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mIgM-mediated splenic marginal zone B cells targeting of folic acid for immunological evasion

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Acta Pharmaceutica Sinica B 2024年第2期14卷 808-820页

作者： Huan Wang Zhuxuan Jiang Zhiwei Guo Gan Luo Tianhao Ding changyou zhan Department of Pharmacology School of Basic Medical Sciences&Department of PharmacyShanghai Pudong HospitalFudan UniversityShanghai 200032China Department of Pharmaceutical Sciences School of PharmacyNaval Medical UniversityShanghai 200433China Shanghai Engineering Research Center for Synthetic Immunology Fudan UniversityShanghai 200032China

Folic acid is a fully oxidized synthetic folate with high bioavailability and stability which has been extensively prescribed to prevent congenital *** we revealed the immunosuppressive effect of folic acid by targeting splenic marginal zone B(MZB)*** acid demonstrates avid binding with the Fc domain of immunoglobulin M(IgM),targeting IgM positive MZB cells in vivo to destabilize IgM-B cell receptor(BCR)complex and block immune *** induced anergy of MZB cells by folic acid provides an immunological escaping window for *** conjugation of folic acid with therapeutic proteins and antibodies induces immunological evasion to mitigate the production of anti-drug antibodies,which is a major obstacle to the long-term treatment of biologics by reducing curative effects and/or causing adverse *** acid acts as a safe and effective immunosuppressant via IgM-mediated MZB cells targeting to boost the clinical outcomes of biologics by inhibiting the production of anti-drug antibodies,and also holds the potential to treat other indications that adverse immune responses need to be transiently shut off.

关键词： Membrane-bound IgM Anti-drugantibodies Bcell anergy Folic acid Marginal zoneBcells Bcell receptor Biologics Targeting

Protein corona mediated liposomal drug delivery for bacterial infection management

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Asian Journal of Pharmaceutical Sciences 2022年第6期17卷 855-866页

作者： Qianwen Shao Tianhao Ding Feng Pan Guanghui Li Shun Shen Jun Qian changyou zhan Xiaoli Wei School of Pharmacy&Department of Pharmacology School of Basic Medical SciencesFudan UniversityShanghai 201203China Department of Pharmacy&Center for Medical Research and Innovation Shanghai Pudong HospitalFudan University Pudong Medical CenterShanghai 201399China Department of Pharmacy Jing’an District Central Hospital of ShanghaiShanghai 200040China

Liposomes have been widely investigated as a class of promising antibiotic delivery systems for the treatment of life-threatening bacterial ***,the inevitable formation of protein corona on the liposomal surface can heavily impact in vivo performance.A better understanding of the effects of protein corona on liposomal behavior can significantly improve antibacterial liposomal drug ***,the critical role of protein corona in mediating liposome-bacteria interactions was *** of negatively charged protein on cationic liposome weakened electrostatic attractionenhanced liposomal binding to the *** complement deposition on anionic liposome composed of phosphatidylglycerol(DSPG s Lip)contributed to a superior binding affinity of DSPG s Lip to planktonic bacteria and biofilms,which was exploited to enhance bacteria-targeted drug *** both ***-related osteomyelitis and pneumonia mice models,DSPG s Lip was demonstrated as a promising antibiotic nanocarrier for managing MRSA infection,indicating the benefits of lipid composition-based protein corona modulation in liposomal antibiotic delivery for bacterial infection treatment.

关键词： Liposome Protein corona Complement Methicillin-resistant staphylococcus aureus Liposome-bacteria interaction

Optimized RNA interference therapeutics combined with interleukin-2 mRNA for treating hepatitis B virus infection

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Signal Transduction and Targeted Therapy 2024年第7期9卷 3063-3076页

作者： Wenjing Zai Min Yang Kuan Jiang Juan Guan Huijing Wang Kongying Hu Chao Huang Jieliang Chen Wei Fu changyou zhan Zhenghong Yuan Key Laboratory of Medical Molecular Virology(MOE/NHC/CAMS) Research Unit of Cure of Chronic Hepatitis B Virus Infection(CAMS)Shanghai Frontiers Science Center of Pathogenic Microbes and InfectionSchool of Basic Medical SciencesShanghai Medical CollegeFudan UniversityShanghaiP.R.China Department of Pharmacology School of Basic Medical SciencesFudan UniversityShanghaiP.R.China Shanghai Engineering Research Center for Synthetic Immunology Fudan UniversityShanghaiP.R.China Eye Institute and Department of Ophthamology Eye and ENT HospitalFudan UniversityShanghaiP.R.China Pharmacy Department of Huashan Hospital Fudan UniversityShanghaiP.R.China Institute of Pediatric Translational Medicine Shanghai Institute for Pediatric Congenital Heart DiseaseShanghai Children’s Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina Shanghai Institute of Infectious Disease and Biosecurity ShanghaiP.R.China

This study aimed to develop a pan-genotypic and multifunctional small interfering RNA(siRNA)against hepatitis B virus(HBV)with an efficient delivery system for treating chronic hepatitis B(CHB),and explore combined RNA interference(RNAi)and immune modulatory modalities for better viral *** synthetic siRNAs targeting consensus motifs distributed across the whole HBV genome were designed and *** lipid nanoparticle(LNP)formulation was optimized by adopting HO-PEG_(2000)-DMG lipid and modifying the molar ratio of traditional polyethylene glycol(PEG)lipid in LNP *** efficacy and safety of this formulation in delivering siHBV(tLNP/siHBV)along with the mouse IL-2(mIL-2)mRNA(tLNP/siHBVIL2)were evaluated in the rAAVHBV1.3 mouse model.A siRNA combination(terms“siHBV”)with a genotypic coverage of 98.55%was selected,chemically modified,and encapsulated within an optimized LNP(tLNP)of high efficacy and security to fabricate a therapeutic formulation for *** results revealed that tLNP/siHBV significantly reduced the expression of viral antigens and DNA(up to 3log_(10)reduction;vs PBS)in dose-and time-dependent manners at single-dose or multi-dose frequencies,with satisfactory safety *** studies showed that tLNP/siHBVIL2 enables additive antigenic and immune control of the virus,via introducing potent HBsAg clearance through RNAi and triggering strong HBV-specific CD4^(+)and CD8^(+)T cell responses by expressed mIL-2 *** adopting tLNP as nucleic acid nanocarriers,the co-delivery of siHBV and mIL-2 mRNA enables synergistic antigenic and immune control of HBV,thus offering a promising translational therapeutic strategy for treating CHB.

关键词： formulation enable offering

Exemplifying interspecies variation of liposome in vivo fate by the effects of anti-PEG antibodies

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Acta Pharmaceutica Sinica B 2024年第11期14卷 4994-5007页

作者： Ercan Wu Juan Guan Yifei Yu Shiqi Lin Tianhao Ding Yuxiu Chu Feng Pan Mengyuan Liu Yang Yang Zui zhang Jian zhang changyou zhan Jun Qian School of Pharmacy Key Laboratory of Smart Drug Delivery(Fudan University)Ministry of Education&Department of PharmacyHuashan HospitalFudan UniversityShanghai 201203China Department of Pharmacy Shanghai Pudong HospitalPudong Medical Center&Department of PharmacologySchool of Basic Medical Sciences&State Key Laboratory of Molecular Engineering of PolymersFudan UniversityShanghai 200032China Department of Medical Oncology Fudan University Shanghai Cancer CenterShanghai 200032China

The different fate of liposomes among species has been discovered and mentioned in many studies, but the underlying mechanisms have not been explored. In the present work, we concentrated on the in vivo fate of PEGylated liposomes (sLip) in three commonly used species (mice, rats, and dogs). It was exhibited that the accelerated blood clearance (ABC) phenomenon and hypersensitivity in large animals (beagle dogs) were much more significant than that in rodents. We demonstrated that anti-PEG IgM (partially) and complement (mostly) determined the elimination of sLip and linked the distinct interspecies performances with the diverse complement capacity among species. Based on the data from animals and clinical patients, it was revealed that the fate of sLip in large animals was closer to that in humans, for the sufficient complement capacity could expose the potential adverse reactions caused by anti-PEG antibodies. Our results suggested that the distinctive interspecies performances of sLip were highly related to the physiological variabilities among species, which should not be overlooked in the innovation and translation of nanomedicines.

关键词： Lipid NanomedicineLiposome Interspecies Anti-PEG antibody Complement system ABC phenomenon In vivo fate

Engineered platelets-based drug delivery platform for targeted thrombolysis

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Acta Pharmaceutica Sinica B 2022年第4期12卷 2000-2013页

作者： Songli Wang Ruifeng Wang Nana Meng Linwei Lu Jun Wang Jianfen Zhou Jiasheng Lu Qianzhu Xu Cao Xie changyou zhan Yao Li Yang Yu Weiyue Lu Min Liu Department of Pharmaceutics School of PharmacyKey Laboratory of Smart Drug Delivery(Ministry of Education and PLA)Fudan UniversityShanghai 201203China The Department of Integrative Medicine Huashan HospitalFudan University and the Institutes of Integrative Medicine of Fudan UniversityShanghai 200041China Department of Pharmacology School of Basic Medical SciencesFudan UniversityShanghai 200032China The National Facility for Protein Science in Shanghai(NFPS) Shanghai 201210China State Key Laboratory of Medical Neurobiology and the Collaborative Innovation Center for Brain Science and Department of Pharmacology School of Basic Medical SciencesFudan UniversityShanghai 200032China Minhang Branch Zhongshan Hospital and Institute of Fudan-Minhang Academic Health SystemMinhang HospitalFudan UniversityShanghai 201199China

Thrombolytic agents have thus far yielded limited therapeutic benefits in the treatment of thrombotic disease due to their short half-life,low targeting ability,and association with serious adverse reactions,such as bleeding *** by the natural roles of platelets during thrombus formation,we fabricated a platelet-based delivery system(NO@uPA/PLTs)comprising urokinase(uPA)and arginine(Arg)for targeted thrombolysis and inhibition of *** anchoring of uPA to the platelet surface by lipid insertion increased the thrombotic targeting and in vivo circulation duration of uPA without disturbing platelet *** oxide(NO)generated by the loaded Arg inhibited platelet aggregation and activation at the damaged blood vessel,thereby inhibiting ***@uPA/PLTs effectively accumulated at the thrombi in pulmonary embolism and carotid artery thrombosis model mice and exerted superior thrombolytic *** addition,the platelet delivery system showed excellent thrombus recurrence prevention ability in a mouse model of secondary carotid artery *** coagulation indicators in vivo showed that the platelet-based uPA and NO co-delivery system possessed a low hemorrhagic risk,providing a promising tool for rapid thrombolysis and efficient inhibition of posttreatment re-embolism.

关键词： Platelet Urokinase Nitric oxide Targeted thrombolysis Thrombus reformation

Nanodisk-based glioma-targeted drug delivery enabled by a stable glycopeptide

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Nanodisk-based glioma-targeted drug delivery enabled by a st...

Enhanced Immunocompatibility of Ligand-targeted Liposomes by Attenuating Natural IgM Absorption

2018年第十二届中国药物制剂大会

作者：王欢 changyou zhan Weiyue Lu Hao Wang Department of Pharmaceutics School of Pharmacy and Key Laboratory of Smart Drug Delivery Fudan University National Pharmaceutical Engineering Research Center China State Institute of Pharmaceutical Industry

Heptapeptide ATWLPPR(A7R) binds specifically to vascular endothelial growth factor receptor 2(VEGFR2) and neuropilin-1(NRP-1) overexpressed in glioma cells, exhibiting high potential to achieve glioma targeted drug delivery. However, in vivo application of A7R peptide remains challenging due to the poor proteolytic stability and inaccessibility of A7R to the brain. To tackle these problems, we identified a glycosylated A7R derivative to enhance in vivo stability and brain transport efficacy. Our results showed that glycosylation of peptide could efficiently improve stability in serum, traverse the blood-brain barrier(BBB) and be uptaken by glioma cells. Furthermore, a novel glioma-targeted drug delivery system was constructed successfully employing glycopeptide as the targeting moiety and nanodisk as the carrier of paclitaxel(PTX). Physicochemical characterization showed that the nanodisk presented suitable size of 50 nm and adequate loading capacity of PTX. Compared to non-glycosylated nanodisk, glycopeptide modification could significantly enhance the uptake of disks by brain capillary endothelial cells through glucose transporter 1(GLUT1). In vivo imaging and glioma fluorescence section results also indicated that nanodisks modified with glycopeptide showed a higher accumulation in glioma. The glycopeptide-enabled PTX delivery system exhibited superior anti-glioma efficacy in intracranial glioma xenograft model. These results suggested that glycosylation of peptides provided an efficient pathway to design multifunctional and stable brain targeting ligands.

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Enhanced Immunocompatibility of Ligand-targeted Liposomes by...

An NIR-Ⅱ-emissive Ru(Ⅱ) metallacycle for efficient and safe immunotherapy

2018年第十二届中国药物制剂大会

作者：官娟 Zui zhang Zhu xuan Jiang Yang Yang changyou zhan School of Basic Medical Sciences ＆ State Key Laboratory of Molecular Engineering of Polymers Fudan University

＜正＞Targeting ligands are anticipated to facilitate precise delivery of therapeutic agents to diseasedhowever,they may also severely affect the interaction of nanocarriers with plasmaIn the present study,we re-inter...

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Science China Chemistry 2025年第1期68卷 5-7页

作者： Chonglu Li Jianbo zhan Biao Dong Institute of Health Inspection and Testing Hubei Provincial Center for Disease Control and Prevention State Key Laboratory on Integrated Optoelectronics College of Electronic Science and Engineering Jilin University

Immunotherapy, as a groundbreaking cancer treatment, has gained considerable attention for its utilization of the body’s immune system to combat tumors [1]. This therapy induces tumor cell apoptosis, triggering a sustained anti-tumor immune response and effectively preventing tumor recurrence and metastasis [2]. The fundamental principle lies in inducing tumor cell death through specific treatment modalities, leading to the release of a cascade of signaling molecules and antigens, thereby mobilizing the immune system to actively identify and attack tumor cells [3].

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Optimizing battery deployment: Aging trajectory prediction enabling homogenous performance grouping

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Journal of Energy Chemistry 2025年第1期100卷 565-577页

作者： Shuquan Wang Feng Gao zhan Ma Hao Tian Yusen zhang School of Control Science and Engineering Shandong University Key Lab of Power System Intelligent Dispatch and Control of Ministry of Education Shandong University

As battery deployments in electric vehicles and energy storage systems grow, ensuring homogeneous performance across units is crucial. We propose a multi-derivative imaging fusion(MDIF) model, employing advanced imaging and machine learning to predict battery aging trajectories from minimal initial data, thus facilitating effective performance grouping before deployment. Utilizing a derivative strategy and Gramian Angular Difference Field for dimensional enhancement, the MDIF model uncovers subtle predictive features from discharge curve data after only ten cycles. The architecture includes a parallel convolutional neural network with lateral connections to enhance feature integration and *** on a self-developed dataset, the model achieves an average root-mean-square error of 0.047 Ah and an average mean absolute percentage error of 1.60%, demonstrating high precision and *** robustness is further validated through transfer learning on two publicly available datasets, adapting with minimal retraining. This approach significantly reduces the testing cycles required, lowering both time and costs associated with battery testing. By enabling precise battery behavior predictions with limited data, the MDIF model optimizes battery utilization and deployment strategies, enhancing system efficiency and sustainability.

关键词： Lithium-ion battery Battery prognostics Fusion model Convolutional neural network Transfer learning