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nanomedicine-boosting icaritin-based immunotherapy of advanced hepatocellular carcinoma

Military Medical Research 2023年第3期10卷 403-414页

作者： Yi Lu Yue Gao Huan Yang Yong Hu Xin Li Department of Polymeric Materials School of Materials Science and EngineeringTongji UniversityShanghai 201804China Institute of Biotechnology RWTH Aachen University52074 AachenGermany DWI-Leibniz-Institute for Interactive Materials e.V. 52056 AachenGermany College of Chemistry Chemical Engineering and BiotechnologyDonghua UniversityShanghai 201620China School of Pharmacy Jiangsu UniversityZhenjiang 212013JiangsuChina Institute of Technical and Macromolecular Chemistry RWTH Aachen University52074 AachenGermany

Traditional treatments for advanced hepatocellular carcinoma(HCC),such as surgical resection,transplantation,radiofrequency ablation,and chemotherapy are unsatisfactory,and therefore the exploration of powerful therapeutic strategies is urgently needed.Immunotherapy has emerged as a promising strategy for advanced HCC treatment due to its minimal side effects and long-lasting therapeutic memory effects.Recent studies have demonstrated that icaritin could serve as an immunomodulator for effective immunotherapy of advanced HCC.Encouragingly,in 2022,icaritin soft capsules were approved by the National Medical Products Administration(NMPA)of China for the immunotherapy of advanced HCC.However,the therapeutic efficacy of icaritin in clinical practice is impaired by its poor bioavailability and unfavorable in vivo delivery efficiency.Recently,functionalized drug delivery systems including stimuli-responsive nanocarriers,cell membrane-coated nanocarriers,and living cell-nanocarrier systems have been designed to overcome the shortcomings of drugs,including the low bioavailability and limited delivery efficiency as well as side effects.Taken together,the development of icaritin-based nanomedicines is expected to further improve the immunotherapy of advanced HCC.Herein,we compared the different preparation methods for icaritin,interpreted the HCC immune microenvironment and the mechanisms underlying icaritin for treatment of advanced HCC,and discussed both the design of icaritin-based nanomedicines with high icaritin loading and the latest progress in icaritinbased nanomedicines for advanced HCC immunotherapy.Finally,the prospects to promote further clinical translation of icaritin-based nanomedicines for the immunotherapy of advanced HCC were proposed.

关键词： Icaritin nanomedicine Advanced hepatocellular carcinoma Immunotherapy Clinical translation

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nanomedicine for acute respiratory distress syndrome: The latest application, targeting strategy, and rational design

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Acta Pharmaceutica Sinica B 2021年第10期11卷 3060-3091页

作者： Qi Qiao Xiong Liu Ting Yang Kexin Cui Li Kong Conglian Yang Zhiping Zhang Tongji School of Pharmacy Huazhong University of Science and TechnologyWuhan 430030China National Engineering Research Center for nanomedicine Huazhong University of Science and TechnologyWuhan 430030China Hubei Engineering Research Center for Novel Drug Delivery System Huazhong University of Science and TechnologyWuhan 430030China

Acute respiratory distress syndrome(ARDS)is characterized by the severe inflammation and destruction of the lung aireblood barrier,leading to irreversible and substantial respiratory function damage.Patients with coronavirus disease 2019(COVID-19)have been encountered with a high risk of ARDS,underscoring the urgency for exploiting effective therapy.However,proper medications for ARDS are still lacking due to poor pharmacokinetics,non-specific side effects,inability to surmount pulmonary barrier,and inadequate management of heterogeneity.The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery.nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy,which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment.Through passive,active,or physicochemical targeting,nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment,thereby showing good therapeutic activity and reduced toxicity.This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy,highlights the strategies for targeted treatment of lung inflammation,presents the innovative drug delivery systems,and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.

关键词： Acute respiratory distress syndrome nanomedicine Anti-inflammatory therapy Drug delivery Targeting strategy Acute lung injury COVID-19 Pathophysiologic feature

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nanomedicine sheds new light on cancer immunotherapy

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Medical Review 2023年第2期3卷 188-192页

作者： Yingying Yu Liangzhu Feng Zhuang Liu Jiangsu Key Laboratory for Carbon-Based Functional Materials&Devices Institute of Functional Nano&Soft Materials(FUNSOM)Soochow UniversitySuzhouJiangsu ProvinceChina Jiangsu Key Laboratory for Carbon-Based Functional Materials&Devices Institute of Functional Nano&Soft Materials(FUNSOM)Soochow University199 Ren’ai RoadSuzhou 215123Jiangsu ProvinceChina

Cancer immunotherapy comprising of immune checkpoint blockade(ICB)therapy,immune cell therapies,cancer vaccines and many others represents a profound arsenal in the fight against different types of cancers.However,their overall clinical objective response rates,particularly against most solid tumors,are still not sufficient owing to a variety of reasons including the heterogenous expression of tumor antigens,limited tumor infiltration of effector immune cells,acquired tumor immunosuppression and some other factors.In recent years,various nanomedicine strategies have been proposed to assist cancer immunotherapy via distinct mechanisms,presenting new promises in many published studies.This perspective will thus provide a brief overview regarding the development of nanomedicine platforms for improving cancer immunotherapy.

关键词： cancer immunotherapy in situ cancer vaccine nanomedicine nanovaccine tumor microenvironment

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nanomedicine potentiates mild photothermal therapy for tumor ablation

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Asian Journal of Pharmaceutical Sciences 2021年第6期16卷 738-761页

作者： Zijun Jiang Tianyi Li Hao Cheng Feng Zhang Xiaoyu Yang Shihao Wang Jianping Zhou Yang Ding Key Laboratory of Drug Quality Control and Pharmacovigilance(Ministry of Education) State Key Laboratory of Natural MedicinesNMPA Key Laboratory for Research and Evaluation of Pharmaceutical Preparations and ExcipientsDepartment of PharmaceuticsChina Pharmaceutical UniversityNanjing 210009China

The booming photothermal therapy(PTT)has achieved great progress in non-invasive oncotherapy,and paves a novel way for clinical oncotherapy.Of note,mild temperature PTT(mPTT)of 42–45°C could avoid treatment bottleneck of the traditional PTT,including nonspecific injury to normal tissues,vasculature and host antitumor immunity.However,cancer cells can resist mPTT via heat shock response and autophagy,thus leading to insufficient mPTT monotherapy to ablate tumor.To overcome the deficient antitumor efficacy caused by thermo-resistance of cancer cells and mono mPTT,synergistic therapies towards cancer cells have been conducted with mPTT.This review summarizes the recent advances in nanomedicine-potentiated mPTT for cancer treatment,including strategies for enhanced single-mode mPTT and mPTT plus synergistic therapies.Moreover,challenges and prospects for clinical translation of nanomedicine-potentiated mPTT are discussed.

关键词： nanomedicine Mild temperature PTT Thermo-resistance Promote mPTT monotherapy Synergistic therapy

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Localized delivery of nanomedicine and antibodies for combating COVID-19

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Acta Pharmaceutica Sinica B 2023年第5期13卷 1828-1846页

作者： Bin Tu Yanrong Gao Xinran An Huiyuan Wang Yongzhuo Huang State Key Laboratory of Drug Research Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China University of Michigan College of Pharmacy Ann ArborMI 48109USA Zhongshan Institute for Drug Discovery SIMMCASZhongshan 528437China NMPA Key Laboratory for Quality Research and Evaluation of Pharmaceutical Excipients Shanghai 201203China Taizhou University School of Advanced StudyInstitute of Natural Medicine and Health ProductTaizhou 318000China

The severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)pandemic has been a major health burden in the world.So far,many strategies have been investigated to control the spread of COVID-19,including social distancing,disinfection protocols,vaccines,and antiviral treatments.Despite the significant achievement,due to the constantly emerging new variants,COVID-19 is still a great challenge to the global healthcare system.It is an urgent demand for the development of new therapeutics and technologies for containing the wild spread of SARS-CoV-2.Inhaled administration is useful for the treatment of lung and respiratory diseases,and enables the drugs to reach the site of action directly with benefits of decreased dose,improved safety,and enhanced patient compliance.Nanotechnology has been extensively applied in the prevention and treatment of COVID-19.In this review,the inhaled nanomedicines and antibodies,as well as intranasal nanodrugs,for the prevention and treatment of COVID-19 are summarized.

关键词： SARS-CoV-2 COVID-19 nanomedicine Orally-inhaled delivery Intranasal delivery Antibody

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Tumor microenvironment reprogramming by nanomedicine to enhance the effect of tumor immunotherapy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 1-37页

作者： Yu Huang Hui Fan Huihui Ti School of Chinese Materia Medica Guangdong Pharmaceutical UniversityGuangzhou 510006China Guangdong Province Precise Medicine Big Date of Traditional Chinese Medicine Engineering Technology Research Center Guangdong Pharmaceutical UniversityGuangzhou 510006China School of Pharmacy Guangdong Pharmaceutical UniversityGuangzhou 510006China

With the rapid development of the fields of tumor biology and immunology, tumor immunotherapy has been used in clinical practice and has demonstrated significant therapeutic potential, particularly for treating tumors that do not respond to standard treatment options. Despite its advances, immunotherapy still has limitations, such as poor clinical response rates and differences in individual patient responses, largely because tumor tissues have strong immunosuppressive microenvironments. Many tumors have a tumor microenvironment (TME) that is characterized by hypoxia, low pH, and substantial numbers of immunosuppressive cells, and these are the main factors limiting the efficacy of antitumor immunotherapy. The TME is crucial to the occurrence, growth, and metastasis of tumors. Therefore, numerous studies have been devoted to improving the effects of immunotherapy by remodeling the TME. Effective regulation of the TME and reversal of immunosuppressive conditions are effective strategies for improving tumor immunotherapy. The use of multidrug combinations to improve the TME is an efficient way to enhance antitumor immune efficacy. However, the inability to effectively target drugs decreases therapeutic effects and causes toxic side effects. Nanodrug delivery carriers have the advantageous ability to enhance drug bioavailability and improve drug targeting. Importantly, they can also regulate the TME and deliver large or small therapeutic molecules to decrease the inhibitory effect of the TME on immune cells. Therefore, nanomedicine has great potential for reprogramming immunosuppressive microenvironments and represents a new immunotherapeutic strategy. Therefore, this article reviews strategies for improving the TME and summarizes research on synergistic nanomedicine approaches that enhance the efficacy of tumor immunotherapy.

关键词： Tumor immunotherapy Tumor micr oenvir onment nanomedicine Tumor repr ogramming

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Non-apoptotic cell death-based cancer therapy:Molecular mechanism,pharmacological modulators,and nanomedicine

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Acta Pharmaceutica Sinica B 2022年第9期12卷 3567-3593页

作者： Xuan Wang Peng Hua Chengwei He Meiwan Chen State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical SciencesUniversity of MacaoMacaoSAR 999078China

As an emerging cancer therapeutic target,non-apoptotic cell death such as ferroptosis,necroptosis and pyroptosis,etc.,has revealed significant potential in cancer treatment for bypassing apoptosis to enhance the undermined therapeutic efficacy triggered by apoptosis resistance.A variety of anticancer drugs,synthesized compounds and natural products have been proven recently to induce non-apoptotic cell death and exhibit excellent anti-tumor effects.Moreover,the convergence of nanotechnology with functional materials and biomedicine science has provided tremendous opportunities to construct non-apoptotic cell death-based nanomedicine for innovative cancer therapy.Nanocarriers are not only employed in targeted delivery of non-apoptotic inducers,but also used as therapeutic components to induce non-apoptotic cell death to achieve efficient tumor treatment.This review first introduces the main characteristics,the mechanism and various pharmacological modulators of different non-apoptotic cell death forms,including ferroptosis,necroptosis,pyroptosis,autophagy,paraptosis,lysosomal-dependent cell death,and oncosis.Second,we comprehensively review the latest progresses of nanomedicine that induces various forms of non-apoptotic cell death and focus on the nanomedicine targeting different pathways and components.Furthermore,the combination therapies of non-apoptotic cell death with photothermal therapy,photodynamic therapy,immunotherapy and other modalities are summarized.Finally,the challenges and future perspectives in this regard are also discussed.

关键词： Non-apoptotic cell death Ferroptosis Necroptosis Pyroptosis Autophagy nanomedicine Combination therapies Anticancer

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Importance of Standardizing Analytical Characterization Methodology for Improved Reliability of the nanomedicine Literature

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Nano-Micro Letters 2022年第11期14卷 18-32页

作者： Shahriar Sharifi Nouf N.Mahmoud Elizabeth Voke Markita P.Landry Morteza Mahmoudi Department of Radiology and Precision Health Program Michigan State UniversityEast LansingMIUSA Faculty of Pharmacy Al-Zaytoonah University of JordanAmman 11733Jordan Department of Biomedical Sciences College of Health SciencesQU HealthQatar University2713 DohaQatar Department of Chemical and Biomolecular Engineering University of CaliforniaBerkeleyBerkeleyCAUSA Innovative Genomics Institute BerkeleyCAUSA California Institute for Quantitative Biosciences University of CaliforniaBerkeleyCAUSA Chan Zuckerberg Biohub San FranciscoCAUSA

Understanding the interaction between biological structures and nanoscale technologies,dubbed the nano-bio interface,is required for successful development of safe and efficient nanomedicine products.The lack of a universal reporting system and decentralized methodologies for nanomaterial characterization have resulted in a low degree of reliability and reproducibility in the nanomedicine literature.As such,there is a strong need to establish a characterization system to support the reproducibility of nanoscience data particularly for studies seeking clinical translation.Here,we discuss the existing key standards for addressing robust characterization of nanomaterials based on their intended use in medical devices or as pharmaceuticals.We also discuss the challenges surrounding implementation of such standard protocols and their implication for translation of nanotechnology into clinical practice.We,however,emphasize that practical implementation of standard protocols in experimental laboratories requires long-term planning through integration of stakeholders including institutions and funding agencies.

关键词： Characterization nanomedicine Standard protocols Reproducibility nanomedicine devices

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GSH-sensitive polymeric prodrug: Synthesis and loading with photosensitizers as nanoscale chemo-photodynamic anti-cancer nanomedicine

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Acta Pharmaceutica Sinica B 2022年第1期12卷 424-436页

作者： Lei Luo Yiming Qi Hong Zhong Shinan Jiang Hu Zhang Hao Cai Yahui Wu Zhongwei Gu Qiyong Gong Kui Luo Huaxi MR Research Center(HMRRC) Department of RadiologyFunctional and Molecular Imaging Key Laboratory of Sichuan ProvinceNational Clinical Research Center for GeriatricsWest China HospitalSichuan UniversityChengdu 610041China College of Pharmaceutical Sciences Southwest UniversityChongqing 400716China Research Unit of Psychoradiology Chinese Academy of Medical SciencesChengdu 610041China Amgen Bioprocessing Centre Keck Graduate InstituteClaremontCA 91711USA

Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.

关键词： Stimuli responsiveness Polymeric prodrug Photodynamic therapy Combinational therapy nanomedicine

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Light-responsive nanomedicine for cancer immunotherapy

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药学学报:英文版 2023年第6期13卷 2346-2368页

作者： Weirong Kang Yuwei Liu Weiping Wang State Key Laboratory of Pharmaceutical Biotechnology the University of Hong KongHong KongChina Department of Pharmacology and Pharmacy Li Ka Shing Faculty of Medicinethe University of Hong KongHong KongChina Laboratory of Molecular Engineering and nanomedicine Dr.Li Dak-Sum Research Centrethe University of Hong KongHong KongChina

Immunotherapy emerged as a paradigm shift in cancer treatments, which can effectively inhibit cancer progression by activating the immune system. Remarkable clinical outcomes have been achieved through recent advances in cancer immunotherapy, including checkpoint blockades, adoptive cellular therapy, cancer vaccine, and tumor microenvironment modulation. However, extending the application of immunotherapy in cancer patients has been limited by the low response rate and side effects such as autoimmune toxicities. With great progress being made in nanotechnology, nanomedicine has been exploited to overcome biological barriers for drug delivery. Given the spatiotemporal control,light-responsive nanomedicine is of great interest in designing precise modality for cancer immunotherapy. Herein, we summarized current research utilizing light-responsive nanoplatforms to enhance checkpoint blockade immunotherapy, facilitate targeted delivery of cancer vaccines, activate immune cell functions, and modulate tumor microenvironment. The clinical translation potential of those designs is highlighted and challenges for the next breakthrough in cancer immunotherapy are discussed.

关键词： Light-responsive nanoparticles Photodynamic therapy Photothermal therapy nanomedicine Cancer therapy Immunotherapy Photopharmacology Light-triggered drug release

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