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新型纳米技术可将囊性纤维化抗生素效力提高10万倍

已有 1991 次阅读 2021-5-16 11:07 |个人分类:药物动态|系统分类:海外观察

新型纳米技术可将囊性纤维化抗生素效力提高10万倍

诸平

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After four hours, if the infection is not treated it kills all the cells (line 1); Unformulated tobramycin keeps the cells alive, but it does not eradicate the infection (line 2); Nano-enhanced tobramycin eradicates the infection.

南澳大利亚大学University of South Australia简称UniSA2021514日提供的消息,该校开发的世界首创新的纳米技术可以改变成千上万的囊性纤维化(cystic fibrosis简称CF)患者的生活,这项开创性的研究表明,它可以提高CF抗生素妥布霉素(Tobramycin)的功效,将其功效提高多达10万倍。

这项新技术使用一种仿生纳米结构材料来增强妥布霉素(一种在严重的CF患者中治疗慢性铜绿假单胞菌肺部感染的处方抗生素),只需2剂就可以根除这种感染。

在澳大利亚,婴儿患囊性纤维化(CF)的比例为1/2500,或每四天会有一名患CF的婴儿出生,此病严重损害人的肺、气道和消化系统,捕获细菌并导致反复感染。肺衰竭是导致CF患者死亡的主要原因。

UniSA的研究团队包括Clive Prestidge教授,尼基•托马斯(Nicky Thomas)博士和博士研究生切尔西·桑恩(Chelsea Thorn)。该研究团队指出,这一发现可能会改变CF患者的生活。

切尔西·桑恩说:“ CF是一种进行性遗传疾病,会引起持续的慢性肺部感染,并限制人的呼吸能力。这种疾病会导致粘稠的粘液阻塞人的呼吸道,吸引病菌和细菌(germs and bacteria),例如铜绿假单胞菌(Pseudomonas aeruginosa),从而导致反复感染和阻塞。

妥布霉素通常用于治疗这类感染,但是越来越多的抗生素无法对肺部感染产生任何重大影响,使患者每月需要进行终身抗生素治疗。我们的研究成功地使用纳米增强的妥布霉素治疗方法,治疗晚期人类细胞培养的肺部感染,并显示了仅用两剂就可以根除严重且持续的此类感染。这对于使用CF的人来说可能是真正的游戏规则改变者。

研究人员使用一种基于生物特征,纳米结构的脂质液晶纳米颗粒(lipid liquid crystal nanoparticle简称LCNP)的材料增强了妥布霉素的活性,并在一种新型的肺部感染模型上对其进行了测试,以展示其穿透细菌的致密表面并杀死感染的独特能力。

尼基·托马斯博士说,这一发现继续了全球根除和预防铜绿假单胞菌(Pseudomonas aeruginosa)的斗争。“妥布霉素通过抑制细菌的合成并引起细胞膜损伤而起作用。然而,由于它是一种浓度依赖性抗生素,因此达到足够高的浓度至关重要。我们的技术在不增加药物毒性的情况下,改善了妥布霉素的性能,因此我们正在做的是一种对慢性肺部感染更为有效的治疗方法。

该技术目前正在进入临床前试验,并希望在未来五年内投放市场。这项研究的研究小组不仅仅包括南澳大利亚大学的研究人员;还有来自罗勒·海瑟尔转化健康研究所(Basil Hetzel Institute for Translational Health and Research);ARC生物纳米科学与技术卓越中心(ARC Centre for Excellence in Bio-Nano Science and Technology);UniSA癌症研究所的生物膜测试设施(Biofilm Test facility at UniSA's Cancer Research Institute);萨尔州亥姆霍兹药物研究所(Helmholtz Institute for Pharmaceutical Research Saarland)以及萨尔大学(Saarland University)的研究人员也参与其中。上述介绍仅供参考,更多信息敬请注意浏览原文或者相关报道

Chelsea R. Thorn, Cristiane de Souza CarvalhoWodarz, Justus C. Horstmann, ClausMichael Lehr, Clive A. Prestidge, Nicky Thomas. Tobramycin Liquid Crystal Nanoparticles Eradicate Cystic FibrosisRelated Pseudomonas aeruginosa Biofilms. Small, 2021; 2100531 DOI: 10.1002/smll.202100531

Abstract

Pseudomonas aeruginosa biofilms cause persistent and chronic infections, most known clinically in cystic fibrosis (CF). Tobramycin (TOB) is a standard anti‐pseudomonal antibiotic; however, in biofilm infections, its efficacy severely decreases due to limited permeability across the biofilm matrix. Herewith, a biomimetic, nanostructured, lipid liquid crystal nanoparticle‐(LCNP)‐formulation is discovered to significantly enhance the efficacy of TOB and eradicate P. aeruginosa biofilm infections. Using an advanced, biologically‐r elevant co‐culture model of human CF bronchial epithelial cells infected with P. aeruginosa biofilms at an air–liquid interface, nebulized TOB‐LCNPs completely eradicated 1 × 109 CFU mL−1 of P. aeruginosa after two doses, a 100‐fold improvement over the unformulated antibiotic. The enhanced activity of TOB is not observed with a liposomal formulation of TOB or with ciprofloxacin, an antibiotic that readily penetrates biofilms. It is demonstrated that the unique nanostructure of the LCNPs drives the enhanced penetration of TOB across the biofilm barrier, but not through the healthy lung epithelium barrier, significantly increasing the available antibiotic concentration at the site of infection. The LCNPs are an innovative strategy to improve the performance of TOB as a directed pulmonary therapy, enabling the administration of lower doses, reducing the toxicity, and amplifying the anti‐iofilm activity of the anti‐pseudomonal antibiotic.

Chelsea R. Thorn, Deepa Raju, Ira Lacdao, Stephanie Gilbert, Piyanka Sivarajah, P. Lynne Howell, Clive A. Prestidge, Nicky Thomas. Protective Liquid Crystal Nanoparticles for Targeted Delivery of PslG: A Biofilm Dispersing Enzyme. ACS Infectious Diseases, 2021; DOI: 10.1021/acsinfecdis.1c00014

Abstract

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The glycoside hydrolase, PslG, attacks and degrades the dominant Psl polysaccharide in the exopolymeric substance (EPS) matrix of Pseudomonas aeruginosa biofilms and is a promising therapy to potentiate the effect of antibiotics. However, the need for coadministration with an antibiotic and the potential susceptibility of PslG to proteolysis highlights the need for an effective delivery system. Here, we compared liposomes versus lipid liquid crystal nanoparticles (LCNPs) loaded with PslG and tobramycin as potential formulation approaches to (1) protect PslG from proteolysis, (2) trigger the enzyme’s release in the presence of bacteria, and (3) improve the total antimicrobial effect in vitro and in vivo in a Caenorhabditis elegans infection model. LCNPs were an effective formulation strategy for PslG and tobramycin that better protected the enzyme against proteolysis, triggered and sustained the release of PslG, improved the antimicrobial effect by 10–100-fold, and increased the survival of C. elegans infected with P. aeruginosa. Digestible LCNPs had the advantage of triggering the enzyme’s release in the presence of bacteria. However, compared to nondigestible LCNPs, negligible differences arose between the LCNPs' ability to protect PslG from proteolysis and potentiate the antimicrobial activity in combination with tobramycin. In C. elegans, the improved antimicrobial efficacy was comparable to tobramycin-LCNPs, although the PslG + tobramycin-LCNPs achieved a greater than 10-fold reduction in bacteria compared to the unformulated combination. Herewith, LCNPs are showcased as a promising protective delivery system for novel biofilm dispersing enzymes combined with antibiotics, enabling infection-directed therapy and improved performance.




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