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Dual-targeting nanovesicles enhance specificity to dynamic tumor cells in vitro and in vivo via manipulation of αvβ3-ligand binding

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Acta Pharmaceutica Sinica B 2020年第11期10卷 2183-2197页

作者： Yang Song Xiangfu Guo Jijun Fu Bing He Xueqing Wang wenbing dai Hua Zhang Qiang Zhang Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China Guangzhou Medical University School of Pharmaceutical SciencesGuangzhou 511436China

The dynamic or flowing tumor cells just as leukemia cells and circulating tumor cells face a microenvironment difference from the solid tumors,and the related targeting nanomedicines are rarely *** existence of fluidic shear stress in blood circulation seems not favorable for the binding of ligand modified nanodrugs with their target ***,the binding feature is very essential in this ***,we utilized HSPC,PEG-DSPE,cholesterol and two avb3 ligands(RGDm7 and DT4)with different binding rates to build dual-targeting nanovesicles,in an effort to achieve a"fast-binding/slow-unbinding"*** was demonstrated that the dual-targeting nanovesicles actualized effi-cient cellular uptake and antitumor effect in vitro both for static and dynamic tumor ***,the potency of the dual-targeting vesicles for flowing tumor cells was better than that for static tumor ***,a tumor metastasis mice model and a leukemia mice model were established to detect the killing ability of the drug-loaded dual-targeting vesicles to dynamic tumor cells in *** therapy efficacy of the dual-targeting system was higher than other controls including single-targeting ***,it seems possible to strengthen drug-targeting to dynamic tumor cells via the control of ligandereceptor interaction.

关键词： Dual-targeting Lipid vesicle Flowing condition Leukemia Circulating tumor cells Fluidic shear stress

An enzyme-responsive and transformable PD-L1 blocking peptide-photosensitizer conjugate enables efficient photothermal

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Bioactive Materials 2023年第4期22卷 47-59页

作者： Yanan Sun Bochen Lyu Chang Yang Bing He Hua Zhang Xueqing Wang Qiang Zhang wenbing dai Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing100191China Department of Pharmaceutics School of Pharmaceutical SciencesHebei Medical UniversityShijiazhuang050017China

Mild photothermal therapy combined with immune checkpoint blockade has received increasing attention for the treatment of advanced or metastatic cancers due to its good therapeutic ***,it remains a challenge to facilely integrate the two therapies and make it potential for clinical *** work designed a peptide-photosensitizer conjugate(PPC),which consisted of a PD-L1 antagonist peptide(CVRARTR),an MMP-2 specific cleavable sequence,a self-assembling motif,and the photosensitizer Purpurin *** single-component PPC can self-assemble into nanospheres which is suitable for intravenous *** PPC nanosphere is cleaved by MMP-2 when it accumulates in tumor sites,thereby initiating the cancer-specific release of the antagonist ***,the nanospheres gradually transform into co-assembled nanofibers,which promotes the retention of the remaining parts within the *** vivo studies demonstrated that PPC nanospheres under laser irradiation promote the infiltration of cytotoxic T lymphocytes and maturation of DCs,which sensitize 4T1 tumor cells to immune checkpoint blockade ***,PPC nanospheres inhibit tumor growth efficiently both in situ and distally and blocked the formation of lung *** present study provides a simple and efficient integrated strategy for breast cancer photoimmunotherapy.

关键词： Transformable nanomedicine Self-assembled peptide Immune checkpoint blockade Photothermal therapy Photoimmunotherapy

Engineering and preliminary evaluation of multiple non-equilibrium nanostructures from a single peptide amphiphile

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Nano Research 2024年第11期17卷 9764-9774页

作者： Weiping Cui Di Wu Liuqing Yang Chang Yang Bing He Hua Zhang Xueqing Wang Lei Zhang wenbing dai Qiang Zhang Department of Pharmaceutics College of Pharmacy Shenyang Pharmaceutical University Shenyang 110016 China Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical Sciences Peking University Beijing 100191 China Ningbo Institute of Marine Medicine Peking University Ningbo 315010 China Electron Microscopy Analysis Laboratory Medical and Health Analysis Center Peking University Beijing 100191 China

Compared with thermodynamically equilibrium supramolecular assemblies, non-equilibrium assemblies from the same building blocks have attracted increasing attentions because their diverse structures and dynamic natures may impart the assemblies with novel functionalities. However, facile access to non-equilibrium assemblies remains a formidable challenge. Herein, we endeavored to exploit various solvent-anti-solvent methods to achieve it using peptide amphiphile C16-VVAAEE-NH_(2) as a model. Through systematical utilization of dialysis, ultrasonic and stirring-dropping methods, as well as tuning of processing parameters, we demonstrated the successful formation of diverse non-equilibrium nanostructures with distinct morphologies and structures that significantly deviate from the thermodynamically favored twisted long ribbons. Additionally, these metastable nanostructures ultimately underwent spontaneous transformation into thermodynamically stable states. The transformation processes of three representative non-equilibrium assemblies were also demonstrated and characterized in detail using transmission electron microscopy, circular dichroism spectrum, and thioflavin T fluorescence spectrum. Furthermore, non-equilibrium assemblies exhibited various degrees of cytotoxic effects, which may stem from their spontaneous, dynamic transformation and interactions with cellular membranes. This study offers valuable approaches for direct access to diverse non-equilibrium supramolecular nanostructures from self-assembling peptide, and also has implications for the development of advanced materials with unprecedented biological functions.

关键词： non-equilibrium nanostructures peptide amphiphile peptide assembly nanomedicine

Molecular Mechanisms of Intracellular Delivery of Nanoparticles Monitored by an Enzyme‑Induced Proximity Labeling

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Nano-Micro Letters 2024年第6期16卷 14-37页

作者： Junji Ren Zibin Zhang Shuo Geng Yuxi Cheng Huize Han Zhipu Fan wenbing dai Hua Zhang Xueqing Wang Qiang Zhang Bing He Department of Pharmaceutics School of Pharmaceutical Sciences Peking University38 Xueyuan RdHaidian DistrictBeijing 100191People’s Republic of China

Achieving increasingly finely targeted drug delivery to organs,tissues,cells,and even to intracellular biomacromolecules is one of the core goals of *** the delivery destination is refined to cellular and subcellular targets,it is essential to explore the delivery of nanomedicines at the molecular ***,due to the lack of technical methods,the molecular mechanism of the intracellular delivery of nanomedicines remains unclear to ***,we develop an enzyme-induced proximity labeling technology in nanoparticles(nano-EPL)for the real-time monitoring of proteins that interact with intracellular ***(lactic-co-glycolic acid)nanoparticles coupled with horseradish peroxidase(HRP)were fabricated as a model(HRP(+)-PNPs)to evaluate the molecular mechanism of nano delivery in *** adding the labeling probe biotin-phenol and the catalytic substrate H_(2)O_(2)at different time points in cellular delivery,nano-EPL technology was validated for the real-time in situ labeling of proteins interacting with ***-EPL achieves the dynamic molecular profiling of 740 proteins to map the intracellular delivery of HRP(+)-PNPs in macrophages over *** on dynamic clustering analysis of these proteins,we further discovered that different organelles,including endosomes,lysosomes,the endoplasmic reticulum,and the Golgi apparatus,are involved in delivery with distinct participation *** importantly,the engagement of these organelles differentially affects the drug delivery efficiency,reflecting the spatial–temporal heterogeneity of nano delivery in *** summary,these findings highlight a significant methodological advance toward understanding the molecular mechanisms involved in the intracellular delivery of nanomedicines.

关键词： Enzyme-induced proximity labeling Intracellular delivery Nano-protein interaction Dynamic molecule profiling Macrophages

Boosting synergism of chemo- and immunotherapies via switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis by bisphosphonate coordination lipid nanogranules

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Acta Pharmaceutica Sinica B 2024年第2期14卷 836-853页

作者： Ge Song Minghui Li Shumin Fan Mengmeng Qin Bin Shao wenbing dai Hua Zhang Xueqing Wang Bing He Qiang Zhang Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Natural and Biomimetic Drugs School of Pharmaceutical SciencesPeking UniversityBeijing 100191China Department of Medical Oncology Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education)Peking University Cancer HospitalBeijing 100142China

Conventional chemotherapy based on cytotoxic drugs is facing tough challenges recently following the advances of monoclonal antibodies and molecularly targeted *** is critical to inspire new potential to remodel the value of this classical therapeutic ***,we fabricate bisphosphonate coordination lipid nanogranules(BC-LNPs)and load paclitaxel(PTX)to boost the chemo-and immuno-therapeutic synergism of cytotoxic *** in BC-LNPs@PTX,a bisphosphonate to block mevalonate metabolism,works as both the structure and drug constituent in nanogranules,where alendronate coordinated with calcium ions to form the particle *** synergy of alendronate enhances the efficacy of paclitaxel,suppresses tumor metastasis,and alters the cytotoxic *** from the paclitaxel-induced apoptosis,the involvement of alendronate inhibits the mevalonate metabolism,changes the mitochondrial morphology,disturbs the redox homeostasis,and causes theaccumulation of mitochondrial ROS and lethal lipid peroxides(LPO).These factors finally trigger the ferroptosis of tumor cells,an immunogenic cell death mode,which remodels the suppressive tumor immune microenvironment and synergizes with ***,by switching paclitaxel-induced apoptosis to mevalonate metabolism-triggered ferroptosis,BC-LNPs@PTX provides new insight into the development of cytotoxic drugs and highlights the potential of metabolism regulation in cancer therapy.

关键词： Bisphosphonate coordinationlipid nanogranules Ferroptosis Mevalonatemetabolism Mitochondrial metabolism Nano-systematic biology

Small GTPases:Structure,biological function and its interaction with nanoparticles

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Asian Journal of Pharmaceutical Sciences 2019年第1期14卷 30-39页

作者： Siyang Song Wenshu Cong Shurong Zhou Yujie Shi wenbing dai Hua Zhang Xueqing Wang Bing He Qiang Zhang Shenyang Pharmaceutical University No.103Wenhua RoadShenyang 110016China Peking University No.38Xueyuan RoadBeijing 100191China

Small GTPase is a kind of GTP-binding protein commonly found in eukaryotic *** plays an important role in cytoskeletal reorganization,cell polarity,cell cycle progression,gene expression and many other significant events in cells,such as the interaction with foreign ***,it is of great scientific significance to understand the biological properties of small GTPases as well as the GTPase-nano interplay,since more and more nanomedicine are supposed to be used in biomedical ***,there is no review in this *** review summarizes the small GTPases in terms of the structure,biological function and its interaction with *** briefly introduced the various nanoparticles such as gold/silver nanoparticles,SWCNT,polymeric micelles and other nano delivery systems that interacted with different *** current nanoparticles exhibited different pharmacological effect modes and various target design concepts in the small GTPases *** will help to elucidate the conclusion that the therapeutic strategy targeting small GTPases might be a new research *** is believed that the in-depth study on the functional mechanism of GTPases can provide insights for the design and study of nanomedicines.

关键词： Small GTPase Nanoparticles Ras Rab Rho

Optimize the combination regimen of Trastuzumab and Nab-paclitaxel in HER2-positive tumors via modulating Caveolin-1 expression by lovastatin

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Asian Journal of Pharmaceutical Sciences 2022年第5期17卷 697-712页

作者： Canyu Yang Shumin Fan Xing Wang Wei Liu Long Yang Bing He wenbing dai Hua Zhang Xueqing Wang Qiang Zhang Department of Pharmacy Administration and Clinical Pharmacy School of Pharmaceutical SciencePeking UniversityBeijing 100191China Beijing Key Laboratory of Molecular Pharmaceutics New Drug Delivery SystemsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Natural and Biomimetic Drugs Peking UniversityBeijing 100191China Department of Pharmacy Peking University Third HospitalBeijing100083China

The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)***,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors ***-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination ***,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor *** the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low ***,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was *** with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.

关键词： Caveolin-1 Nab-paclitaxel Trastuzumab Combination regimen optimization

A biomimetic antitumor nanovaccine based on biocompatible calcium pyrophosphate and tumor cell membrane antigens

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Asian Journal of Pharmaceutical Sciences 2021年第1期16卷 97-109页

作者： Minghui Li Mengmeng Qin Ge Song Hailiang Deng Dakuan Wang Xueqing Wang wenbing dai Bing He Hua Zhang Qiang Zhang Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems State Key Laboratory of Natural and Biomimetic DrugsSchool of Pharmaceutical SciencesPeking UniversityBeijing 100191China

Currently,the cancer immunotherapy has made great progress while antitumor vaccine attracts substantial ***,the selection of adjuvants as well as antigens are always the most crucial issues for better *** this study,we proposed a biomimetic antitumor nanovaccine based on biocompatible nanocarriers and tumor cell membrane ***,endogenous calcium pyrophosphate nanogranules with possible immune potentiating effect are designed and engineered,both as delivery vehicles and ***,these nanocarriers are coated with lipids and B16-OVA tumor cell membranes,so the biomembrane proteins can serve as tumor-specific *** was found that calcium pyrophosphate nanogranules themselves were compatible and possessed adjuvant effect,while membrane proteins including tumor associated antigen were transferred onto the *** was demonstrated that such a biomimetic nanovaccine could be well endocytosed by dendritic cells,promote their maturation and antigen-presentation,facilitate lymph retention,and trigger obvious immune *** was confirmed that the biomimetic vaccine could induce strong T-cell response,exhibit excellent tumor therapy and prophylactic effects,and simultaneously possess nice *** general,the present investigation might provide insights for the further design and application of antitumor vaccines.

关键词： Biomimetic nanovaccine Calcium pyrophosphate Membrane antigens Tumor immunotherapy Adjuvant

A magnetism/laser-auxiliary cascaded drug delivery to pulmonary carcinoma

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Acta Pharmaceutica Sinica B 2020年第8期10卷 1549-1562页

作者： Jialiang Lin Qingqing Yin Binlong Chen Haoran Zhang Dong Mei Jijun Fu Bing He Hua Zhang wenbing dai Xueqing Wang Yiguang Wang Qiang Zhang Beijing Key Laboratory of Molecular Pharmaceutics and New Drug Delivery Systems School of Pharmaceutical SciencesPeking UniversityBeijing 100191China State Key Laboratory of Natural and Biomimetic Drugs Peking UniversityBeijing 100191China School of Pharmaceutical Science Guangzhou Medical UniversityGuangzhou 511436China

Although high-efficiency targeted delivery is investigated for years, the efficiency of tumor targeting seems still a hard core to smash. To overcome this problem, we design a three-step delivery strategy based on streptavidin-biotin interaction with the help of c(RGDfK), magnetic fields and *** ultrasmall superparamagnetic iron oxide nanoparticles(USIONPs) modified with c(RGDfK) and biotin are delivered at step 1, followed by streptavidin and the doxorubicin(Dox) loaded nanosystems conjugated with biotin at steps 2 and 3, respectively. The delivery systems were proved to be efficient on A549 cells. The co-localization of signal for each step revealed the targeting mechanism. The external magnetic field could further amplify the endocytosis of USPIONs based on c(RGDfK), and magnify the uptake distinctions among different test groups. Based on photoacoustic imaging, laser-heating treatment could enhance the permeability of tumor venous blood vessels and change the insufficient blood flow in cancer. Then, it was noticed in vivo that only three-step delivery with laser-heating and magnetic fields realized the highest tumor distribution of nanosystem. Finally, the magnetism/laser-auxiliary cascaded delivery exhibited the best antitumor efficacy. Generally, this study demonstrated the necessity of combining physical, biological and chemical means of targeting.

关键词： auxiliary overcome delivery