Triple-targeting nanosystems with synergistic effects on iron Trojan horse, fluoroquinolone antibiotics, and photodynamic therapy specifically kill intracellular MRSA.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Theranostics Pub Date : 2025-08-16 eCollection Date: 2025-01-01 DOI:10.7150/thno.109374
Kuiyu Meng, Liwen Yuan, Lulu Feng, Yaoyao Zhang, Hao Wu, Jie Zhang, Mubbashar Abbas, Wei Qu, Dongmei Chen, Shuyu Xie
{"title":"Triple-targeting nanosystems with synergistic effects on iron Trojan horse, fluoroquinolone antibiotics, and photodynamic therapy specifically kill intracellular MRSA.","authors":"Kuiyu Meng, Liwen Yuan, Lulu Feng, Yaoyao Zhang, Hao Wu, Jie Zhang, Mubbashar Abbas, Wei Qu, Dongmei Chen, Shuyu Xie","doi":"10.7150/thno.109374","DOIUrl":null,"url":null,"abstract":"<p><p><b>Rationale:</b> Iron is necessary for the survival of microorganisms. The uptake network is highly expressed by host cells and methicillin-resistant <i>Staphylococcus aureus</i> (MRSA) and competes with heme iron. Gallium porphyrin (GaPR), a heme mimetic compound, was synthesized to develop an innovative nanosystem as a triple-targeting agent for uptake network recognition. GaPR is also used as a dual therapeutic molecule of \"iron trojan horse\" and photosensitizer to achieve synergistic antibacterial effects with levofloxacin to eradicate intracellular MRSA-a problem that conventional therapeutic techniques cannot overcome due to limited drug penetration, antibiotic resistance, and off-target effects. <b>Methods:</b> A library of hemimetic compounds was synthesized. GaPR was selected as the optimal candidate owing to its antibacterial activities and competitive binding affinity for iron uptake receptors. The optimal GaPR and the photosensitizer tetrakis-(4-carboxyphenyl)-porphyrin (TCPP) were used to prepare a levofloxacin (Lev)-loaded zirconium-based organometallic scaffold (Lev-GaPR-PCN). Hyaluronic acid (HA) was linked to the Lev-GaPR-PCN surface via ROS-reactive thioketal bonds (TK). The triple-targeting performance and synergistic efficacy of HA-Lev-GaPR-PCN against intracellular MRSA were tested <i>in vitro</i> and <i>in vivo</i>. <b>Results:</b> GaPR showed strong bactericidal activity against MRSA by interfering with iron metabolism. GaPR-PCN exhibited excellent binding ability with host-derived heme-binding proteins (Hpx/LRP1 and Hpg/CD163) and the iron-regulated surface determinant (Isd) system of MRSA for infection site, infected cell, and intracellular targeting. HA coating enabled covert circulation and decreased nonspecific uptake by healthy cells (< 5% fluorescence intensity after 6 h) while promoting infection-induced release via hyaluronidase and ROS. <i>In vitro</i>, HA-Lev-GaPR-PCN achieved 3.42-fold greater colocalization with intracellular MRSA (Pearson correlation: 0.41 vs. 0.12 for PCN-224 controls) and decreased the extracellular/intracellular minimum inhibitory concentrations (MICs) of Lev under PDT from 8/64 μg/mL to 1/2 μg/mL. <i>In vivo</i>, it resulted in prolonged retention (72 h vs. 36 h) and a 1.5-2.5-fold greater fluorescence intensity at infection sites for non-HA nanosystems. Compared to Lev alone, it decreased the bacterial load by 501-fold (2.7 log) and abscesses (diameter: 0.6 cm vs. 3.3 cm) by combining chemical, metabolic, and physical antibacterial mechanisms without causing toxic effects. <b>Conclusion:</b> This study represents a paradigm shift in intracellular infection therapy for MRSA and other resistant bacteria using a hemimetic compound as a triple-targeting and dual therapeutic agent that provides a streamlined, clinically feasible solution with high efficacy and specificity.</p>","PeriodicalId":22932,"journal":{"name":"Theranostics","volume":"15 17","pages":"9326-9343"},"PeriodicalIF":13.3000,"publicationDate":"2025-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439474/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Theranostics","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.7150/thno.109374","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0

Abstract

Rationale: Iron is necessary for the survival of microorganisms. The uptake network is highly expressed by host cells and methicillin-resistant Staphylococcus aureus (MRSA) and competes with heme iron. Gallium porphyrin (GaPR), a heme mimetic compound, was synthesized to develop an innovative nanosystem as a triple-targeting agent for uptake network recognition. GaPR is also used as a dual therapeutic molecule of "iron trojan horse" and photosensitizer to achieve synergistic antibacterial effects with levofloxacin to eradicate intracellular MRSA-a problem that conventional therapeutic techniques cannot overcome due to limited drug penetration, antibiotic resistance, and off-target effects. Methods: A library of hemimetic compounds was synthesized. GaPR was selected as the optimal candidate owing to its antibacterial activities and competitive binding affinity for iron uptake receptors. The optimal GaPR and the photosensitizer tetrakis-(4-carboxyphenyl)-porphyrin (TCPP) were used to prepare a levofloxacin (Lev)-loaded zirconium-based organometallic scaffold (Lev-GaPR-PCN). Hyaluronic acid (HA) was linked to the Lev-GaPR-PCN surface via ROS-reactive thioketal bonds (TK). The triple-targeting performance and synergistic efficacy of HA-Lev-GaPR-PCN against intracellular MRSA were tested in vitro and in vivo. Results: GaPR showed strong bactericidal activity against MRSA by interfering with iron metabolism. GaPR-PCN exhibited excellent binding ability with host-derived heme-binding proteins (Hpx/LRP1 and Hpg/CD163) and the iron-regulated surface determinant (Isd) system of MRSA for infection site, infected cell, and intracellular targeting. HA coating enabled covert circulation and decreased nonspecific uptake by healthy cells (< 5% fluorescence intensity after 6 h) while promoting infection-induced release via hyaluronidase and ROS. In vitro, HA-Lev-GaPR-PCN achieved 3.42-fold greater colocalization with intracellular MRSA (Pearson correlation: 0.41 vs. 0.12 for PCN-224 controls) and decreased the extracellular/intracellular minimum inhibitory concentrations (MICs) of Lev under PDT from 8/64 μg/mL to 1/2 μg/mL. In vivo, it resulted in prolonged retention (72 h vs. 36 h) and a 1.5-2.5-fold greater fluorescence intensity at infection sites for non-HA nanosystems. Compared to Lev alone, it decreased the bacterial load by 501-fold (2.7 log) and abscesses (diameter: 0.6 cm vs. 3.3 cm) by combining chemical, metabolic, and physical antibacterial mechanisms without causing toxic effects. Conclusion: This study represents a paradigm shift in intracellular infection therapy for MRSA and other resistant bacteria using a hemimetic compound as a triple-targeting and dual therapeutic agent that provides a streamlined, clinically feasible solution with high efficacy and specificity.

对铁特洛伊木马、氟喹诺酮类抗生素和光动力疗法具有协同作用的三重靶向纳米系统特异性杀死细胞内MRSA。
理由:铁是微生物生存所必需的。摄取网络在宿主细胞和耐甲氧西林金黄色葡萄球菌(MRSA)中高度表达,并与血红素铁竞争。合成了一种拟血红素化合物卟啉镓(GaPR),开发了一种创新的纳米系统,作为摄取网络识别的三靶向剂。GaPR还被用作“铁特洛伊木马”和光敏剂的双重治疗分子,与左氧氟沙星实现协同抗菌作用,根除细胞内mrsa,这是传统治疗技术由于药物渗透有限、抗生素耐药和脱靶效应而无法克服的问题。方法:合成半拟化合物文库。GaPR因其抗菌活性和对铁摄取受体的竞争性结合亲和力而被选为最佳候选。采用最佳GaPR和光敏剂四甲基(4-羧基苯基)卟啉(TCPP)制备了负载左氧氟沙星(Lev)的锆基有机金属支架(Lev-GaPR- pcn)。透明质酸(HA)通过ros反应性硫基键(TK)与Lev-GaPR-PCN表面连接。体外和体内检测HA-Lev-GaPR-PCN对细胞内MRSA的三重靶向性能和协同效应。结果:GaPR通过干扰铁代谢对MRSA具有较强的杀菌活性。GaPR-PCN与宿主来源的血红素结合蛋白(Hpx/LRP1和Hpg/CD163)以及MRSA铁调控的表面决定因子(Isd)系统具有良好的结合能力,可靶向感染部位、感染细胞和细胞内。透明质酸涂层可实现隐蔽循环,减少健康细胞的非特异性摄取(6小时后荧光强度< 5%),同时促进感染诱导的通过透明质酸酶和ROS释放。在体外,HA-Lev-GaPR-PCN与细胞内MRSA的共定位能力提高了3.42倍(Pearson相关性为0.41比0.12),并将PDT作用下Lev的细胞外/细胞内最低抑制浓度(mic)从8/64 μg/mL降至1/2 μg/mL。在体内,它延长了滞留时间(72小时比36小时),非ha纳米系统感染部位的荧光强度提高了1.5-2.5倍。与单独使用Lev相比,它通过结合化学、代谢和物理抗菌机制,减少了501倍(2.7 log)的细菌负荷和脓肿(直径:0.6 cm vs 3.3 cm),而不会产生毒性作用。结论:本研究代表了细胞内感染治疗MRSA和其他耐药细菌的范式转变,使用半拟化合物作为三重靶向和双重治疗剂,提供了一种高效、特异性强、临床可行的流线型解决方案。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
Theranostics
Theranostics MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
25.40
自引率
1.60%
发文量
433
审稿时长
1 months
期刊介绍: Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信