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Chinese Chemical Letters 2024年第4期35卷 382-388页

作者： Shiyu Hou Maolin Sun Liming Cao Chaoming Liang Jiaxin Yang Xinggui Zhou Jinxing Ye Ruihua Cheng school of Chemical Engineering East China University of Science and TechnologyShanghai 200237China school of biomedical and Pharmaceutical sciences Guangdong University of TechnologyGuangzhou 510006China school of pharmacy East China University of Science and TechnologyShanghai 200237China

Microchannels enable the fast and efficient mixing of multiphase fluids.In this study, a millimeter-scale three-dimensional(3D) circular cyclone-type microreactor was designed for the mixing.The flow characteristics and mixing intensity were simulated by computational fluid dynamics simulations at a flow rate range of 12–96 m L/min using a water/ethyl acetate system.In the 3D variable-diameter structure,the microreactor induced paired opposite vortices and abruptly changed the local pressure to achieve a stable turbulent effect within the theoretical range of laminar flow.Tracer injection simulations indicated that sufficient mixing units successfully promote fluid dispersion.Diazo-coupling experiments showed a segregation index of X_S= 0.00,039 within a residence time of 9 s.Extraction experiments on the nbutanol/succinic acid/water system showed that the 3D circular cyclone-type microreactor achieved 100%extraction efficiency(E) in 4.25 s, and the overall volume mass transfer coefficient(K_La) reached 0.05–1.5s^(-1) in 12–96 m L/min.The isolated yield of the phase transfer alkylation and oxidation reactions in the 3D circular cyclone-type microreactor achieved 99% within 36 s, which was superior to the coil microreactor and batch reactor.

关键词： Microfluidics Passive microreactor CFD simulation Extraction Liquid-liquid biphase reaction

Targeted anti-cancer therapy: Co-delivery of VEGF siRNA and Phenethyl isothiocyanate (PEITC) via cRGD-modified lipid nanoparticles for enhanced anti-angiogenic efficacy

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Asian Journal of Pharmaceutical sciences 2024年第2期19卷 170-187页

作者： Bao Li Haoran Niu Xiaoyun Zhao Xiaoyu Huang Yu Ding Ke Dang Tianzhi Yang Yongfeng Chen Jizhuang Ma Xiaohong Liu Keda Zhang Huichao Xie Pingtian Ding school of pharmacy Shenyang Pharmaceutical UniversityShenyang 110016China school of Life science and Biopharmaceutics Shenyang Pharmaceutical University Shenyang 110016 China Department of Basic Pharmaceutical sciences school of pharmacy Husson University Bangor ME 04401USA College of pharmacy Shenzhen Technology UniversityShenzhen 518118China

Anti-tumor angiogenesis therapy, targeting the suppression of blood vessel growth in tumors, presents a potent approach in the battle against cancer. Traditional therapies have primarily concentrated on single-target techniques, with a specific emphasis on targeting the vascular endothelial growth factor, but have not reached ideal therapeutic efficacy. In response to this issue, our study introduced a novel nanoparticle system known as CS-siRNA/PEITC&L-cRGD NPs. These chitosan-based nanoparticles have been recognized for their excellent biocompatibility and ability to deliver genes. To enhance their targeted delivery capability, they were combined with a cyclic RGD peptide (cRGD). Targeted co-delivery of gene and chemotherapeutic agents was achieved through the use of a negatively charged lipid shell and cRGD, which possesses high affinity for integrin αvβ3 overexpressed in tumor cells and neovasculature. In this multifaceted approach, co-delivery of VEGF siRNA and phenethyl isothiocyanate (PEITC) was employed to target both tumor vascular endothelial cells and tumor cells simultaneously. The co-delivery of VEGF siRNA and PEITC could achieve precise silencing of VEGF, inhibit the accumulation of HIF-1α under hypoxic conditions, and induce apoptosis in tumor cells. In summary, we have successfully developed a nanoparticle delivery platform that utilizes a dual mechanism of action of anti-tumor angiogenesis and pro-tumor apoptosis, which provides a robust and potent strategy for the delivery of anti-cancer therapeutics.

关键词： Anti-angiogenesis Tumor apoptosis Nanoparticles VEGF siRNA Hypoxia inducible factor(HIF)-1 protein Phenethyl isothi ocyanate(PEITC)

pH-Responsive polymer boosts cytosolic siRNA release for retinal neovascularization therapy

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Acta Pharmaceutica Sinica B 2024年第2期14卷 781-794页

作者： Shuai Guo Chunhui Li Changrong Wang Xiaowen Cao Xinyue Liu Xing-Jie Liang Yuanyu Huang Yuhua Weng school of Medical Technology Advanced Research Institute of Multidisciplinary ScienceSchool of Life ScienceKey Laboratory of Molecular Medicine and BiotherapyKey Laboratory of Medical Molecule Science and Pharmaceutics EngineeringBeijing Institute of TechnologyBeijing 100081China school of pharmacy Shandong New Drug Loading&Release Technology and Preparation Engineering LaboratoryBinzhou Medical UniversityYantai 264003China school of Ophthalmology and Optometry School of Biomedical EngineeringThe Eye HospitalWenzhou Medical UniversityWenzhou 325027China Chinese Academy of sciences(CAS) Key Laboratory for Biomedical Effects of Nanomaterials and NanosafetyCAS Center for Excellence in NanoscienceNational Center for Nanoscience and Technology of ChinaBeijing 100190China

Small interfering RNA(siRNA)has a promising future in the treatment of ocular diseases due to its high efficiency,specificity,and low toxicity in inhibiting the expression of target genes and proteins.However,due to the unique anatomical structure of the eye and various barriers,delivering nucleic acids to the retina remains a significant challenge.In this study,we rationally design PACD,an A-B-C type non-viral vector copolymer composed of a hydrophilic PEG block(A),a siRNA binding block(B)and a pH-responsive block(C).PACDs can self-assemble into nanosized polymeric micelles that compact siRNAs into polyplexes through simple mixing.By evaluating its pH-responsive activity,gene silencing efficiency in retinal cells,intraocular distribution,and anti-angiogenesis therapy in a mouse model of hypoxia-induced angiogenesis,we demonstrate the efficiency and safety of PACD in delivering siRNA in the retina.We are surprised to discover that,the PACD/siRNA polyplexes exhibit remarkable intracellular endosomal escape efficiency,excellent gene silencing,and inhibit retinal angiogenesis.Our study provides design guidance for developing efficient nonviral ocular nucleic acid delivery systems.

关键词： SiRNA Oculardeliverysystem Block polymer Endosomalescape Retinal neovascularization Blood-retinal barrier VEGFA Safety

Laser speckle contrast imaging based on uniting spatiotemporal Fourier transform

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Chinese Optics Letters 2024年第1期22卷 98-104页

作者：翟林君杜永兆吴循循刁勇傅玉青 school of biomedical science Huaqiao UniversityQuanzhou 362021China College of Engineering Huaqiao UniversityQuanzhou 362021China

We propose a laser speckle contrast imaging method based on uniting spatiotemporal Fourier transform.First,the raw speckle images are entirely transformed to the spatiotemporal frequency domain with a three-dimensional(3D)fast Fourier transform.Second,the dynamic and static speckle components are extracted by applying 3D low-pass and high-pass filtering in the spatiotemporal frequency domain and inverse 3D Fourier transform.Third,we calculate the time-averaged modulation depth with the average of both components to map the two-dimensional blood flow distribution.The experiments demonstrate that the proposed method could effectively improve computational efficiency and imaging quality.

关键词： uniting spatiotemporal Fourier transform laser speckle contrast image fluctuation modulation 3D Fourier transform

Comparative Evaluation of Antitumor Chinese Patent Medicine Injections Based on Evidence-Based Medicine and Markov Model

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World Journal of Traditional Chinese Medicine 2024年第2期10卷 220-229页

作者： Jing Yang Yan-Peng Wang Wen-Gong Yu Yu-Yao Guan Prince Emmanuel Opoku Amponsah Xian-Shuai Tang Ying-Zi Sun Lei Zheng school of Medicine and pharmacy Ocean University of China Department of pharmacy Shandong Medical College Department of pharmacy Cheeloo College of Medicine Shandong Provincial Third Hospital Shandong University biomedical Engineering Graduate school University of Arizona

Objective: The objective of this study was to explore the safety, efficacy, economy, and other aspects of frequently-used antitumor Chinese patent medicine injections through a comprehensive evaluation of evidence-based medical research to provide scientific information and decision-making basis for drug selection, rational drug use, public awareness of safe drug use, and medical insurance. Materials and Methods: The names of five frequently used antitumor Chinese patent medicine injections were used as search terms, including the compound Sophora flavescens injection, Kangai injection, Aidi injection, Kanglaite injection, and Brucea javanica oil emulsion injection. Relevant evidence-based medical research was extracted from the databases. A descriptive evaluation was conducted, and the Markov model was used for the cost-benefit analysis. Finally, the above injections are ranked by comprehensive scores using the multi-criteria decision analysis and Delphi method. Results: The five injections had their own advantages in enhancing the effectiveness of anti-tumor treatments, improving the quality of life for cancer patients, and reducing the incidence of adverse reactions. From the perspective of economy and other attributes, compound S. flavescens was superior to B. javanica oil, Aidi, Kangai, and Kanglaite. After a comprehensive evaluation of the above five injections, the compound S. flavescens injection received the highest score. Conclusions: Compound S. flavescens, Kangai, Aidi, B. javanica oil, and Kanglaite have their own advantages in effectiveness and no significant difference in safety. Compound S. flavescens injection has the highest comprehensive score. Clinical attention should be paid to monitoring the initial stage of medication and special groups.

关键词： Anti-tumor Chinese patent medicine comprehensive evaluation medication safety pharmacoeconomics rational drug use

Biofabrication of nanocomposite-based scaffolds containing human bone extracellularmatrix for the differentiation of skeletal stem and progenitor cells

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Bio-Design and Manufacturing 2024年第2期7卷 121-136页

作者： Yang-Hee Kim Janos M.Kanczler Stuart Lanham Andrew Rawlings Marta Roldo Gianluca Tozzi Jonathan I.Dawson Gianluca Cidonio Richard O.C.Oreffo Faculty of Medicine Bone and Joint Research GroupCentre for Human DevelopmentStem Cells and RegenerationInstitute of Developmental SciencesUniversity of SouthamptonSouthampton SO166YDUK school of pharmacy and biomedical science University of PortsmouthPortsmouth PO12DTUK school of Engineering Faculty of Engineering and ScienceUniversity of GreenwichGreenwich ME44TBUK Center for Life Nano-and Neuro-science(CLN2S) Italian Institute of Technology00161 RomeItaly

Autograft or metal implants are routinely used in skeletal repair.However,they fail to provide long-term clinical resolution,necessitating a functional biomimetic tissue engineering alternative.The use of native human bone tissue for synthesizing a biomimeticmaterial inkfor three-dimensional(3D)bioprintingof skeletal tissueis anattractivestrategyfor tissueregeneration.Thus,human bone extracellular matrix(bone-ECM)offers an exciting potential for the development of an appropriate microenvironment for human bone marrow stromal cells(HBMSCs)to proliferate and differentiate along the osteogenic lineage.In this study,we engineered a novel material ink(LAB)by blending human bone-ECM(B)with nanoclay(L,Laponite®)and alginate(A)polymers using extrusion-based deposition.The inclusion of the nanoﬁller and polymeric material increased the rheology,printability,and drug retention properties and,critically,the preservation of HBMSCs viability upon printing.The composite of human bone-ECM-based 3D constructs containing vascular endothelial growth factor(VEGF)enhanced vascularization after implantation in an ex vivo chick chorioallantoic membrane(CAM)model.The inclusion of bone morphogenetic protein-2(BMP-2)with the HBMSCs further enhanced vascularization and mineralization after only seven days.This study demonstrates the synergistic combination of nanoclay with biomimetic materials(alginate and bone-ECM)to support the formation of osteogenic tissue both in vitro and ex vivo and offers a promising novel 3D bioprinting approach to personalized skeletal tissue repair.

关键词： Extracellular matrix Nanoclay Bone 3D bioprinting

Photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes to promote PD-L1 multivalent binding for effective immune checkpoint blockade therapy

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1428-1440页

作者： Youngjoo Lee Sukyung Song Suah Yang Jinseong Kim Yujeong Moon Nayeon Shim Hong Yeol Yoon Sehoon Kim Man Kyu Shim Kwangmeyung Kim KU-KIST Graduate school of Converging science and Technology Korea UniversitySeoul 02841Republic of Korea Medicinal Materials Research Center Biomedical Research DivisionKorea Institute of Science and Technology(KIST)Seoul 02792Republic of Korea College of pharmacy Graduate School of Pharmaceutical SciencesEwha Womans UniversitySeoul 03760Republic of Korea Department of Bioengineering Korea UniversitySeoul 02841Republic of Korea

Immune checkpoint blockade(ICB)therapy targeting PD-L1 via monoclonal antibody(m Ab)has shown extensive clinical benefits in the diverse types of advanced malignancies.However,most patients are completely refractory to ICB therapy owing to the PD-L1 recycling mechanism.Herein,we propose photo-induced crosslinked and anti-PD-L1 peptide incorporated liposomes(immune checkpoint blockade liposomes;ICB-LPs)to promote PD-L1 multivalent binding for inducing lysosomal degradation of PD-L1 in tumor cells.The ICB-LPs are prepared by formulation of DC_(8,9)PC with photo-polymerized diacetylenic moiety,1,2-dipalmitoylphosphatidylcholine(DPPC)and anti-PD-L1peptide(D-form NYSKPTDRQYHF)-conjugated DSPE-PEG_(2k)(anti-PD-L1-DSPE-PEG_(2k))in a molar ratio of 45:45:10,followed by cross-linking of liposomal bilayer upon UV irradiation.The 10 mol% antiPD-L1-DSPE-PEG_(2k)incorporated ICB-LPs have a nano-sized lipid bilayer structure with an average diameter of 137.7±1.04 nm,showing a high stability in serum condition.Importantly,the ICB-LPs efficiently promote the multivalent binding with PD-L1 on the tumor cell membrane,which are endocytosed with aim to deliver PD-L1 to the lysosomes,wherein the durable PD-L1 degradation is observed for72 h,in contrast to anti PD-L1 m Abs showing the rapid PD-L1 recycling within 9 h.The in vitro coculture experiments with CD8^(+)T cells show that ICB-LPs effectively enhance the T cell-mediated antitumor immune responses against tumor cells by blocking the PD-L1/PD-1 axis.When ICB-LPs are intravenously injected into colon tumor-bearing mice,they efficiently accumulate within the targeted tumor tissues via both passive and active tumor targeting,inducing a potent T cell-mediated antitumor immune response by effective and durable PD-L1 degradation.Collectively,this study demonstrates the superior antitumor efficacy of crosslinked and anti-PD-L1 peptide incorporated liposome formulation that promotes PD-L1 multivalent binding for trafficking of PD-L1 toward the lysosomes instead of the recycling endosome

关键词： Cancer immunotherapy Immune checkpoint blockade PEGylated liposome Crosslinked lipid nanoparticles Anti-PD-L1 peptide Tumor-targeting PD-L1 multivalent binding Lysosomal PD-L1 degradation

Preparation of baicalin colon-targeted granules and its intervention effect on ulcerative colitis in rats

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Particuology 2024年第2期85卷 13-21页

作者： Yongqing Huang Yuxin Zhou Yao Shen Jin Wang Liangliang Zhou Zhenhua Chen Jiangxi Provincial Key Laboratory of Drug Design and Evaluation School of PharmacyJiangxi Science and Technology Normal UniversityNanchang330013China

Baicalin(BA)is a flavonoid extracted from the dried root of Scutellaria baicalensis Georgi with excellent antioxidant and anti-inflammatory biological activities.In this study,Eudragit S100 was used as the colonic target material to prepare BA colonic targeting granules(EBCGs)based on plasticizer dry powder coating technology to improve the targeting transportation performance of BA.In vitro studies showed that EBCGs with pH-sensitive properties were successfully prepared by plasticizer dry powder coating,and in vivo animal imaging studies showed that EBCGs could deliver BA to the colon and inhibit the release of BA in the upper gastrointestinal tract(GIT).In vivo studies showed that EBCGs had good therapeutic effects in colitis,which reduced expression levels of tumor necrosis factor alpha(TNF-α)and interleukin-1β(IL-1β)and increased superoxide dismutase(SOD)activities in the colonic tissues of rats with colitis.In conclusion,Eudragit S100 could be used for the preparation of multi-unit oral colon-targeted formulations by plasticizer dry powder coating technology,and our prepared EBCGs had good colon-targeting properties,which could improve the therapeutic effect and provide a potential application for ulcerative colitis(UC).

关键词： Plasticizer dry powder coating Colon-targeted granulesIn vivo imaging Ulcerative colitis

Remodeling the tumor microenvironment by vascular normalization and GSH-depletion for augmenting tumor immunotherapy

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Chinese Chemical Letters 2024年第2期35卷 329-334页

作者： Jin Wang Qingqing Zhang Yanchen Li Xiaoyan Pan Yuanyuan Shan Jie Zhang school of pharmacy Health Science CenterXi'an Jiaotong UniversityXi'an 710061China Department of pharmacy The First Affiliated Hospital of Xi'an Jiaotong UniversityXi'an 710061China

Remodeling tumor microenvironment(TME)is a very promising and effective strategy to enhance the effects of chemotherapy,photodynamic therapy,and immunotherapy.Normalization of tumor vasculature as well as depletion of glutathione(GSH)can improve the TME.Here,we developed a novel therapeutic nanoparticle functional enzyme ultra QDAU5 nanoparticles(FEUQ Nps)based on a fluorescence-on and releasable strategy by combining a vascular normalization inducer,a GSH depleting agent,and an activated fluorophore.In which the cleavage of disulfide bonds releases active molecules that induce vascular normalization and improve the hypoxic microenvironment.In addition,it may deplete GSH in cancer cells,thus inducing the production of reactive oxygen species(ROS)and lipid peroxide(LPO)and promoting iron toxicity.It may also lead to endoplasmic stress and release of calmodulin,which activates the immune system.Meanwhile,quenched fluorophores are turned on in the presence of galactosidase(GLU)for tumor-specific labeling.In summary,we developed novel therapeutic agent nanoparticles with the function of vascular normalization inducers to achieve specific labeling of hepatocellular carcinoma while exerting efficient antitumor effects in vivo.

关键词： Vascular normalization Tumor microenvironment GSH depletion Ferroptosis Activated immune

Radiation-based immunogenic vaccine combined with a macrophage“checkpoint inhibitor”for boosting innate and adaptive immunity against metastatic colon cancers

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Acta Pharmaceutica Sinica B 2024年第5期14卷 2247-2262页

作者： Hongbo Xu Xianya Qin Yuanyuan Guo Siyu Zhao Xingxing Feng Runzan Zhang Tianyi Tian Li Kong Conglian Yang Zhiping Zhang Tongji school of pharmacy Huazhong University of Science and TechnologyWuhan 430030China Hubei Engineering Research Center for Novel Drug Delivery System Wuhan 430030China Wuhan Liyuan Hospital of Tongji school of pharmacy Huazhong University of Science and TechnologyWuhan 430077China

Immunogenic dying tumor cells hold promising prospects as cancer vaccines to activate systemic immunity against both primary and metastatic tumors.Especially,X-ray-induced dying tumor cells are rich in highly immunogenic tumor-associated antigens and self-generated dsDNA as potent adjuvants.However,we found that the X-ray induction process can result in the excessive exposure of phosphatidylserine in cancer vaccines,which can specifically bind with the MerTK receptor on macrophages,acting as a“checkpoint”to facilitate immune silence in the tumor microenvironment.Therefore,we developed a novel strategy combining X-ray-induced cancer vaccines with UNC2250,a macrophage MerTK“checkpoint inhibitor,”for treating peritoneal carcinomatosis in colon cancer.By incorporating UNC2250 into the treatment regimen,immunosuppressive efferocytosis of macrophages,which relies on MerTK-directed recognition of phosphatidylserine on vaccines,was effectively blocked.Consequently,the immune analysis revealed that this combination strategy promoted the maturation of dendritic cells and M1-like repolarization of macrophages,thereby simultaneously eliciting robust adaptive and innate immunity.This innovative approach utilizing X-ray-induced vaccines combined with a checkpoint inhibitor may provide valuable insights for developing effective cancer vaccines and immunotherapies targeting colon cancer.

关键词： Immunogenic cell death Cancer vaccine X-ray Efferocytosis Macrophage STING Adaptive immunity Innate immunity