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Oncology Research 2024年第4期32卷 691-702页

作者： JIJIE XIAO HONG XIAO YUJUN CAI JIANWEI LIAO JUE LIU LIN YAO SHAOLIN LI Department of Radiology The Fifth Affiliated Hospital of Sun Yat-Sen UniversityZhuhai510900China Department of Ultrasound The Third Affiliated Hospital of Sun Yat-Sen UniversityGuangzhou528405China PCFM Lab of Ministry of Education School of Materials Science and EngineeringGuangzhou510275China

Osteosarcoma is a malignant tumor originating from bone tissue that progresses rapidly and has a poor patient prognosis.Immunotherapy has shown great potential in the treatment of osteosarcoma.However,the immunosuppressive microenvironment severely limits the efficacy of osteosarcoma treatment.The dual pH-sensitive nanocarrier has emerged as an effective antitumor drug delivery system that can selectively release drugs into the acidic tumor microenvironment.Here,we prepared a dual pH-sensitive nanocarrier,loaded with the photosensitizer Chlorin e6(Ce6)and CD47 monoclonal antibodies(aCD47),to deliver synergistic photodynamic and immunotherapy of osteosarcoma.On laser irradiation,Ce6 can generate reactive oxygen species(ROS)to kill cancer cells directly and induces immunogenic tumor cell death(ICD),which further facilitates the dendritic cell maturation induced by blockade of CD47 by aCD47.Moreover,both calreticulin released during ICD and CD47 blockade can accelerate phagocytosis of tumor cells by macrophages,promote antigen presentation,and eventually induce T lymphocyte-mediated antitumor immunity.Overall,the dual pH-sensitive nanodrug loaded with Ce6 and aCD47 showed excellent immune-activating and anti-tumor effects in osteosarcoma,which may lay the theoretical foundation for a novel combination model of osteosarcoma treatment.

关键词： Immunotherapy Osteosarcoma nanodrug Photodynamic therapy CD47

Engineered protein nanodrug as an emerging therapeutic tool

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Nano Research 2022年第6期15卷 5161-5172页

作者： Yuanxin Li Jing Sun Jingjing Li Kai Liu Hongjie Zhang State Key Laboratory of Rare Earth Resource Utilization Changchun Institute of Applied ChemistryChinese Academy of SciencesChangchun 130022China University of Science and Technology of China Hefei 230026China Institute of Organic Chemistry University of UlmAlbert-Einstein-Allee 11Ulm 89081Germany Department of Chemistry Tsinghua UniversityBeijing 100084China

Functional proteins are the most versatile macromolecules.They can be obtained by extraction from natural sources or by genetic engineering technologies.The outstanding selectivity,specificity,binding activity,and biocompatibility endow engineered proteins with outstanding performance for disease therapy.Nevertheless,their stability is dramatically impaired in blood circulation,hindering clinical translations.Thus,many strategies have been developed to improve the stability,efficacy,bioavailability,and productivity of therapeutic proteins for clinical applications.In this review,we summarize the recent progress in the fabrication and application of therapeutic proteins.We first introduce various strategies for improving therapeutic efficacy via bioengineering and nanoassembly.Furthermore,we highlight their diverse applications as growth factors,nanovaccines,antibody-based drugs,bioimaging molecules,and cytokine receptor antagonists.Finally,a summary and perspective for the future development of therapeutic proteins are presented.

关键词： therapeutic proteins nanodrug genetic engineering structural modification therapeutic efficacy

Intratympanic injection of hydrogel nanodrug for the prevention and treatment of sensorineural hearing loss

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中华耳科学杂志:英文版 2023年第4期18卷 235-239页

作者： Tianying Zhai Pingping Ai Zhaohui Tang Chaoliang He Xuesi Chen Shiming Yang Nan Wu Senior Department of Otolaryngology-Head&Neck Surgery PLA General HospitalBeijingChina National Clinical Research Center for Otolaryngologic Disease BeijingChina State Key Lab of Hearing Science Ministry of EducationBeijingChina Beijing Key Lab of Hearing Impairment Prevention&Treatment BeijingChina Zhejiang Chinese Medical University HangzhouChina Changchun Institute of Applied Chemistry Chinese Academy of SciencesChangchunChina

Safe and efficient drug delivery to the inner ear has always been the focus of prevention and treatment of sensorineural deafness.The rapid development of nanodrug delivery systems based on hydrogel has provided a new opportunity.Among them,thermo-sensitive hydrogels promote the development of new dosage form for intratympanic injection.This smart biomaterial could transform to semisolid phase when the temperature increased.Thermo-sensitive hydrogel nanodrug delivery system is expected to achieve safe,efficient,and sustained inner ear drug administration.This article introduces the key techniques and the latest progress in this field.

关键词： Thermo-sensitive hydrogel nanodrug Sensorineural hearing loss Intratympanic injection

Local T regulatory cells depletion by an integrated nanodrug system for efficient chem-immunotherapy of tumor

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Science China Chemistry 2019年第9期62卷 1230-1244页

作者： Fan Gao Qian Cheng Miao-Deng Liu Lei Rong Chuan-Jun Liu Xian-Zheng Zhang Key Laboratory of Biomedical Polymers of Ministry of Education Department of ChemistryWuhan University

T regulatory(Treg) cell is a major immunosuppressive factor that restrains the antitumor effect of immunotherapy, because it gets more after the immune activation and is hardly to be eliminated. Here, an acid-sensitive integrated nanodrug system is designed to activate antitumor immune response as well as locally deplete Treg cells with low side effect. The nanosystem is synthetized by coordinating doxorubicin(DOX) and pentoxifylline(PTX) with Zn ions, then stabilized via liposome encapsulation(denoted as DTX@Lipo). DTX@Lipo can activate antitumor immune effect by chemotherapy of DOX. Besides, the release of PTX inhibits c-Rel expression, leading to the reduction of Treg cells in tumor site. Owing to the good tumor accumulation and local drug release ability, DTX@Lipo exhibits better biosafety and convenience than traditional antibody blockade method for Treg cells depletion. According to the results of in vivo experiments, the nanodrug system can significantly increase the ratio between effector T(Teff) cells and Treg cells locally, resulting in an immunoactivated tumor microenvironment. Importantly, it exhibits significant antitumor effect when combined with PD-1 blockade therapy, providing great potential for tumor therapy.

关键词： tumor T regulatory cell nanodrug system PD-1 immune response

Highly efficient tumor-targeted nanomedicine assembled from affibody-drug conjugate for colorectal cancer therapy

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Nano Research 2023年第4期16卷 5256-5264页

作者： Xiaoyuan Yang Xuelin Xia Wei Huang Xiaoxia Xia Deyue Yan School of Chemistry and Chemical Engineering Shanghai Jiao Tong UniversityShanghai 200240China State Key Laboratory of Microbial Metabolism School of Life Sciences and BiotechnologyShanghai Jiao Tong UniversityShanghai 200240China

Affibody is a new class of small non-immunoglobulin affinity proteins that possesses high affinity at the picomole level to several tumor overexpressed receptors.Owing to the simple framework,affibody is flexible for modification with payload,but the relatively low molecular weight of this construction simultaneously results in short half-life time which hinders its application in cancer therapy.In this work,we prepared a nanomedicine self-assembled from the conjugate of affibody(ZPDGFRβ:09591,PDGFRβ:platelet-derived growth factor receptorβ)with monomethyl auristatin E(MMAE)through cathepsin B cleavable dipeptide linker for targeted colorectal cancer therapy.The nanoscale characteristics of ZPDGFRβ:09591-MMAE affibody-drug conjugate nanomedicine(ZPDGFRβ:09591-M ADCN)resulted in enhanced pharmacokinetics,improved drug accumulation,and promoted biosecurity performance than those of free drugs.As a result,ZPDGFRβ:09591-M ADCN exhibited excellent antitumor efficacy with tumor inhibition rates(TIR)over 99.0%in PDGFRβ-positive tumor models with small solid tumors(~150 mm^(3))or large established tumors(~500 mm^(3)),indicating that ZPDGFRβ:09591-MMAE ADCN is promising for the clinic application in colorectal cancer therapy.

关键词： olecular self-assembly ZPDGFRβ:09591 affibody monomethyl auristatin E(MMAE) nanodrug targeted delivery

Applications and challenges of low temperature plasma in pharmaceutical field

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Journal of Pharmaceutical Analysis 2021年第1期11卷 28-36页

作者： Lingge Gao Xingmin Shi Xili Wu School of Public Health Medical Science CenterXi’an Jiaotong UniversityXi’an710061China Second Affiliated Hospital Xi’an Jiaotong UniversityXi’an710004China

Low temperature plasma(LTP)technology has shown an outstanding application value in the pharmaceutical filed in recent ten years.This paper reviews the research advances in LTP,including its effects on enhancing or inhibiting drug activity,its combined use with drugs to treat cancers,its effects on the improvement of drug delivery system,its use in preparation of new inactivated virus vaccines,its use with mass spectrometry for rapid detection of drug quality,and the anti-tumor and sterilization effects of plasma-activated liquids.The paper also analyzes the challenges of LTP in the pharmaceutical filed,hoping to promote related research.

关键词： Low temperature plasma Pharmacy nanodrug Drug delivery system Plasma-activated liquids

A smart dual-drug nanosystem based on coassembly of plant and food-derived natural products for synergistic HCC immunotherapy

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Acta Pharmaceutica Sinica B 2021年第1期11卷 246-257页

作者： Bingchen Zhang Jiali Jiang Pengyu Wu Junjie Zou Jingqing Le Juanfang Lin Chao Li Bangyue Luo Yongjie Zhang Rui Huang Jingwei Shao Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy College of ChemistryFuzhou UniversityFuzhou 350116China Institute of Oceanography Minjiang UniversityFuzhou 350108China

Nanotechnology has emerged as an ideal approach for achieving the efficient chemo agent delivery.However,the potential toxicity and unclear internal metabolism of most nano-carriers was still a major obstacle for the clinical application.Herein,a novel"core-shell"co-assembly carrier-free nanosystem was constructed based on natural sources of ursolic acid(UA)and polyphenol(EGCG)with the EpCAM-aptamer modification for hepatocellular carcinoma(HCC)synergistic treatment.As the nature products derived from food-plant,UA and EGCG had good anticancer activities and low toxicity.With the simple and"green"method,the nanodrugs had the advantages of good stability,p H-responsive and strong penetration of tumor tissues,which was expected to increase tumor cellular uptake,long circulation and effectively avoid the potential defects of traditional carriers.The nanocomplex exhibited the low cytotoxicity in the normal cells in vitro,good biosafety of organic tissues and efficient tumor accumulation in vivo.Importantly,UA combined with EGCG showed the immunotherapy by activating the innate immunity and acquired immunity resulting in significant synergistic therapeutic effect.The research could provide new ideas for the research and development of self-assembly delivery system in the future,and offer effective intervention strategies for clinical HCC treatment.

关键词： Natural product Ursolic acid EGCG Aptamer Co-assembly nanodrug HCC Synergistic treatment Immunotherapy

Engineering a Floxuridine-integrated RNA Prism as Precise Nanomedicine for Drug Delivery

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Chemical Research in Chinese Universities 2020年第2期36卷 274-280页

作者： PAN Gaifang MA Yuan ZHANG Jiao GUO Yuanyuan DING Fei GE Huan LI Qifeng ZHU Xinyuan ZHANG Chian School of Chemistry and Chemical Engineering State Key Laboratory of Metal Matrix CompositesShanghai Key Laboratory of Electrical Insulation and Thermal AgeingShanghai Jiao Tong UniversityShanghai 200240P.R.China Department of Paediatric Neurosurgery Xinhua HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghai 200092P.R.China

Herein,we report a geometrically well-defined prism assembled by two floxuridine(F)integrated RNA strands as a precise nanomedicine for chemodrug delivery.Owing to the similarity between chemotherapeutic F and uridine(U),all uridines in the component RNA strands are replaced by F during their in vitro transcription syntheses.By specifically designing their sequences,F-containing S-shape tiles with the single-stranded loops are constructed and then further assemble into the RNA prism through T-junction interactions and sticky-end cohesions.The present study demonstrates that the F-integrated RNA prism can serve as an efficient platform for chemodrug delivery and anticancer treatment.We believe that the study would help the future development of RNA-based nanomedicine in various applications.

关键词： Self-assembly Floxuridine RNA prism Precise nanodrug Drug delivery

In Vivo Animal Model Evaluation of a Powerful Oral Nanomedicine for Treating Breast Cancer in BALB/c Mice Using 4T1 Cell Lines without Chemotherapy

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Advances in Nanoparticles 2022年第3期11卷 73-109页

作者： Zahra Fakhroueian Alireza Massiha Pegah Esmaeilzadeh Mehdi Assmar Afshin Zahedi Pouriya Esmaeilzadeh Sara Rezaei Shahab Rabiei Lalehdasht School of Chemical Engineering (Nanomedicine) College of Engineering University of Tehran Tehran Iran Department of Biotechnology Lahijan Branch Islamic Azad University Lahijan Iran Institute of Pharmacy Martin Luther University Halle Wittenberg Halle (Saale) Germany Department of Microbiology Lahijan Branch Islamic Azad University Lahijan Iran Department of Veterinary Pathology Islamic Azad University Rasht Branch Rasht Iran Department of Chemical Engineering Sharif University of Technology Tehran Iran Research Department Production and Laboratory Company ZFP Rasht Iran Department of Biology Faculty of Science Rasht Branch Islamic Azad University Guilan Iran

Nanopharmaceuticals containing quantum dot nanoparticles (Q-Dot NPs) for treating serious cancers such as breast cancer have made fantastic proposals. In this study, ZnO quantum dot NPs are formulated via ZnO@PVP nanopolymer as co-assistants coordinating with efficacious suitable wetting agents, PEG-binding compound, and W/O emulsifier for producing eco-friendly water-based nanodrug. Several characterization techniques containing SEM, TEM, FTIR, photoluminescence, zeta potential, and UV-Vis absorption were employed for ZnO Q-Dot NPs in nanodrug. This work aims to investigate the anti-tumor effects of such nanomedicine on the 4T1 breast cancer cell line in BALB/c mice, being elaborated through intraperitoneal, injection (IVP) and oral therapy. The impressive findings showed that ZnO nanodrug caused changes in blood factors, having the most effectiveness at 40 μg/ml concentration after two weeks of oral treatments. The significant increase in white blood cells (WBC) neutrophils and meaningful decreases in lymphocytes and especially cholesterol were powerful simultaneous impacts, successfully treating malignant breast cancer masses. In this significant animal model research for breast cancer, the sick mice recovered entirely and even had a safe space to mate. Histopathological results showed no evidence of breast tumor formation or metastasis in the group treated with nanodrug and their children. This nanomedicine has a therapeutic effect, and is ready to be applied for treating volunteer breast cancer patients. However, its prevention (inhibitory) effect can also be analyzed and added to current data in future studies.

关键词： Nanomedicine nanodrug ZnO Q-Dot NPs In Vivo Breast Cancer BALB/c Mice 4T1 Cell Lines Metastasis Oral Treatment

A New Type of Nanogel Carrier based on Mixed Pluronic Loaded with Low-Dose Antitumor Drugs

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Journal of Wuhan University of Technology(Materials Science) 2019年第4期34卷 960-967页

作者：尹美珍 SU Zhenhong CUI Bingcun HAN Yingchao DAI Honglian 喻昕 School of Medicine Hubei Polytechnic UniversityHuangshi 435003China School of Medicine Inner Mongolia University for NationalitiesInner Mongolia Tongliao 028000China State Key Laboratory of Advanced Technology for Materials Synthesis and Processing and Biomedical Materials and Engineering CenterWuhan University of TechnologyWuhan 430070China

To design a new type of antitumor nanodrug carrier with good biocompatibility, a drug delivery system with a 2.19% drug-loading rate, measured by high-performance liquid chromatography(HPLC), was prepared by membrane hydration using a mixed polymer: Pluronic■ F-127, which binds folic acid(FA), Pluronic■ F-68 and triptolide(TPL)(FA-F-127/F-68-TPL). As a control, another drug delivery system based on a single polymer(FA-F-127-TPL) with a 1.90% drug-loading rate was prepared by substituting F-68 with F-127. The average particle sizes of FA-F-127/F-68-TPL and FA-F-127-TPL measured by a particle size analyzer were 30.7 nm and 31.6 nm, respectively. Their morphology was observed by atomic force microscopy(AFM). The results showed that FA-F-127-TPL self-assembled into nanomicelles, whereas FA-F-127/F-68-TPL self-assembled into nanogels. An MTT assay showed that a very low concentration of FA-F-127/F-68-TPL or FA-F-127-TPL could significantly inhibit the proliferation of multidrug-resistant(MDR) breast cancer cells(MCF-7/ADR cells) and induce cell death. The effects were significantly different from those of free TPL(P < 0.01). Using the fluorescent probe Nile red(Nr) as the drug model, FA-F-127/F-68-Nr nanogels and FAF-127-Nr nanomicelles were prepared and then incubated with human hepatocarcinoma(HepG2) and MCF-7/ADR cells, and the fluorescence intensity in the cells was measured by a multifunctional microplate reader. The results indicated that both FA-F-127/F-68-Nr and FA-F-127-Nr had sustained release in the cells, but HepG2 and MCF-7/ADR cells exhibited significantly higher endocytosis of FA-F-127/F-68-Nr than that of FA-F-127-Nr(P < 0.01). A nude mice transplanted tumor model was prepared to monitor FA-F-127/F-68-Nr in the tumor tissue and organs by whole-body fluorescent imaging. The results showed that FA-F-127/F-68-Nr targeted tumor tissues. The prepared nanogels had small particle size, were easy to swallow, exhibited slow release property,targeted tumor cells, and could improve the antitumor effects of TPL;he

关键词： pluronic nanogels nanodrug carriers triptolide