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stimuli-responsive Gene Delivery Nanocarriers for Cancer Therapy

Nano-Micro Letters 2023年第3期15卷 299-331页

作者： Qingfei Zhang Gaizhen Kuang Wenzhao Li Jinglin Wang Haozhen Ren Yuanjin Zhao Department of Hepatobiliary Surgery The Affiliated Drum Tower Hospital of Nanjing University Medical SchoolHepatobiliary Institute of Nanjing UniversityNanjing 210008People’s Republic of China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhou 325001People’s Republic of China State Key Laboratory of Bioelectronics School of Biological Science and Medical EngineeringSoutheast UniversityNanjing 210096People’s Republic of China Chemistry and Biomedicine Innovation Center Nanjing UniversityNanjing 210023People’s Republic of China

Gene therapy provides a promising approach in treating cancers with high efficacy and selectivity and few adverse effects.Currently,the development of functional vectors with safety and effectiveness is the intense focus for improving the delivery of nucleic acid drugs for gene therapy.For this purpose,stimuli-responsive nanocarriers displayed strong potential in improving the overall efficiencies of gene therapy and reducing adverse effects via effective protection,prolonged blood circulation,specific tumor accumulation,and controlled release profile of nucleic acid drugs.Besides,synergistic therapy could be achieved when combined with other therapeutic regimens.This review summarizes recent advances in various stimuliresponsive nanocarriers for gene delivery.Particularly,the nanocarriers responding to endogenous stimuli including pH,reactive oxygen species,glutathione,and enzyme,etc.,and exogenous stimuli including light,thermo,ultrasound,magnetic field,etc.,are introduced.Finally,the future challenges and prospects of stimuli-responsive gene delivery nanocarriers toward potential clinical translation are well discussed.The major objective of this review is to present the biomedical potential of stimuli-responsive gene delivery nanocarriers for cancer therapy and provide guidance for developing novel nanoplatforms that are clinically applicable.

关键词： stimuli-responsive Nanocarrier Gene therapy Gene delivery Cancer

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stimuli-responsive nano vehicle enhances cancer immunotherapy by coordinating mitochondria-targeted immunogenic cell death and PD-L1 blockade

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Acta Pharmaceutica Sinica B 2022年第5期12卷 2533-2549页

作者： Qiuyi Li Cheng Chen Jinxia Kong Lian Li Junlin Li Yuan Huang Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin(DOX) massively amplified ICD via substantial generation of reactive oxygen species(ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways:(1) ROS elevated endoplasmic reticulum(ER) stress, leading to surface exposure of calreticulin;(2) ROS promoted release of various mitochondriaassociated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback,we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.

关键词： Immunogenic cell death Mitochondrial targeting PD-L1 blockade Endoplasmic reticulum stress Mitochondria-associated damage molecules stimuli-responsive Antitumor immune responses Antitumor efficacy

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Synthesis of stimuli-responsive Block Copolymers and Block Copolymer Nano-assemblies

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Chinese Journal of Chemistry 2022年第8期40卷 965-972页

作者： Yuan Liu Yu Sun Wangqing Zhang Key Laboratory of Functional Polymer Materials of the Ministry of Education Institute of Polymer ChemistryCollege of ChemistryNankai UniversityTianjin 300071China

Block copolymers have aroused much interest,and their application has been rapidly expanded.In recent years,our group has committed to exploring synthesis and self-assembly of block copolymers.We have designed and synthesized several new thermo-responsive polymers and photo-responsive polymers by living/controlled radical polymerization(LCRP)and investigated their stimuli-responsive properties.Aiming at convenient and efficient synthesis of block copolymer nano-assemblies,we have developed several methods based on polymerization-induced self-assembly(PISA).Herein,we give a short summary of our research in these years.The aim of this account is to stimulate innovative synthesis strategies of block copolymer nano-assemblies,and promote more scientific research cooperation to face the exciting opportunities and challenges encountered in block copolymers.

关键词： Block copolymers Living/controlled radical polymerization(LCRP) stimuli-responsive Self-assembly Nanostructures

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stimuli-responsive emulsions:Recent advances and potential applications

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Chinese Journal of Chemical Engineering 2022年第1期35卷 193-209页

作者： Xue-hui Ge Liangji Mo Anhe Yu Chenzi Tian Xiaoda Wang Chen Yang Ting Qiu Engineering Research Center of Reactive Distillation Fujian Province UniversityCollege of Chemical EngineeringFuzhou UniversityFuzhou 350108China Qingyuan Innovation Laboratory Quanzhou 362801China

responsive emulsions are the emulsions that can be reversibly switched on-demand between“stable”and“unstable”by environmental stimulus or trigger,which allows a simple and effective adjustment approach to achieve emulsification and demulsification.In recent years,stimuli-responsive emulsions acting as smart soft material are received considerable attention with the advantages of simple manipulation,good reversibility,low cost,easy treatment,and little effect on the system.In this paper,the recent research progress of emulsions that can respond to external stimuli,including pH,light,magnetic field,CO_(2)/N_(2) and dual responsive are reviewed.Also,the potential applications based on responsive emulsion are discussed,such as catalytic reactions,heavy oil recovery,polymer particles synthesis and optical sensor,aiming to summarize the latest achievements and put forward the possible development trends of responsive emulsions.

关键词： stimuli-responsive Emulsions Switchable surfactants Interface

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Recent developments in stimuli-responsive hydrogels for biomedical applications

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Biosurface and Biotribology 2022年第4期8卷 290-306页

作者： Shuyun Liu Xiaozhuang Li Lu Han School of Medicine and Pharmaceutics Laboratory for Marine Drugs and BioproductsPilot National Laboratory for Marine Science and TechnologyOcean University of ChinaQingdaoShandongChina

Hydrogels exhibit a performance similar to that of the extracellular matrix and are compatible with human tissues and organs.stimuli-responsive hydrogels that can respond smartly to a variety of stimuli have recently attracted extensive interest for biomedical applications.The response of these hydrogels to various single/multiple stimuli shows great potential for drug delivery,biosensors,wound dressing,cancer therapy,and tissue engineering.This review summarises the recent advances in the design of different stimuli-responsive hydrogels and their biomedical applications.We herein describe the mechanisms underlying the stimulus-response,and summarise the strategies for fabri-cating stimuli-responsive hydrogels that can respond to single or multiple stimuli from endogenous(i.e.pH,enzymes,glucose,and reactive oxygen species)or exogenous(i.***.magnetic and electric fields,temperature,and photo)sources.The current challenges faced by stimuli-responsive hydrogels are discussed and an outlook on future research directions is provided.

关键词： drug delivery hydrogels stimuli-responsive tissue engineering

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Smart anticorrosion coating based on stimuli-responsive micro/nanocontainer:a review

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Journal of Oceanology and Limnology 2020年第4期38卷 1045-1063页

作者： CAI Haoyuan WANG Peng ZHANG Dun CAS Key Laboratory of Marine Environmental Corrosion and Bio-fouling Institute of OceanologyChinese Academy of SciencesQingdao 266071China University of Chinese Academy of Sciences Beijing 100049China Open Studio for Marine Corrosion and Protection Pilot National Laboratory for Marine Science and Technology(Qingdao)Qingdao 266237China Center for Ocean Mega-Science Chinese Academy of SciencesQingdao 266071China

Smart coating for corrosion protection of metal materials(steel,magnesium,aluminum and their alloys)has drawn great attention because of their capacity to prevent crack propagation in the protective coating by releasing functional molecules(healing agents or corrosion inhibitors)on demand from delivery vehicle,that is,micro/nanocontainer made up of a shell and core material or a coating layer,in a controllable manner.Herein,we summarize the recent achievements during the last 10 years in the field of the micro/nanocontainer with different types of stimuli-responsive properties,i.e.,pH,electrochemical potential,redox,aggressive corrosive ions,heat,light,magnetic field,and mechanical impact,for smart anticorrosion coating.The state-of-the-art design and fabrication of micro/nanocontainer are emphasized with detailed examples.

关键词： corrosion protection micro/nanocontainer stimuli-responsive smart anticorrosion coating

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Engineering cancer vaccines using stimuli-responsive biomaterials

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Nano Research 2018年第10期11卷 5355-5371页

作者： Yu Zhao Yugang Guo Li Tang Institute of Bioengineering Ecole polytechnique federale de Lausanne (EPFL) Lausanne CH-1015 Switzerland Institute of Materials Science & Engineering Ecole polytechnique federale de Lausanne (EPFL) Lausanne CH- 1015 Switzerland

Cancer vaccines aimed at expanding the pool or increasing the activity of tumor-specific T cells against malignancies is an important immunotherapy modality that has been extensively pursued in the past decades. However, the clinical efficacy of cancer vaccines remains modest in comparison to other immunotherapies, such as checkpoint blockade and adoptive T cell therapy. This unsatisfactory performance is likely due to the suboptimal selection of tumor antigens for vaccine and inefficient delivery platform. Recently, vaccines designed to target cancer neoantigens have shown marked promise in both preclinical and early clinical studies. However, enormous challenges need to be overcome to develop a highly efficient and safe delivery strategy for targeting cancer vaccines to professional antigen-presenting cells and eliciting optimized immune response against cancers. To meet these challenges, biomaterials, particularly biomaterials that are designed to respond to certain environmental stimuli, termed as stimuli-responsive biomaterials, are being actively developed to precisely manipulate the trafficking and release of cancer vaccines in vivo for enhanced therapeutic efficacy and safety. In this mini review, we provide a brief overview of the recent advances in applying stimuli-responsive biomaterials in enhancing non-cellular cancer vaccines while focusing on the chemistry and material design with varied responsiveness. We also discuss the present challenges and opportunities in the field and provide a perspective for future directions.

关键词： cancer vaccine stimuli-responsive biomaterial nanoparticle immune response lymph node targeting cross-presentation

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Recent advances in stimuli-responsive theranostic systems with aggregation-induced emission characteristics

聚集体(英文)

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聚集体(英文) 2021年第1期2卷 48-65页

作者： Jing-Jing Hu Wenlian Jiang Lizhen Yuan Chong Duan Qiming Yuan Zi Long Xiaoding Lou Fan Xia Engineering Research Center of Nano-Geomaterials of Ministry of Education Faculty of Materials Science and ChemistryChina University of GeosciencesWuhanChina

Theranostic systems by integrating the tumor imaging and tumor therapeutic capabilities into one platform have attracted numerous attentions from worldwide researchers.Despite the great developments,their clinical application is still in the nascent stage,owing to the unsatisfied imaging quality and limited therapeutic efficacy.Fortunately,the emerging of aggregation-induced emission(AIE)molecules with unique fluorescence property offers an opportunity to solve the imaging problem.Besides,further utilizing the tumor microenvironments and external triggers to design the stimuli-responsive imaging-guided therapy could enhance the therapeutic efficacy and reduce the side effects.In this review,the advancements in stimuli-responsive theranostic systems with AIE characteristics are summarized.Theranostic systems are first classified according to their treatment modes,and then subdivided based on various stimuli,including pH,redox,enzyme,and light.In each section,the design strategies and application examples are introduced.At last,the current state of the art,limitations,as well as prospects are also discussed.

关键词： aggregation induced emission imaging stimuli-responsive theranostics tumor therapy

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Nanoformulation of metal complexes： Intelligent stimuli- responsive platforms for precision therapeutics

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Nano Research 2018年第10期11卷 5474-5498页

作者： Ming Hu Xiangzhao Ai Zhimin Wang Zhijun Zhang Haolun Cheong Wenmin Zhang Jun Lin Juan Li Huanghao Yang Bengang Xing Division of Chemistry & Biological Chemistry School of Physical & Mathematical Sciences Nanyang Technological University Singapore 637371 Singapore College of Chemistry Fuzhou University Fuzhou 350116 China State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 China

Precision medicine is a potential effective therapeutic for various human diseases. Currently, metal complex-based drugs are being successfully used in clinical applications owing to diverse properties such as multiple redox states, photo-induced ligand exchange, and preferential ligand and coordination numbers, which facilitate drug design and development. However, drawbacks such as toxicity, lack of specificity, and severe side effects have hampered their therapeutic outcome. Therefore, innovative strategies for improving the specificity and pharmacokinetics of conventional metal complex-based therapeutic agents are required. Recently, nanotechnology, which provides a unique toolbox for developing effective and safer medicine, has attracted considerable attention, mainly because of their ability to reduce side effects and enhance drug loading efficiency and pharmacokinetics. Considering the promising chemical and physical properties of diverse nanostructures, nanoformulation of metal complexes can be used to effectively address the problems associated with current metallodrug complexes, especially those based on stimuli-responsive therapeutic strategies, with excellent spatial, temporal, and dosage control. In this review, we have mainly focused on the specificity and environment-responsiveness of metallodrug nanoformulations as therapeutics, and summarized the recent strategies being used for developing metal complex-functionalized intelligent nanoplatforms, which respond to various types of stimuli, including endogenous signals （pH, redox condition,s, and enzyme activities） or external triggers （light irradiation and magnetic field manipulations）. In addition, we have also discussed the potential challenges associated with use of metallodrugs and their nanoformulations as effective precision therapy with improved specificity and minimal side effects.

关键词： precision therapeutics metal drug complex multifunctionalnanomaterials stimuli-responsive

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stimuli-responsive gel-micelles with flexible modulation of drug release for maximized antitumor efficacy

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Nano Research 2018年第8期11卷 4245-4264页

作者： Djamila Aouameur Hao Cheng Yaw Opoku-Damoah Bo Sun Qiuling Dong Yue Han Jianping Zhou Yang Ding State Key Laboratory of Natural Medicines Department of Pharmaceutics China Pharmaceutical University 24 TongjiaxiangNanjing 210009 China Department of Radiation Oncology Lineberger Comprehensive Cancer Center Carolina Center for Cancer NanotechnologyExcellence Carolina Institute of Nanomedicine University of North Carolina at Chapel Hill Chapel Hill NC27599 USA Djamila Aouameur and Hao Cheng contributed equally to this work.

Engineered stimuli-responsive drug delivery devices hold vast promise in biological applications for disease treatment due to their maximized therapeutic efficacy In this study a novel, stably cross-linked, and pH-sensitive biodegradable gel-micelle was constructed with amphiphilic conjugates of trimethylene dipiperidine- methacrylic anhydride-hyaluronic acid-stearylamine （TMDP-MA-HA-SA, TMHS） to improve tumor-targeting with flexible intracellular delivery of paditaxel （PTX）. The cross-linked methacrylate bonds significantly improved the biostability of TMHS gel-micelle （~ 200 nm） over the non-cross-linked under physiological conditions, while hyaluronic acid plays an important role in active tumor targetability. The gradual degradation of cross-linked hyaluronic acid shell was triggered by the concentrated hyaluronidase. Meanwhile, under acidic conditions （pH 〈 6.5）, the tertiary amines of pH-sensitive TMDP moieties were protonated and thereby solubilized the gel-micellar core-portions. The resultant pH-triggered inner-core spaces rapidly prompted PTX release in the presence of multiple cytosolic enzymes that mainly degraded the remaining hydrophobic stearylamine core. During the in vitro cytotoxicity assay, PTX-loaded TMHS gel-micelles （ct~） revealed anticancer efficacy against human hepatocellular carcinoma HepG2 cells with ICs0 of 1.42 gg/mL （PTX concentration）, significantly lower than other groups. In parallel, the in vivo anti-tumor efficacy of CLTMHSptx gel-micelles against BALB/c xenograft tumor animal model demonstrated the greater tumor growth inhibition capacity of 72.06%, compared to other treatment groups at a safe concentration. Consequently, the cross-linked and stimuli-responsive CLTMHSFrx gel-micelles hold a great potential for flexible modulation of intracellular delivery of hydrophobic anticancer drugs with maximized antitumor efficacy.

关键词： stimuli-responsive cross-linked gel-micelles biostability flexible drug release maximized antitumorefficacy

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