Acta Pharmaceutica Sinica B
·
2014
·
IF 0
Meihong Huang,Jiaqi Song,Bingzheng Lu,Huizhi Huang,Yizhen Chen,Wei Yin,Wenbo Zhu,Xinwen Su,Chuanbin Wu,Haiyan Hu
In this work, retinal penetration of fluorescein was achieved in vitro by covalent attachment of taurine to fluorescein, yielding the F–Tau conjugate. Nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HRMS) were used to confirm the successful synthesis of F–Tau. The cellular uptake of F–Tau in adult retinal pigment epithelial cells (ARPE-19) and human retinal microvascular endothelial cells (hRMECs) was visualized via confocal scanning microscopy. The results indicated an improvement of solubility and a reduction of log P of F–Tau compared with fluorescein. As compared with fluorescein, F–Tau showed little toxicity, and was retained longer by cells in uptake experiments. F–Tau also displayed higher transepithelial permeabilities than fluorescein in ARPE-19 and hRMECs monolayer cells ( P <0.05). These results showed that taurine may be a useful ligand for targeting small-molecule hydrophobic pharmaceuticals into the retina.
研究领域:
药理学
·
生物化学
·
眼科学
✓ 已验证
DOI
PubMed
JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 6.8
Ting Xu,Zihan Xue,Xinhui Li,Miaomiao Zhang,Ruige Yang,Shangshang Qin,Yong Guo
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital- and community-acquired infections, necessitating the development of novel antibacterials. Here, we designed and synthesized 30 osthole derivatives with pyridinium quaternary ammonium moieties. In vitro bioassay showed that compounds 8u and 8ac exhibited potent antibacterial activity against S. aureus ATCC 29213 and ten clinical MRSA isolates (MIC = 0.5–1 μg/mL), with low hemolytic activity, rapid bactericidal effects, and minimal resistance induction. In MRSA-infected mouse models of skin abscesses and sepsis, 8u and 8ac also displayed excellent antibacterial effects and safety, which were comparable to vancomycin. Mechanistic studies revealed that 8u and 8ac selectively target bacterial membranes via binding to phosphatidylglycerol (PG), increasing intracellular reactive oxygen species (ROS), inducing content leakage, and ultimately causing bacterial death. These findings suggest 8u and 8ac as promising novel lead candidates for anti-MRSA drug development.
研究领域:
药理学
·
微生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2019
·Vol. 9
·期 1
·1901100
·
IF 6.27
Wen Ma,Sui-Nan Sha,Pei-Ling Chen,Meng Yu,Jian-Jun Chen,Chao-Bo Huang,Bin Yu,Yun Liu,Li-Han Liu,Zhi-Qiang Yu
Nowadays, cell membrane-targeted therapy, which owns high antitumor efficacy by avoiding cell barriers, has received great attention. Here, a cell membrane-targeted self-delivery theranostic chimeric peptide CMP-PpIX is designed for simultaneously targeted photodynamic therapy (PDT) of tumor and real-time therapeutic feedback. Self-assembled CMP-PpIX nanoparticles can effectively accumulate in tumor by enhanced permeability and retention effect without additional vector. And this chimeric peptide CMP-PpIX has low background fluorescence, which is due to its relatively high intramolecular Förster resonance energy transfer (FRET) quenching efficiency between 5(6)-carboxyfluorescein (FAM) and 4-(dimethylaminoazo)-benzene-4-carboxylic acid (Dabcyl). More importantly, CMP-PpIX can be anchored on the tumor cell membrane for more than 8 h. Under irradiation, reactive oxygen species produced by CMP-PpIX directly damage cell membrane and rapidly induce apoptosis, which significantly improve the efficacy of PDT in vitro and in vivo. Then, peptide sequence Asp-Glu-Val-Asp (DEVD) is subsequently cleaved by activated caspase-3 and activated caspase-7, which separates the FAM and Dabcyl and terminates the FRET process. Therefore, fluorescence of FAM is recovered to monitor the expression of activated caspase-3 in vitro and in vivo to feedback real-time PDT therapeutic efficacy. In general, a novel cell membrane-targeted self-delivery theranostic chimeric peptide offers new promise for effective imaging-guided PDT.
研究领域:
肿瘤学
·
生物医学工程
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Communications Biology
·
2023
·Vol. 6
·期 1
·1-14
·
IF 5.9
Tang Ziyi,Jiang Wuqiao,Li Shuangli,Huang Xue,Yang Yi,Chen Xiaorong,Qiu Jingyi,Xiao Chuyu,Xie Ying,Zhang Xu,Li Jianguo,Verma Chandra Shekhar,He Yun,Yang Aimin
Antimicrobial peptides are promising alternatives to conventional antibiotics. Herein, we report a class of “tadpole-like” peptides consisting of an amphipathic α-helical head and an aromatic tail. A structure-activity relationship (SAR) study of “tadpole-like” temporin-SHf and its analogs revealed that increasing the number of aromatic residues in the tail, introducing Arg to the α-helical head and rearranging the peptide topology dramatically increased antimicrobial activity. Through progressive structural optimization, we obtained two peptides, HT2 and RI-HT2, which exhibited potent antimicrobial activity, no hemolytic activity and cytotoxicity, and no propensity to induce resistance. NMR and molecular dynamics simulations revealed that both peptides indeed adopted “tadpole-like” conformations. Fluorescence experiments and electron microscopy confirmed the membrane targeting mechanisms of the peptides. Our studies not only lead to the discovery of a series of ultrashort peptides with potent broad-spectrum antimicrobial activities, but also provide a new strategy for rational design of novel “tadpole-like” antimicrobial peptides.
研究领域:
生物化学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
BIOMATERIALS
·
2019
·
IF 10.273
Hong Cheng,Gui-Ling Fan,Jing-Hao Fan,Ping Yuan,Fu-An Deng,Xiao-Zhong Qiu,Xi-Yong Yu,Shi-Ying Li
In recent years, epigenetics has attracted great attentions in the field of biomedicine , which is used to denote the heritable changes in gene expression without any variation in DNA sequence , including DNA methylation , histone modification and so on. Inspired by it, a simple and versatile amino acids modification strategy is proposed in this paper to regulate the subcellular distribution of photosensitizer for plasma membrane targeted photodynamic therapy (PDT). Particularly, the plasma membrane anchoring ability and photo toxicity of the photosensitizer against different cell lines could be effectively manipulated at a single amino acid level. Systematic researches indicate that the number and variety of amino acids have a significant influence on the plasma membrane targeting effect of the photosensitizer. Furthermore, after self-assembling into nanoparticles , the obtained nano photosensitizers (NPs) also exhibit a good biocompatibility and plasma membrane targeting ability, which are conducive to enhancing the PDT therapeutic effect under light irradiation. Both in vitro and in vivo investigations confirm a robust tumor inhibition effect of NPs with a good biocompatibility. This epigenetics-inspired photosensitizer modification strategy would contribute to the development of structure-based drug design for tumor precision therapy.
研究领域:
生物医学
·
药物设计
·
肿瘤学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Ting Xu,Xiaoting Yan,Ayue Kang,Longhua Yang,Xinhui Li,Yue Tian,Ruige Yang,Shangshang Qin,Yong Guo
The escalation of multidrug-resistant bacterial infections, especially infections caused by methicillin-resistant Staphylococcus aureus (MRSA), underscores the urgent need for novel antimicrobial drugs. Here, we synthesized a series of amphiphilic 2-phenyl-1H-phenanthro[9,10-d]imidazole-antimicrobial peptide (AMP) mimic conjugates (III1–30). Among them, compound III13 exhibited excellent antibacterial activity against G+ bacteria and clinical MRSA isolates (MIC = 0.5–2 μg/mL), high membrane selectivity, and low toxicity. Additionally, compared with traditional clinical antibiotics, III13 demonstrated rapid bactericidal efficacy and was less susceptible to causing bacterial resistance. Mechanistic studies revealed that III13 targets phosphatidylglycerol (PG) on bacterial membranes to disrupt membrane integrity, leading to an increase in intracellular ROS and leakage of proteins and DNA, ultimately causing bacterial cell death. Furthermore, III13 possessed good fluorescence properties with potential for further dynamic monitoring of the antimicrobial process. Notably, III13 showed better in vivo efficacy against MRSA compared to vancomycin, suggesting its potential as a promising candidate for anti-MRSA medication.
研究领域:
微生物学
·
药物化学
·
感染病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ADVANCED FUNCTIONAL MATERIALS
·
2017
·Vol. 27
·期 25
·1700220
·
IF 12.124
Li-Han Liu,Wen-Xiu Qiu,Yao-Hui Zhang,Bin Li,Chi Zhang,Fan Gao,Lu Zhang,Xian-Zheng Zhang
The cell membrane is the most important protective barrier in living cells and cell membrane targeted therapy may be a high-performance therapeutic modality for tumor treatment. Here, a novel charge reversible self-delivery chimeric peptide C 16 –PRP–DMA is developed for long-term cell membrane targeted photodynamic therapy (PDT). The self-assembled C 16 –PRP–DMA nanoparticles can effectively target to tumor by enhanced permeability and retention effect without additional carriers. After undergoing charge reverse in acidic tumor microenvironment, C 16 –PRP–DMA inserts into the tumor cell membrane with a long retention time of more than 14 h, which is very helpful for in vivo applications. It is found that under light irradiation, the reactive oxygen species generated by the inserted C 16 –PRP–DMA would directly disrupt cell membrane and rapidly induce cell necrosis, which remarkably increases the PDT effect in vitro and in vivo. This novel self-delivery chimeric peptide with a long-term cell membrane targeting property provides a new prospect for effective PDT of cancer.
研究领域:
癌症研究
·
药学
·
生物技术
·
纳米医学
✓ 已验证
产品关联
DOI
高影响因子
Applied Materials Today
·
2019
·
IF 8.013
Hong Cheng,Ping Yuan,Guiling Fan,Linping Zhao,Rongrong Zheng,Bin Yang,Xiaozhong Qiu,Xiyong Yu,Shiying Li,Xianzheng Zhang
Tumor therapeutic efficiency is largely determined by the delivery efficacy of therapeutic agent to its final target, especially for photodynamic therapy (PDT). Although plasma membrane or nuclear targeted photosensitizer delivery is considered to be a promising strategy for enhanced photodynamic tumor therapy, they have been confronted with some difficulties and challenges. In this work, the self-delivery chimeric peptide nanorods (denoted as pnPNP) are developed for plasma membrane and nucleus dual-targeted photosensitizer delivery to achieve the synergetic in situ PDT. In vitro investigations demonstrate that the dual-targeting capability benefits the efficient subcellular localization of pnPNP in plasma membrane and nucleus. Plasma membrane targeted PDT of pnPNP could improve the membrane permeability to enhance the cellular uptake, even trigger the membrane disruption and cause cell necrosis directly. Upon light irradiation, the internalized pnPNP could effectively disrupt lysosomal structures and realize the nuclear permeation for supplementary nuclear targeted PDT. Abundant experiments verify that the plasma membrane and nucleus dual-targeted PDT exhibit a far better anti-tumor effect than the single nuclear targeted PDT. This synergistic subcellular dual-targeting strategy maximizes the PDT therapeutic efficacy, which also provides a new insight for the development of advanced drug delivery systems.
研究领域:
生物医学工程
·
纳米医学
·
癌症治疗
·
分子生物学
✓ 已验证
产品关联
DOI
高影响因子
JOURNAL OF NANOSCIENCE AND NANOTECHNOLOGY
·
2018
·Vol. 18
·期 12
·8124-8132
·
IF 1.354
Fan Dongxiao,Yao Chen,Zhou Wenya,Li Xinsong
To develop new antimicrobial synthetic lipopeptides with optimizing peptide length, cationic tripeptides RWR/WRR were N-terminal fatty acylated, and self-assembled with 1-dodecanethiol-anchored gold nanoparticles (Au-DT NPs) via hydrophobic interaction. The ultrashort lipopeptides and
their nano-assemblies were effective against a variety of microorganisms, with minimal inhibitory concentrations ranging from 0.5 to 8 μg/mL. Hemolysis analysis and in vitro cytotoxicity assay revealed that self-assembling with Au-DT NPs would improve biological toxicity of
lipopeptides, especially for the most active lipopeptides (Palmitoyl-RWR, Palmitoyl-WRR) with long lipid tails. As lipopeptides/ Au-DT NPs displayed slower bactericidal kinetics compared with free lipopeptides, the mode of action was further investigated. Difference in membrane targeting mechanism
between lipopeptides and their nano-assemblies may be attributed to the structural architecture. The simple composition and diverse specificities of lipopeptides/Au-DT NPs, as well as their biocompatibility could make them as economically available potent antimicrobial agents for various applications.
研究领域:
纳米技术
·
生物医学工程
·
微生物学
·
药学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Advanced Science
·
2023
·
IF 15.1
Ming-Yu Wu,Xiaoyu Xu,Rui Hu,Qingrong Chen,Luojia Chen,Yuncong Yuan,Jie Li,Li Zhou,Shun Feng,Lianrong Wang,Shi Chen,Meijia Gu
Candida albicans ( C. albicans ), a ubiquitous polymorphic fungus in humans, causes different types of candidiasis, including oral candidiasis (OC) and vulvovaginal candidiasis (VVC), which are physically and mentally concerning and financially costly. Thus, developing alternative antifungals that prevent drug resistance and induce immunity to eliminate Candida biofilms is crucial. Herein, a novel membrane-targeted aggregation-induced emission (AIE) photosensitizer (PS), TBTCP-QY, is developed for highly efficient photodynamic therapy (PDT) of candidiasis. TBTCP-QY has a high molar absorption coefficient and an excellent ability to generate 1 O 2 and •OH, entering the interior of biofilms due to its high permeability. Furthermore, TBTCP-QY can efficiently inhibit biofilm formation by suppressing the expression of genes related to the adhesion ( ALS3 , EAP1 , and HWP1 ), invasion ( SAP1 and SAP2 ), and drug resistance ( MDR1 ) of C. albicans , which is also advantageous for eliminating potential fungal resistance to treat clinical infectious diseases. TBTCP-QY-mediated PDT efficiently targets OC and VVC in vivo in a mouse model, induces immune response, relieves inflammation, and accelerates the healing of mucosal defects to combat infections caused by clinically isolated fluconazole-resistant strains. Moreover, TBTCP-QY demonstrates excellent biocompatibility, suggesting its potential applications in the clinical treatment of OC and VVC.
研究领域:
微生物学
·
药理学
·
免疫学
·
传染病学
✓ 已验证
DOI
PubMed
高影响因子
ACS Nano
·
2019
·
IF 13.903
Chi Zhang,Fan Gao,Wei Wu,Wen-Xiu Qiu,Lu Zhang,Runqing Li,Ze-Nan Zhuang,Wuyang Yu,Han Cheng,Xian-Zheng Zhang
Here, a protein farnesyltransferase (PFTase)-driven plasma membrane (PM)-targeted chimeric peptide, PpIX-C6-PEG8-KKKKKKSKTKC-OMe (PCPK), was designed for PM-targeted photodynamic therapy (PM-PDT) and enhanced immunotherapy via tumor cell PM damage and fast release of damage-associated molecular patterns (DAMPs). The PM targeting ability of PCPK originates from the cellular K-Ras signaling, which occurs exclusively to drive the corresponding proteins to PM by PFTase. With the conjugation of the photosensitizer protoporphyrin IX (PpIX), PCPK could generate cytotoxic reactive oxygen species to deactivate membrane-associated proteins, initiate lipid peroxidation, and destroy PM with an extremely low concentration (1 μM) under light irradiation. The specific PM damage further induced the fast release of DAMPs (high-mobility group box 1 and ATP), resulting in antitumor immune responses stronger than those of conventional cytoplasm-localized PDT. This immune-stimulating PM-PDT strategy also exhibited the inhibition effect for distant metastatic tumors when combined with programmed cell death receptor 1 blockade therapy.
研究领域:
癌症生物学
·
药学
·
免疫学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2022
·
IF 16.744
Shanshan Tie,Wentao Su,Yannan Chen,Shida Wu,Hao Wu,Yukun Song,Siyuan Fei,Mingqian Tan
The purpose of this study is to design a cell membrane and mitochondrial targeting nanoparticle with glutathione stimulus response to deliver procyanidin for effective treatment of inflammatory bowel disease (IBD). The dual targeting procyanidin nanoparticles were prepared with amphiphilic stearic acid modified hyaluronic acid using cystamine dihydrochloride as a linker for encapsulation of (5-carboxypentyl) (triphenyl) phosphonium bromide conjugated procyanidins. As expected, the procyanidin nanoparticles showed good mitochondrial targeting ability, with a Pearson’s correlation coefficient of 0.91 at 4 h. In vivo imaging of IBD mice model demonstrated a remarkable colon accumulation of the targeting procyanidin nanoparticles. Significant glutathione stimulus release of procyanidin was found in the presence of 10 mM of glutathione at pH 7.4. In vivo experiments showed that the colon length of targeting procyanidin nanoparticle-treated IBD mice increased by 20.84% compared with the IBD mice. The weight loss, disease activity index score, oxidative stress level and the release of proinflammatory cytokines were significantly ameliorated. The composition and relative abundance of gut microbiota, and the number of short chain fatty acids were improved upon the uptake of targeting procyanidin nanoparticles. This study provided a dual targeting and glutathione response strategy to improve the bioavailability of procyanidin in IBD treatment.
研究领域:
纳米技术
·
药学
·
炎症
·
胃肠病学
·
生物医学工程
✓ 已验证
产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）