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Logic-gated tumor-microenvironment nanoamplifier enables targeted delivery of CRISPR/Cas9 for multimodal cancer therapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 795-807页

作者： Yongchun Pan Xiaowei Luan Fei Zeng Xuyuan Wang Shurong Qin Qianglan Lu Guanzhong He Yanfeng Gao Xiaolian Sun Xin Han Bangshun He Yujun Song Department of laboratory Medicine Nanjing First HospitalNanjing Medical UniversityNanjing 210006China College of Engineering and Applied Sciences State Key Laboratory of Analytical Chemistry for Life ScienceNanjing UniversityNanjing 210023China State key laboratory of Natural Medicines Key Laboratory of Drug Quality Control and PharmacovigilanceDepartment of Pharmaceutical AnalysisChina Pharmaceutical UniversityNanjing 211198China School of Medicine&Holistic Integrative Medicine Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources IndustrializationNanjing University of Chinese MedicineNanjing 210023China

Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies.However,the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression.Here,we propose a self-amplifying logic-gated gene editing strategy for gene/H_(2)O_(2)-mediated/starvation multimodal cancer therapy.In this approach,a hypoxia-degradable covalent-organic framework(COF) is synthesized to coat a-ZIF-8 in which glucose oxidase(GOx) and CRISPR system are packaged.To intensify intracellular redox dyshomeostasis,DNAzymes which can cleave catalase mRNA are loaded as well.When the nano system gets into the tumor,the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx,which amplifies intracellular H^(+)and hypoxia,accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells.These tandem reactions deplete glucose and oxygen,leading to logic-gated-triggered gene editing as well as synergistic gene/H_(2)O_(2)-mediated/starvation therapy.Overall,this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.

关键词： CRISPRdelivery Enzymeencapsulation Logic gate Hybridmaterial Hypoxia Gene editing Precise nanomedicine Multimodal therapy

Oral peptide therapeutics for diabetes treatment: State-of-the-art and future perspectives

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2006-2025页

作者： Bingwen Ding Zhu Zhu Cong Guo Jiaxin Li Yong Gan Miaorong Yu State key laboratory of drug Research and Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China School of Pharmacy Henan UniversityKaifeng 475004China NMPA key laboratory for quality Research and Evaluation of Pharmaceutical Excipients National Institutes for Food and Drug ControlBeijing 100050China

Diabetes,characterized by hyperglycemia,is a major cause of death and disability worldwide.Peptides,such as insulin and glucagon-like peptide-1(GLP-1)analogs,have shown promise as treatments for diabetes due to their ability to mimic or enhance insulin's actions in the body.Compared to subcutaneous injection,oral administration of anti-diabetic peptides is a preferred approach.However,biological barriers significantly reduce the efficacy of oral peptide therapeutics.Recent advancements in drug delivery systems and formulation techniques have greatly improved the oral delivery of peptide therapeutics and their efficacy in treating diabetes.This review will highlight(1)the benefits of oral anti-diabetic peptide therapeutics;(2)the biological barriers for oral peptide delivery,including pH and enzyme degradation,intestinal mucosa barrier,and biodistribution barrier;(3)the delivery platforms to overcome these biological barriers.Additionally,the review will discuss the prospects in this field.The information provided in this review will serve as a valuable guide for future developments in oral anti-diabetic peptide therapeutics.

关键词： Oral peptides Diabetes Delivery platforms Insulin Glucagon-like peptide-1 Biodistribution Biological barriers Targeted delivery

HPLC combined with chemometrics for quality control of Huamoyan Granules or Capsules

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Chinese Herbal Medicines 2024年第3期16卷 449-456页

作者： Minhang Dou Jiayi Huang Mimi Yu Huahua Li Yang Song Ziwei Peng Shouying Du Jie Bai School of Chinese Materia Medica Beijing University of Chinese Medicine Beijing Institute for drug control NMPA Key Laboratory for Quality Evaluation of Traditional Chinese Medicine (Traditional Chinese Patent Medicine)Beijing Key Laboratory of Analysis and Evaluation on Chinese Medicine

Objective:Huamaoyan Granules(HMYG) and Huamaoyan Capsules(HMYC) are Chinese patent medicines with different dosage forms of the same prescription.Due to the different preparation process,the chemical composition of these Chinese patent medicines varies greatly among different forms,but there were few studies on the difference comparison and quality control of them.In order to improve the effectiveness and safety in its clinical application,an idea combining high performance liquid chromatogra p hy(HPLC) and chemometrics was put forward to study the quality control of Chinese patent medicines in different dosage forms of the same prescription.Methods:The differential markers of HMYG and HMYC were explored based on HPLC fingerprint and chemometrics including orthogonal projections to latent structures-discriminant analysis(OPLS-DA),principal component analysis(PCA),and hierarchical cluster analysis(HCA).Finally,the quantitative analysis method of related components was established by HPLC.Results:A quality control method for HMYG and HMYC was established.Firstly,the chemical components of HMYG and HMYC were systematically analyzed by HPLC fingerprinting.Further exploration showed that there were 20 characteristic peaks and 57 common peaks.Then,the potential differential markers between HMYG and HMYC were explored by chemometrics,and the differential markers were screened after intersection with the 20 characteristic peaks.Finally,HPLC quantitative analysis methods for nine components were established,including seven differential markers(neochlorogenic acid,protocatechualdehyde,chlorogenic acid,cryptochlorogenic acid,caffeic acid,rosmarinic acid and salvianolic acid A).The results of HPLC quantitative analysis showed that the contents of eight components in HMYG and HMYC samples were significantly different.According to the above results,the differential markers between HMYG and HMYC screened based on HPLC fingerprint and chemometrics can effectively characterize the differences between the two dosage forms.Conclusi

关键词： chemometrics Chinese patent medicine high performance liquid chromatography fingerprint Huamoyan Granules/Capsules quality control synovitis

Worm-like micelles facilitate the intestinal mucus diffusion and drug accumulation for enhancing colorectal cancer therapy

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Chinese Chemical Letters 2024年第6期35卷 427-432页

作者： Yihan Zhou Duo Gao Yaying Wang Li Liang Qingyu Zhang Wenwen Han Jie Wang Chunliu Zhu Xinxin Zhang Yong Gan State key laboratory of drug Research and Center of Pharmaceutics Shanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China School of Chinese Materia Medica Nanjing University of Chinese MedicineNanjing 210023China University of Chinese Academy of Sciences Beijing 100049China NMPA key laboratory for quality Research and Evaluation of Pharmaceutical Excipients National Institutes for Food and Drug ControlBeijing 100050China School of Pharmacy Shanghai University of Traditional Chinese MedicineShanghai 201203China

Local delivery of nanoparticles holds promise for colorectal cancer(CRC)therapy.However,the presence of the mucus layer on the epithelium poses a significant challenge to drug delivery,thereby adversely affecting treatment efficiency.It is crucial to develop efficient drug delivery carriers that can effectively overcome mucus barriers to treat colorectal cancer.Herein,we utilized poly(1,4-butadiene)-b-poly(ethylene oxide)polymers to prepare four distinct geometries of polymeric micelles,namely linear micelles(LMs),worm-like micelles(WLMs),large spherical micelles(LSMs),and small spherical micelles(SSMs)to investigate the influence of shape effects on overcoming colonic mucosal barrier.We found that the carriers exhibited diverse shapes while maintaining comparable physicochemical properties.Of these,WLMs had an aspect ratio similar to segmented filamentous bacteria,which exhibited superior mucus penetration ability,leading to prolonged drug release kinetics and faster entry into epithelial cells compared to LSMs.Furthermore,rectally administrated 10-hydroxycamptothecin-loaded WLMs traversed the colorectal mucus in orthotopic CRC nude mice model,penetrated and accumulated within tumor tissue,and effectively aggregated within cancer cells,thereby inducing significantly robust antitumor outcomes in vivo.These findings underscore the significance of shape design in overcoming colonic mucosal absorption barriers,offering a novel approach for the development of drug delivery carriers tailored for effective tumor therapy.

关键词： Worm-like micelles Mucus penetration Shape dependent Transmucosal delivery Colorectal cancer

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铜基催化剂用于一氧化碳电还原为多碳产品

Science China Materials 2024年第6期67卷 1684-1705页

作者：赵雯刘娟王光滔王新天杨传举李剑王鋙葶孙晓莲林日琛左淦丞朱文磊 State key laboratory of Pollution control and Resource Reuse Frontiers Science Center for Critical Earth Material CyclingState Key Laboratory of Pollution Control and Resource Reusethe Frontiers Science Center for Critical Earth Material CyclingSchool of the EnvironmentNanjing UniversityNanjing 210023China State key laboratory of Analytical Chemistry for Life Science School of Chemistry and Chemical EngineeringNanjing UniversityNanjing 210023China State key laboratory of Natural Medicines Key Laboratory of Drug Quality Control and PharmacovigilanceSchool of PharmaceuticsChina Pharmaceutical UniversityNanjing 210009China key laboratory of Energy Thermal Conversion and control of Ministry of Education School of Energy and EnvironmentSoutheast UniversityNanjing 211189China Jiangsu Engineering Lab of Water and Soil Eco-remediation School of EnvironmentNanjing Normal UniversityNanjing 210023China

电化学二氧化碳还原(ECO_(2)R)是一种将碳和可再生能源的能量储存在多碳产品(C_(2+))的化学键中的有效途径.然而,反应涉及的复杂步骤为CO_(2)直接转化为C_(2+)设置了巨大的障碍.一种利用CO作为“中转站”,通过串联ECO_(2)R和电化学CO还... 详细信息

电化学二氧化碳还原(ECO_(2)R)是一种将碳和可再生能源的能量储存在多碳产品(C_(2+))的化学键中的有效途径.然而,反应涉及的复杂步骤为CO_(2)直接转化为C_(2+)设置了巨大的障碍.一种利用CO作为“中转站”,通过串联ECO_(2)R和电化学CO还原(ECOR)以提高生产C_(2+)的选择性和反应速率的策略引起了人们的广泛关注.本文总结了铜基电催化剂在ECOR中催化特定C_(2+)生成的设计策略.其次,从各个方面总结了催化剂工程的代表性设计策略,并介绍了电解反应器改进方面的最新进展.最后,阐述了该研究领域面临的主要挑战和未来前景.这些见解和观点将为铜基电催化剂的设计提供有益指导.

关键词： CO electroreduction Cu-based catalysts multi-car-bon products

A novel alternative for pyrogen detection based on a transgenic cell line

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Signal Transduction and Targeted Therapy 2024年第3期9卷 1221-1229页

作者： Qing He Chuan-Fei Yu Gang Wu Kai-Qin Wang Yong-Bo Ni Xiao Guo Zhi-Hao Fu Lan Wang De-Jiang Tan Hua Gao Can Wang Gang Chen Xu-Hong Chen Bo Chen Jun-Zhi Wang National Institutes for Food and drug control BeijingChina School of Life Science and Biopharmaceutics Shenyang Pharmaceutical UniversityShenyangChina Shanghai Institute for Food and drug control ShanghaiChina keyMed Biosciences Inc. ChengduChina

Pyrogen,often as a contaminant,is a key indicator affecting the safety of almost all parenteral drugs(including biologicals,chemicals,traditional Chinese medicines and medical devices).It has become a goal to completely replace the in vivo rabbit pyrogen test by using the in vitro pyrogen test based on the promoted‘reduction,replacement and refinement’principle,which has been highly considered by regulatory agencies from different countries.We used NF-κB,a central signalling molecule mediating inflammatory responses,as a pyrogenic marker and the monocyte line THP-1 transfected with a luciferase reporter gene regulated by NF-κB as an in vitro model to detect pyrogens by measuring the intensity of a fluorescence signal.Here,we show that this test can quantitatively and sensitively detect endotoxin(lipopolysaccharide from different strains)and nonendotoxin(lipoteichoic acid,zymosan,peptidoglycan,lectin and glucan),has good stability in terms of NF-κB activity and cell phenotypes at 39 cell passages and can be applied to detect pyrogens in biologicals(group A&C meningococcal polysaccharide vaccine;basiliximab;rabies vaccine(Vero cells)for human use,freeze-dried;Japanese encephalitis vaccine(Vero cells),inactivated;insulin aspart injection;human albumin;recombinant human erythropoietin injection(CHO Cell)).The within-laboratory reproducibility of the test in three independent laboratories was 85%,80%and 80%and the interlaboratory reproducibility among laboratories was 83.3%,95.6%and 86.7%.The sensitivity(true positive rate)and specificity(true negative rate)of the test were 89.9%and 90.9%,respectively.In summary,the test provides a novel alternative for pyrogen detection.

关键词： pyrogen rabbit replace

Anti-inflammatory mechanism of the non-volatile ingredients performance liquid chromatography-heated electron spray ionization-high resolution mass spectroscope and cell metabolomics

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Journal of Traditional Chinese Medicine 2024年第2期44卷 260-267页

作者： JING Wenguang LIN Xiaoyu LI Chu ZHAO Xiaoliang CHENG Xianlong WANG Penglong WEI Feng MA Shuangcheng Institute of control of Chinese Traditional Medicine and Ethnic Medicine National Institutes for Food and Drug ControlBeijing 102629China School of Traditional Chinese Medicine Beijing University of Chinese MedicineBeijing 102488China Beijing key laboratory of Traditional Chinese Medicine Basic Research on Prevention and Treatment of Major Diseases Experimental Research CenterChina Academy of Chinese Medical SciencesBeijing 100700China

OBJECTIVE:To explore the anti-inflammatory components and mechanism of the non-volatile ingredients of patchouli.METHODS:High performance liquid chromatographyheated electron spray ionization-high resolution mass spectroscope(HPLC-HESI-HRMS)was used to analyze the chemical constituents of the non-volatile ingredients of patchouli.The anti-inflammatory activity of ingredients was evaluated using lipopolysaccharide(LPS)induced RAW264.7 cell inflammation model,and the antiinflammatory mechanism was investigated using multivariate statistical analysis of cell metabolomics.RESULTS:The non-volatile ingredients of patchouli were characterized by HPLC-HESI-HRMS,and 36 flavonoids and 18 other components were identified.These ingredients of patchouli not only had a good protective effect on the LPS-induced inflammation model of RAW264.7 cells,but also regulated the expression levels of arginine,L-leucine,cholesterol,fructose and sorbitol by down-regulating arginine metabolism,aminoacyl-tRNA biosynthesis,polyol/sorbitol pathway,so as to reduce inflammation and reduce cell damage.CONCLUSION:The non-volatile ingredients of patchouli had good anti-inflammatory effect and exerted its curative effect by regulating endogenous metabolic pathway to reduce inflammatory response.

关键词： Pogostemon non-volatile ingredients anti-inflammatory cell metabolomics

Genome engineering of the human gut microbiome

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Journal of Genetics and Genomics 2024年第5期51卷 479-491页

作者： Linggang Zheng Juntao Shen Ruiyue Chen Yucan Hu Wei Zhao Elaine Lai-Han Leung Lei Dai Dr Neher's Biophysics laboratory for Innovative drug Discovery/State key laboratory of quality Research in Chinese Medicine Macao University of Science and TechnologyTaipaMacao 999078China CAS key laboratory of Quantitative Engineering Biology Shenzhen Institute of Synthetic BiologyShenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China University of Chinese Academy of Sciences Beijing 100049China Cancer Center Faculty of Health ScienceUniversity of MacaoMacao 999078China MOE Frontiers Science Center for Precision Oncology University of MacaoMacao 999078China

The human gut microbiome,a complex ecosystem,significantly influences host health,impacting crucial aspects such as metabolism and immunity.To enhance our comprehension and control of the molecular mechanisms orchestrating the intricate interplay between gut commensal bacteria and human health,the exploration of genome engineering for gut microbes is a promising frontier.Nevertheless,the complexities and diversities inherent in the gut microbiome pose substantial challenges to the development of effective genome engineering tools for human gut microbes.In this comprehensive review,we provide an overview of the current progress and challenges in genome engineering of human gut commensal bacteria,whether executed in vitro or in situ.A specific focus is directed towards the advancements and prospects in cargo DNA delivery and high-throughput techniques.Additionally,we elucidate the immense potential of genome engineering methods to enhance our understanding of the human gut microbiome and engineer the microorganisms to enhance human health.

关键词： Non-model gut commensals Genomeediting reagents Cargo delivery High-throughput genome engineering

Effect of microstructure on lipolysis behavior of milk fat globules during gastrointestinal digestion

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Food Science and Human Wellness 2024年

作者： Xinyun Zhou Ting Guo Chen Chen Hadiatullah Hadiatullah Yunping Yao Changmo Li Xingguo Wang State key laboratory of Food Nutrition and Safety key laboratory of Food Nutrition and Safety Ministry of Education College of Food Science and Engineering Tianjin University of Science & Technology Tianjin key laboratory for Modern drug Delivery & High-Efficiency Collaborative Innovation Center of Chemical Science and Engineering School of Pharmaceutical Science and Technology Tianjin University Collaborative Innovation Center of Food Safety and quality control in Jiangsu Province National Engineering Research Center for Functional Food School of Food Science and Technology Jiangnan University

Milk fat globules (MFG) are the primary source of energy and functional factor in dairy-based products. To evaluate the suitability of commercial MFG substitutes for infant and adult consumers， the lipolysis properties and regulatory factors in digesting bovine， caprine， and human MFG were compared. The lipolysis kinetic models of bovine and caprine MFG are comparable， with bovine MFG displaying the highest degree of lipolysis (50.21%) during gastric digestion in infants， resulting in the production short-chain saturated fatty acids. Caprine MFG has a high rate of lipolysis due to its weak phospholipid-glycoprotein layer， which is prominent in both infants’ and adults’ digestion. The effects of consuming bovine and caprine MFG for adults are comparable in terms of lipolysis properties and nutritional value of fatty acid. After gastrointestinal digestion， human MFG has the highest digestibility (93.98%). The advantages of human MFG include its phospholipid structure， exogenous lipase， and lipolysis-regulating proteins. This study provides recommendation for the selection of milk fat substitutes and improvements in commercial dairy.

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