efficacy,as well as ***,anti-tumor mechanisms of bacteria are summarized,which refer to intrinsic tumoricidal activities,immune activation,bacteria metabolism,and their capability to regulate gut microbiota ***,bacteria could act as carriers to deliver various types of therapeutics to achieve combination therapy with improved *** addition,several challenges for anti-tumor applications of bacteria are discussed regarding the delivery,efficacy and safety issues,and potential solutions are also ***,the possible improvements and perspectives are discussed in the end,which provide a guideline for the design of advanced bacteria-based tumor therapeutics in the future.

关键词： Bacteria Tumor targeting Immunotherapy Combination therapy Genetic engineering Surface decoration

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Recent progress of vaccines administration via microneedles for cancer immunotherapy

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Chinese Chemical Letters 2024年第3期35卷 96-103页

作者： Yuanzheng Chen Jiaojiao Zhu Jinsong Ding wenhu zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Key Laboratory of Biological Nanotechnology of National Health Commission Changsha 410008China

Therapeutic cancer vaccines have undergone a resurgence in the past *** of the high level of immune cell accumulation and abundant capillary lymphatic system in the dermis,percutaneous vaccination is considered to be an ideal treatment *** convenient administration,the recent development of microneedles(MNs)provides a safe,painless,and low-cost transdermal delivery strategy,which could bypass the first-pass metabolism of vaccines for enhanced stability and ***,the therapeutic effect of MNs-based cancer vaccines is not optimal,which is limited by the complex set of host,tumor,and environmental factors,as well as the limited vaccine loading ***,further improvements are still required to push their clinical *** this critical review,we deliberate on how to improve the therapeutic effect of MNs-based vaccines for cancer immunotherapy,summarize the recent advances in MNs-based cancer vaccination,and provide an overview of various design strategies and mechanisms for active or passive targeting delivery,aiming to develop safer,more effective,and more stable MNs-based cancer ***,we briefly describe the potential of vaccine platforms in combination with other therapies,suggest the need to design vaccines according to specific circumstances,and discuss the biosafety of repeated administration for enhancing clinical efficacy.

关键词： Transdermal delivery Microneedles Cancer vaccine Immunotherapy Nanoparticle Lymph node

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Repurposing disulfiram with CuET nanocrystals:Enhancing anti-pyroptotic effect through NLRP3 inflammasome inhibition for treating inflammatory bowel diseases

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Acta Pharmaceutica Sinica B 2024年第6期14卷 2698-2715页

作者： Xueming Xu Yuanfeng Han Jiali Deng Shengfeng Wang Shijie Zhuo Kai Zhao wenhu zhou Hematology and Department of Critical Care Medicine The Third Xiangya HospitalCentral South UniversityChangsha 410013China Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Hunan Chidren's Hospital Changsha 410007China Department of Pharmacy The Third Xiangya HospitalCentral South UniversityChangsha 410013China Key Laboratory of Biological Nanotechnology of National Health Commission Changsha 410008China

Drug repurposing offers a valuable strategy for identifying new therapeutic applications for existing ***,disulfiram(DSF),a drug primarily used for alcohol addiction treatment,has emerged as a potential treatment for inflammatory diseases by inhibiting pyroptosis,a form of programmed cell *** therapeutic activity of DSF can be further enhanced by the presence of Cu^(2+),although the underlying mechanism of this enhancement remains *** this study,we investigated the mechanistic basis of Cu^(2+)-induced enhancement and discovered that it is attributed to the formation of a novel copper ethylthiocarbamate(CuET)*** exhibited significantly stronger anti-pyroptotic activity compared to DSF and employed a distinct mechanism of ***,despite its potent activity,CuET suffered from poor solubility and limited permeability,as revealed by our druggability *** overcome these intrinsic limitations,we developed a scalable method to prepare CuET nanocrystals(CuET NCs)using a metal coordination-driven self-assembly *** studies demonstrated that CuET NCs exhibited a 6-fold improvement in ***,CuET NCs exhibited high biodistribution in the intestine,suggesting their potential application for the treatment of inflammatory bowel diseases(IBDs).To evaluate their therapeutic efficacy in vivo,we employed a murine model of DSS-induced colitis and observed that CuET NCs effectively attenuated inflammation and ameliorated colitis *** findings highlight the discovery of CuET as a potent anti-pyroptotic agent,and the development of CuET NCs represents a novel approach to enhance the druggability of CuET.

关键词： Drug repurposing Pyroptosis Nanoparticles Bioavailability Disulfiram DSS-induced colitis NLRP3 inflammasome CuET

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Mn-based cGAS-STING activation for tumor therapy

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Chinese Journal of Cancer Research 2023年第1期35卷 19-43页

作者： Aiping Huang wenhu zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Changsha Medical University Academician WorkstationChangsha 410219China

Immunotherapy has efficiently revolutionized the treatment of human neoplastic ***,the overall responsive rate of current immunotherapy is still unsatisfactory,benefiting only a small proportion of ***,significant attention has been paid to the modulation of tumor microenvironment(TME)for the enhancement of ***,recent studies have shown that cyclic GMP-AMP synthasestimulator of interferon gene(cGAS-STING)was initially found as an innate immune sensor to recognize cytoplasmic DNA(such as bacterial,viral,micronuclei,and mitochondrial).It is a promising signaling pathway to activate antitumor immune responses via type I interferon ***,Mn^(2+)was found to be a critical molecule to sensitize the activation of the cGAS-STING pathway for better *** activation led to the development of Mn^(2+)-based strategies for tumor immunotherapy via the activation of the cGAS-STING *** this critical review,we aimed to summarize the recent progress of this field,focusing on the following three ***,we briefly introduced the signaling pathway of cGAS-STING activation,and its regulation effect on the antitumor immunity cycle has been *** with this,several agonists of the cGAS-STING pathway were introduced with their potential as immunotherapeutic ***,the basic biological functions of Mn^(2+)have been illustrated,focusing on its critical roles in the cGAS-STING pathway ***,we systematically reviewed the Mn^(2+)-based strategies for tumor immunotherapy,which can be classified by the methods based on Mn^(2+)alone or Mn^(2+)combined with other therapeutic *** finally speculated the future perspectives of the field and provided rational suggestions to develop better Mn^(2+)-based therapeutics.

关键词： Tumor immunity metal ions combinatorial therapy targeting nanoparticles

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Converting bacteria into autologous tumor vaccine via surface biomineralization of calcium carbonate for enhanced immunotherapy

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Acta Pharmaceutica Sinica B 2023年第12期13卷 5074-5090页

作者： Lina Guo Jinsong Ding wenhu zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Key Laboratory of Biological Nanotechnology of National Health Commission Xiangya HospitalChangsha 410008China

Autologous cancer vaccine that stimulates tumor-specific immune responses for personalized immunotherapy holds great potential for tumor ***,its efficacy is still suboptimal due to the immunosuppressive tumor microenvironment(ITM).Here,we report a new type of bacteria-based autologous cancer vaccine by employing calcium carbonate(CaCO_(3))biomineralized Salmonella(Sal)as an in-situ cancer vaccine producer and systematical ITM ***_(3) can be facilely coated on the Sal surface with calcium ionophore A23187 co-loading,and such biomineralization did not affect the bioactivities of the *** intratumoral accumulation,the CaCO_(3) shell was decomposed at an acidic microenvironment to atenuate tumor acidity,accompanied by the release of Sal and Ca^(2+)/***,Sal served as a cancer vaccine producer by inducing cancer cells'immunogenic cell death(ICD)and promoting the gap junction formation between tumor cells and dendritic cells(DCs)to promote antigen ***^(2+),on the other hand,was intermalized into various types of immune cells with the aid of A23187 and synergized with Sal to systematically regulate the immune system,including DCs maturation,macrophages polarization,and T cells *** a result,such bio-vaccine achieved remarkable effcacy against both primary and metastatic tumors by eliciting potent anti-tumor immunity with full *** work demonstrated the potential of bioengineered bacteria as bio-active vaccines for enhanced tumor immunotherapy.

关键词： Bacteria-mediated cancer therapy Tumor microenvironment Calcium carbonate Mineralization Metalloimmunology Autologous tumor vaccine Immunotherapy Tumor metastasis

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Macrophage-targeted nanomedicine for chronic diseases immunotherapy

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Chinese Chemical Letters 2022年第2期33卷 597-612页

作者： Yuejia Song Yaqian Huang Fang zhou Jinsong Ding wenhu zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Academician Workstation Changsha Medical UniversityChangsha 410219China Department of Pharmacy Southern University of Science and Technology HospitalShenzhen 518055China

Macrophage is the key innate immune effector in first-line defense against the pathogens, and can be polarized into different phenotypes to regulate a variety of immunological functions. However, the plasticity of macrophage is extraordinarily recruited, activated, and polarized under pathological conditions,playing paramount roles in occurrence, development, and prognosis of various chronic diseases, such as rheumatoid arthritis(RA), atherosclerosis(AS), and cancer. To this end, macrophage has become an important therapeutic target for etiological treatment of these diseases. Meanwhile, with the development of nanotechnology, various nano-drug delivery systems have been explored to target macrophages for disease modulation, displaying unique advantages to address both pharmaceutic and biopharmaceutic limitations of various drugs. This review aims to summarize the recent progress of macrophage-targeted nanomedicine for chronic diseases immunotherapy. First, the origin, polarization and biological functions of macrophages have been introduced, in which macrophages can differentiate into different phenotypes in response to physiological stimuli to play various immunological roles. Then, the macrophage disorder has been reviewed in related with various chronic diseases, and several representative diseases, including AS, RA, obesity, and cancer, have been discussed in detail to elucidate the pathological contributions of macrophages for disease progress. Next, strategies to regulate macrophages for diseases immunotherapy, such as macrophages depletion, macrophage reprograming, inhibition of macrophage recruitment,are summarized, and particular attention has been paid on bio-functional nanomaterials to engineer macrophages via different mechanisms. Further, methods for macrophage-targeting delivery nanosystems are discussed based on both passive and active targeting approaches. Finally, the perspective is speculated for potential clinical translation, and there still has

关键词： Nanoparticles Delivery Macrophages Polarization Immunotherapy

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Macrophages-regulating nanomedicines for sepsis therapy

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Chinese Chemical Letters 2023年第3期34卷 100-112页

作者： Jiali Deng Rui Wang Shu Huang Jinsong Ding wenhu zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Department of Orthopedics Hunan Provincial People’s HospitalThe First-Affiliated Hospital of Hunan Normal UniversityChangsha 410005China

Sepsis is the leading cause of death in intensive care unit(ICU), which is caused by deregulated immune responses to pathogens infection. Clinically, sepsis treatment is limited to antibiotics and supportive care, while there still lacks of specific molecular therapy. As a type of immune dysfunction disease,macrophages have been recognized as the key immune cells precipitating in the whole process of sepsis,which is activated into M1-like to trigger various inflammatory responses at early stage whereas polarized into M2-like to cause immunosuppression in later stage. Therefore, great attention has been paid on the design of nanomedicines to regulate the functions of macrophages for etiological treatment of sepsis, by virtue of the unique advantages of nano-drug delivery systems, such as enhanced drug bioavailability, targetability, reduced side-effects. This critical review aims to summarize the recent progress of macrophages-regulating nanoparticles for sepsis therapy. First, the essential roles of macrophages in the development and progression of sepsis have been introduced, including the positive roles of macrophages to combat infections and dysfunction of macrophages to cause body damages. We then focus our main attention to discuss the nanomedicines with different therapeutic mechanisms corresponding to each stage of sepsis, such as infection blockage, inflammation inhibition, immune functions recovery, as well as multifunctional nanomedicines. Finally, a few limitations of current nanomedicines are highlighted,and future perspective are speculated for potential clinical translation, which might pave the way for the development of macrophages-centered nanomedicines for more effective sepsis therapy.

关键词： Nanomedicine Sepsis Macrophages Infections Inflammation Immunity

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Copper carbonate nanoparticles as an effective biomineralized carrier to load macromolecular drugs for multimodal therapy

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中国化学快报:英文版 2023年第9期34卷 204-209页

作者： Liping Dong Jinsong Ding Lemei Zhu Yujun Liu Xiang Gao wenhu zhou Changsha Medical University Academician WorkstationChangsha 410219China Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China State Key Laboratory of Toxicology and Medical Countermeasures Institute of Pharmacology and ToxicologyBeijing 100850China Key Laboratory of Biological Nanotechnology of National Health Commission Changsha 410000China

Macromolecular drugs have attracted great interest as biotherapy to cure previously untreatable *** clinical translation,biomacromolecules encounter several common druggability difficulties,such as in vivo instability and poor penetration to cross physiologic barriers,thus requiring sophisticated systems for drug *** by the natural biomineralization via interaction between inorganic ions and biomacromolecules,herein we rationally screened biocompatible transition metals to biomineralize with carbonate for macromolecules *** the metal ions,Cu^(2+)was found to be the best candidate,and its superiority over the widely studied Ca^(2+)minerals was also *** on this finding,copper carbonate nanoparticles were prepared via a simple mixing process to co-load glucose oxidase(GOx)and a HIF-αDNAzyme(DZ),achieving ultra-high loading capacity of 61%.Upon encapsulation into nanoparticles,enzymatic activity of both drugs was passivated to avoid potential side-effects during circulation,while the drugs could be rapidly released within 1 h in response to acidic p H to fully recover their *** nanoparticles could accumulate into tumor via intravenous injection,facilitate the cell membrane penetration,and release the payloads of GOx,DZ and Cu^(2+)inside cells to exert a series of anti-tumor *** caused tumor starvation by catalytic glucose consumption,and the concomitantly generated H_(2)O_(2)byproduct boosted the Cu^(2+)-mediated chemodynamic therapy(CDT).Meanwhile,the DZ silenced HIF-αexpression to sensitize both starvation therapy and *** a result,a synergistic tumor growth inhibition was *** work provides a simple method to prepare biomineralized nanoparticles,and offers a general approach for macromolecular drugs delivery via Cu^(2+)-based biomineralization.

关键词： Metal ions Biomineralization Drug delivery Nanomedicine Tumor therapy

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“三全育人”视域下药剂学课程思政实施路径探索

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药学教育 2024年第3期40卷 36-39,49页

作者：林玲马云潇唐海飞周文虎中南大学湘雅药学院长沙410013 湘潭医卫职业技术学院湘潭411104

在专业课教学过程中融入思政元素,推动从“思政课程”向“课程思政”的转变,是实现“三全育人”的重要举措。基于药学专业核心课程药剂学课程思政建设,教学团队从教师队伍的建设、课堂教学思政元素的挖掘、实验课的思政建设、创新创业... 详细信息

在专业课教学过程中融入思政元素,推动从“思政课程”向“课程思政”的转变,是实现“三全育人”的重要举措。基于药学专业核心课程药剂学课程思政建设,教学团队从教师队伍的建设、课堂教学思政元素的挖掘、实验课的思政建设、创新创业实践的利用、实习过程中的德育教育、思政课程考查体系的完善等方面,探索课程思政的实施路径。

关键词：药剂学课程思政药学三全育人

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Fenton metal nanomedicines for imaging-guided combinatorial chemodynamic therapy against cancer

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Asian Journal of Pharmaceutical Sciences 2022年第2期17卷 177-192页

作者： Peng Liu Ying Peng Jinsong Ding wenhu zhou Xiangya School of Pharmaceutical Sciences Central South UniversityChangsha 410013China Henan Key Laboratory of Biomolecular Recognition and Sensing Shangqiu Normal UniversityShangqiu 476000China

Chemodynamic therapy(CDT)is considered as a promising modality for selective cancer therapy,which is realized via Fenton reaction-mediated decomposition of endogenous H_(2)O_(2) to produce toxic hydroxyl radical(•OH)for tumor *** extensive efforts have been made to develop CDT-based therapeutics,their in vivo efficacy is usually unsatisfactory due to poor catalytic activity limited by tumor microenvironment,such as anti-oxidative systems,insufficient H_(2)O_(2),and mild *** mitigate these issues,we have witnessed a surge in the development of CDT-based combinatorial nanomedicines with complementary or synergistic mechanisms for enhanced tumor *** virtue of their bio-imaging capabilities,Fenton metal nanomedicines(FMNs)are equipped with intrinsic properties of imaging-guided tumor *** this critical review,we summarize recent progress of this field,focusing on FMNs for imaging-guided combinatorial tumor ***,various Fenton metals with inherent catalytic performances and imaging properties,including Fe,Cu and Mn,were introduced to illustrate their possible applications for tumor ***,CDT-based combinatorial systems were reviewed by incorporating many other treatment means,including chemotherapy,photodynamic therapy(PDT),sonodynamic therapy(SDT),photothermal therapy(PTT),starvation therapy and ***,various imaging approaches based on Fenton metals were presented in ***,challenges are discussed,and future prospects are speculated in the field to pave way for future developments.

关键词： combinatorial medicines equipped

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