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MOF-based magnetic microrobot swarms for pH-responsive targeted drug delivery

Science China Chemistry 2024年第4期67卷 1216-1223页

作者： Qinyi Cao Yifan Zhang Yanping Tang Changjin Wu Jizhuang Wang Dan Li College of Chemistry and Materials Science Jinan UniversityGuangzhou 510632China Guangdong Provincial Key laboratory of Functional Supramolecular Coordination Materials and Applications Jinan UniversityGuangzhou 510632China Guangdong Provincial Key laboratory of Spine and Spinal Cord Reconstruction The Fifth Affiliated Hospital(Heyuan Shenhe People’s Hospital)Jinan UniversityHeyuan 517000China jnu-hkust joint laboratory for neuroscience and innovative drug research College of PharmacyJinan UniversityGuangzhou 510632China Department of Chemistry The University of Hong KongHong KongChina

Metal-organic frameworks(MOFs)hold significant potential as vehicles for drug delivery due to their expansive specific surface area,biocompatibility,and versatile attributes.Concurrently,magnetically actuated micro/nano-robots(MNRs)offer distinct advantages,such as untethered and precise manipulation.The fusion of these technologies presents a promising avenue for achieving non-invasive targeted drug delivery.Here,we report a MOF-based magnetic microrobot swarm(MMRS)for targeted therapy.Our approach overcomes limitations associated with a single MNR,including limited drug loading and the risk of loss during manipulation.We select Zeolitic Imidazolate Framework-8(ZIF-8)as the drug vehicle for its superior loading potential and p H-sensitive decomposition.Our design incorporates magnetic responsive components into the one-pot synthesis of Fe@ZIF-8,enabling collective behaviors under actuation.Tuning the yaw angle of alternating magnetic fields and nanoparticles'amount,the MMRSs with controllable size achieve instantaneous transformation among different configurations,including vortex-like swarms,chain-like swarms,and elliptical swarms,facilitating adaptation to environmental variations.Transported to the subcutaneous T24 tumor site,the MMRSs with encapsulated doxorubicin(DOX)automatically degrade and release the drug,leading to a dramatic reduction of the tumor in vivo.Our investigation signifies a significant advancement in the integration of biodegradable MOFs into microrobot swarms,ushering in new avenues for accurate and non-invasive targeted drug delivery.

关键词： magnetic microrobot swarm MOF nanoparticles magnetic propulsion pH-responsive drug release targeted drug delivery

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Targeting calcium signaling in Alzheimer’s disease: challenges and promising therapeutic avenues

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Neural Regeneration research 2024年第3期19卷 501-502页

作者： LinLin Song YongPei Tang Betty Yuen Kwan Law Neher’s Biophysics laboratory for innovative drug Discovery State Key Laboratory of Quality Research in Chinese MedicineMacao University of Science and TechnologyMacao Special Administration RegionChina

The critical role of calcium dyshomeostasis in the pathogenesis of Alzheimer’s disease(AD):AD is a progressive neurodegenerative disease characterized by cognitive decline,memory impairment,and behavioral changes.With an estimated 50 million people being affected worldwide,the incidence of AD is constantly increasing globally.The hallmark of AD is the accumulation of amyloid-beta protein(Aβ)in the form of amyloid plaques and hyperphosphorylated tau protein in the form of neurofibrillary tangles.However,increasing evidence suggests that calcium ion(Ca2+)dysregulation also plays a crucial role in the pathogenesis of AD(Calvo-Rodriguez and Bacskai,2021).As a key second messenger,Ca2+regulates a wide range of cellular processes,including the release of neurotransmitters,gene expression,and cell death.Ca^(2+)also regulates the activity of Calcium/calmodulin-dependent protein kinase II,which is critical for synaptic plasticity,learning,and memory(Kaushik et al.,2022).Alternation in the Ca^(2+)signal is an early event in the pathogenesis of AD,which can lead to synaptic dysfunction,neuronal loss,and cognitive impairment.

关键词： Alzheimer homeostasis globally

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Investigating epithelial-neuronal signaling contribution in visceral pain through colon organoid-dorsal root ganglion neuron co-cultures

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Neural Regeneration research 2024年第6期19卷 1199-1200页

作者： Francesco Margiotia Lorenzo Di Cesare Mannelli Antonino Morabito Carla Ghelardini Elena Lucarini Department of neuroscience Psychology Drug Research and Child Health-NEUROFARBA-Pharmacology and Toxicology Section University of Florence Department of neuroscience Psychology Drug Research and Child Health-NEUROFARBA University of Florence 3. Meyer Children's Hospital IRCCS

Abdominal pain is a common symptom associated with irritable bowel syndrome and inflammatory bowel diseases(IBDs), affecting about 20% of the global population(Grundy et al., 2019). Current pain therapies are poorly effective on visceral pain of intestinal origin and present several side effects, hence the need to identify novel molecular and cellular targets for drug development. The pathophysiology of visceral-abdominal pain,

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Fine-tuning the activation behaviors of ternary modular cabazitaxel prodrugs for efficient and on-target oral anti-cancer therapy

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Asian Journal of Pharmaceutical Sciences 2024年第2期19卷 188-203页

作者： Mingyang Zhang Yifan Miao Can Zhao Tong Liu Xiyan Wang Zixuan Wang Wenxin Zhong Zhonggui He Chutong Tian Jin Sun Department of Pharmaceutics Wuya College of InnovationShenyang Pharmaceutical UniversityShenyang 110016China Key laboratory of Advanced drug Delivery Systems of Zhejiang Province Hangzhou 310058China joint International research laboratory of Intelligent drug Delivery Systems Ministry of EducationShenyang 110016China Liaoning Provincial Institute of drug Inspection and Testing Shenyang 110036China

The disulfide bond plays a crucial role in the design of anti-tumor prodrugs due to its exceptional tumor-specific redox responsiveness. However, premature breaking of disulfide bonds is triggered by small amounts of reducing substances (e.g., ascorbic acid, glutathione, uric acid and tea polyphenols) in the systemic circulation. This may lead to toxicity, particularly in oral prodrugs that require more frequent and high-dose treatments. Fine-tuning the activation kinetics of these prodrugs is a promising prospect for more efficient on-target cancer therapies. In this study, disulfide, steric disulfide, and ester bonds were used to bridge cabazitaxel (CTX) to an intestinal lymph vessel-directed triglyceride (TG) module. Then, synthetic prodrugs were efficiently incorporated into self-nanoemulsifying drug delivery system (corn oil and Maisine CC were used as the oil phase and Cremophor EL as the surfactant). All three prodrugs had excellent gastric stability and intestinal permeability. The oral bioavailability of the disulfide bond-based prodrugs (CTX-(C)S-(C)S-TG and CTX-S-S-TG) was 11.5- and 19.1-fold higher than that of the CTX solution, respectively, demonstrating good oral delivery efficiency. However, the excessive reduction sensitivity of the disulfide bond resulted in lower plasma stability and safety of CTX-S-S-TG than that of CTX-(C)S-(C)S-TG. Moreover, introducing steric hindrance into disulfide bonds could also modulate drug release and cytotoxicity, significantly improving the anti-tumor activity even compared to that of intravenous CTX solution at half dosage while minimizing off-target adverse effects. Our findings provide insights into the design and fine-tuning of different disulfide bond-based linkers, which may help identify oral prodrugs with more potent therapeutic efficacy and safety for cancer therapy.

关键词： Steric disulfide bond Triglyceride-like pr odrugs Cabazitaxel Lymphatic transport Oral chemotherapy

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Phase separation of Nur77 mediates XS561-induced apoptosis by promoting the formation of Nur77/Bcl-2 condensates

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1204-1221页

作者： Xiaohui Chen Meichun Gao Yongzhen Xia Xin Wang Jingbo Qin Hongying He Weirong Liu Xiaowei Zhang Shuangzhou Peng Zhiping Zeng Ying Su Xiaokun Zhang School of Pharmaceutical Science Fujian Provincial Key Laboratory of Innovative Drug Target ResearchXiamen UniversityXiamen 361002China NucMito Pharmaceuticals Co. Ltd.Xiamen 361000China Department of Clinical laboratory the Fifth Affiliated Hospital of Sun Yat-sen UniversityZhuhai 519000China

The orphan nuclear receptor Nur77 is a critical regulator of the survival and death of tumor cells.The pro-death effect of Nur77 can be regulated by its interaction with Bcl-2,resulting in conversion of Bcl-2 from a survival to killer.As Bcl-2 is overexpressed in various cancers preventing them from apoptosis and promoting their resistance to chemotherapy,targeting the apoptotic pathway of Nur77/Bcl-2 may lead to new cancer therapeutics.Here,we report our identification of XS561 as a novel Nur77 ligand that induces apoptosis of tumor cells by activating the Nur77/Bcl-2 pathway.In vitro and animal studies revealed an apoptotic effect of XS561 in a range of tumor cell lines including MDA-MB-231 triple-negative breast cancer(TNBC)and MCF-7/LCC2 tamoxifen-resistant breast cancer(TAMR)in a Nur77-dependent manner.Mechanistic studies showed XS561 potently induced the translocation of Nur77 from the nucleus to mitochondria,resulting in mitochondria-related apoptosis.Interestingly,XS561-induced accumulation of Nur77 at mitochondria was associated with XS561 induction of Nur77 phase separation and the formation of Nur77/Bcl-2 condensates.Together,our studies identify XS561 as a new activator of the Nur77/Bcl-2 apoptotic pathway and reveal a role of phase separation in mediating the apoptotic effect of Nur77 at mitochondria.

关键词： XS561 Nur77 Bcl-2 Apoptosis Mitochondria Phase separation TNBC TAMR

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Adenosine A_(2A)receptor blockade attenuates excitotoxicity in rat striatal medium spiny neurons during an ischemic-like insult

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Neural Regeneration research 2024年第2期19卷 255-257页

作者： Elisabetta Coppi Federica Cherchi Alasdair J.Gibb Department of neuroscience PsychologyDrug Research and Child HealthUniversity of FlorenceFlorenceItaly Department of neuroscience Physiology and PharmacologyUniversity College LondonLondonUK

During brain ischemia,excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage.Indeed,anoxic depolarization,consisting of massive neuronal depolarization due to the loss of membrane ion gradients,occurs in vivo or in vitro during an energy failure.The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors,namely:A_(1),A_(2A),A_(2B),and A_(3).The A_(2A)receptor subtype is highly expressed in striatal medium spiny neurons,which are particularly susceptible to ischemic damage.Evidence indicates that the A2Areceptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours.We recently added new knowledge to the mechanisms by which the adenosine A2Areceptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation.We demonstrated that the selective block of A2Areceptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K+channel modulation and a presynaptic inhibition of glutamate release by the A2Areceptor antagonist.The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A2Areceptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.

关键词： adenosine A_(2A)receptors anoxic depolarization brain ischemia glutamate excitotoxicity medium spiny neurons oxygen and glucose deprivation

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Organic thin-film transistors and related devices in life and health monitoring

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Nano research 2024年第2期17卷 426-444页

作者： Chenfang Sun Tie Wang Tianjin Key laboratory of drug Targeting and Bioimaging Life and Health Intelligent Research InstituteTianjin University of TechnologyTianjin 300384China

The early determination of disease-related biomarkers can significantly improve the survival rate of patients.Thus,a series of explorations for new diagnosis technologies,such as optical and electrochemical methods,have been devoted to life and health monitoring.Organic thin-film transistor(OTFT),as a state-of-the-art nano-sensing technology,has attracted significant attention from construction to application owing to the merits of being label-free,low-cost,facial,and rapid detection with multi-parameter responses.Nevertheless,interference from non-specific adsorption is inevitable in complex biological samples such as body liquid and exhaled gas,so the reliability and accuracy of the biosensor need to be further improved while ensuring sensitivity,selectivity,and stability.Herein,we overviewed the composition,mechanism,and construction strategies of OTFTs for the practical determination of disease-related biomarkers in both body fluids and exhaled gas.The results show that the realization of bio-inspired applications will come true with the rapid development of high-effective OTFTs and related devices.

关键词： organic thin-film transistors biosensors biomarkers organic bioelectronics organic semiconductors healthcare

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Palladium-catalyzed multi components oxy-aminofluorination and aminofluorination of gem-difluoroalkenes

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Chinese Chemical Letters 2024年第2期35卷 420-425页

作者： Fen Wu Xin Li Junbiao Chang Dachang Bai State Key laboratory of Antiviral drugs NMPA Key Laboratory for Research and Evaluation of Innovative DrugKey Laboratory of Green Chemical Media and ReactionsMinistry of EducationSchool of Chemistry and Chemical EngineeringPingyuan LaboratoryHenan Normal UniversityXinxiang 453007China State Key laboratory of Organometallic Chemistry Shanghai Institute of Organic ChemistryChinese Academy of SciencesShanghai 200032China

Organofluorine compounds are widely used in the realm of drug discovery and material science.Herein,we developed palladium catalyzed intermolecular aminofluorination and oxy-aminofluorination of gem‑difluoroalkenes with N-fluorobenzenesulfonimide(NFSI),in which NFSI was used as the nitrogen source and oxidant.The reaction provides an efficient and straightforward synthesis route of a series ofα-trifluoromethyl benzylic amines.Notably,three/four components oxy-aminofluorination processes were realized to giveα-trifluoromethyl benzylic ether with a terminal amino group,which proceed through C(sp^(3))-O bond cleavage of easily available ether and simultaneous introduced a fluorine,an amino and an oxy substituent in one pot with excellent regioselectivity.The divergent reactivity not only included the incorporation of one ether molecular,but also much more challenged two ether insertion with excellent selectivity through succession C(sp^(3))-O bonds cleavage.This protocol allows for concise synthesis of high value amines with fluoroalkyl-substituents and selectively transformation of easily available ethers by high-valent palladium catalysis.

关键词： Palladium Multi components Aminofluorination Oxy-aminofluorination C(sp^(3))-O bond cleavage

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Rhodium-catalyzed Doyle-Kirmse rearrangement reactions of sulfoxoniun ylides

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Chinese Chemical Letters 2024年第4期35卷 363-366页

作者： Ying-Di Hao Zhi-Qian Lin Xiao-Yu Guo Jiao Liang Can-Kun Luo Qian-Tao Wang Li Guo Yong Wu Key laboratory of drug-Targeting and drug Delivery System of the Education Ministry and Department of Medicinal Chemistry Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial TechnologyWest China School of PharmacySichuan UniversityChengdu 610041China

Doyle-Kirmse rearrangement reactions have received continuous attention as an important method for constructing complex chemical structures. Herein, we disclosed an efficient rhodium-catalyzed DoyleKirmse rearrangement reaction, which can simultaneously construct C–C bonds and C–X(X = S/Se) bonds using sulfoxonium ylides as starting materials to obtain sulfur-or selenium-containing compounds. This strategy is characterized by the safer and greener carbene precursor, high yields and broad substrate scope, possessing a wide range of application.

关键词： Sulfoxonium ylides Rhodium(Ⅱ)-catalyzed Carbene Rearrangement reactions One-pot process

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Glucagon-like peptide 1 receptor activation:anti-inflammatory effects in the brain

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Neural Regeneration research 2024年第8期19卷 1671-1677页

作者： Yolanda Diz-Chaves Zainab Maastor Carlos Spuch José Antonio Lamas Lucas C.González-Matías Federico Mallo Biomedical research Centre(CINBIO) Laboratory of EndocrinologyUniversity of VigoGalicia Sur Health Research InstituteVigoSpain Translational neuroscience research Group Galicia Sur Health Research InstituteCIBERSAMHospitalÁlvaro CunqueiroSala InvestigaciónEstrada Clara CampoamorVigoSpain Biomedical research Centre(CINBIO) Laboratory of NeuroscienceUniversity of VigoGalicia Sur Health Research InstituteVigoSpain

The glucagon-like peptide 1 is a pleiotropic hormone that has potent insulinotropic effects and is key in treating metabolic diseases such as diabetes and obesity.Glucagon-like peptide 1 exerts its effects by activating a membrane receptor identified in many tissues,including diffe rent brain regions.Glucagon-like peptide 1 activates several signaling pathways related to neuroprotection,like the support of cell growth/survival,enhancement promotion of synapse formation,autophagy,and inhibition of the secretion of proinflammatory cytokines,microglial activation,and apoptosis during neural morphogenesis.The glial cells,including astrocytes and microglia,maintain metabolic homeostasis and defe nse against pathogens in the central nervous system.After brain insult,microglia are the first cells to respond,followed by reactive astrocytosis.These activated cells produce proinflammato ry mediators like cytokines or chemokines to react to the insult.Furthermore,under these circumstances,mic roglia can become chro nically inflammatory by losing their homeostatic molecular signature and,consequently,their functions during many diseases.Several processes promote the development of neurological disorders and influence their pathological evolution:like the formation of protein aggregates,the accumulation of abnormally modified cellular constituents,the formation and release by injured neurons or synapses of molecules that can dampen neural function,and,of critical impo rtance,the dysregulation of inflammato ry control mechanisms.The glucagonlike peptide 1 receptor agonist emerges as a critical tool in treating brain-related inflammatory pathologies,restoring brain cell homeostasis under inflammatory conditions,modulating mic roglia activity,and decreasing the inflammato ry response.This review summarizes recent advances linked to the anti-inflammato ry prope rties of glucagon-like peptide 1 receptor activation in the brain related to multiple sclerosis,Alzheimer’s disease,Parkinson’s disease,vascular dementia,or chronic migrai

关键词： astrocytes brain glucagon-like peptide 1 receptor inflammation microglia

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