Innate Antimicrobial Nanotherapeutics for the Treatment of H. pylori Infection

用于治疗幽门螺杆菌感染的先天抗菌纳米疗法

• 批准号: 8466968
• 负责人: Liangfang Zhang
• 金额: $ 31.69万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466968
• 关键词: Address; Adverse effects; Affect; Aftercare; Amoxicillin; Animal Model; Antibiotics; Apoptosis; Bacteria; Bacterial Drug Resistance; Bacterial Infections; Binding; Biocompatible; Biological; Biological Assay; Biomedical Engineering; Brassica rapa; Cell Proliferation; Cell membrane; Chronic; Clarithromycin; Colony-forming units; Communicable Diseases; Communities; Development; Diffuse; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Effectiveness; Engineering; Environment; Flax; Goals; Gold; Helicobacter Infections; Helicobacter pylori; Histology; Immune response; Inflammation; Investigation; Joints; Juglans; Length; Linolenic Acids; Liposomes; Medical; Membrane; Metronidazole; Molecular Biology; Molecular Structure; Mucous body substance; Nanotechnology; Patients; Pharmaceutical Preparations; Population; Positioning Attribute; Property; Proton Pump Inhibitors; Public Health; Research; Resistance; Resources; Schools; Soybeans; Specificity; Stomach; Surface; System; Technology; Testing; Therapeutic; Time; Toxic effect; Toxicity Tests; Treatment Efficacy; Ulcer; Vegetable Oils; Work; absorption; antimicrobial; bactericide; base; compliance behavior; cost; design; immunogenicity; improved; in vivo; innovation; killings; malignant stomach neoplasm; medical schools; mouse model; nano; nanoengineering; nanoparticle; nanotherapeutic; novel therapeutics; resistant strain; standard care; success; unsaturated bonds

DESCRIPTION (provided by applicant): The primary goal of this project is to combine linolenic acid (a natural compound from vegetable oils) with an innovative nano-delivery technology to develop a new nanotherapeutic for eradicating Helicobacter pylori (H. pylori) infection burden. This work is driven by our recent discovery that the liposomal formulation of linolenic acid can effectively and rapidly kill both replicating (also called spiral) and dormant (also called coccoid forms of H. pylori bacteria as well as clinically isolated H. pylori strains that are normally resistant to exiting antibiotics. The current standard treatment of H. pylori infection, termed trile therapy, consists of the administration of a proton pump inhibitor (PPI) and two antibiotics (clarithromycin plus amoxicillin or metronidazole). However, the triple therapy is associated with poor compliance of patients, side effects of the antibiotics, and high cost. Moreover, the increasing emergence of H. pylori strains resistant to some of these antibiotics have resulted in a progressive decline in recent years to unacceptable low eradication rates ranging from ~60% to 75%. Herein, we aim to develop a unique and robust nanotherapeutic to treat H. pylori infection with high effectiveness and without adverse side effects. We will test the physicochemical and biological properties and working mechanism of the proposed nanotherapeutics. Using an H. pylori Sydney strain (SS1) mouse model, we will also thoroughly evaluate the antimicrobial efficacy, toxicity and pharmacokinetics of the nanotherapeutics against H. pylori infection. Overall, three specific aims will be addressed in this proposal, including: (i) to investigate the antimicrobial specificity and working mechanism of liposomal linolenic acid (LipoLLA) against H. pylori bacteria; (ii) to engineer a pH-sensitive nanoparticle-stabilized liposome system for "smart" drug delivery to the stomach mucus lining; and (iii) to test the therapeutic efficacy and toxicity of nanoparticle-stabilized LipoLLA for the treatment of H. pylori infection in a mouse model. The success of this project will provide a new, effective, safe, and inexpensive medication to treat H. pylori infection that will benefit millions of patients. Thi work will also have significant impacts on advancing bioengineering and nanotechnology research by developing a unique and powerful nanoparticle-stabilized liposome system that can tolerate the acidic stomach environment and selectively deliver payloads to the stomach mucus lining. Moreover, this work will also improve the fundamental understanding of how to kill bacteria through disrupting the properties of bacterial plasma membrane and thus avoiding inducing bacterial drug resistance.

描述（由申请人提供）：该项目的主要目标是将亚麻酸（植物油的天然化合物）与创新的纳米递送技术相结合，以开发出一种新的纳米疗法，以消除幽门螺杆菌（H.幽门螺杆菌）感染负担。这项工作是由我们最近发现的，即亚麻酸的脂质体配方可以有效，迅速地杀死复制（也称为螺旋）和休眠（也称为幽门螺杆菌细菌的肠形形式），以及临床上孤立的幽门螺杆菌菌株以及通常抗性的抗体抗体的抗体疗法。 administration of a proton pump inhibitor (PPI) and two antibiotics (clarithromycin plus amoxicillin or metronidazole). However, the triple therapy is associated with poor compliance of patients, side effects of the antibiotics, and high cost. Moreover, the increasing emergence of H. pylori strains resistant to some of these antibiotics have resulted in a progressive decline in recent years to unacceptable low eradication rates在本文中，我们旨在开发出独特而强大的纳米疗法，以高效治疗幽门螺杆菌感染，而没有不良的副作用。我们将测试所提出的纳米疗法的物理化学和生物学特性以及工作机制。使用幽门螺杆菌悉尼菌株（SS1）小鼠模型，我们还将彻底评估纳米疗法对幽门螺杆菌感染的抗菌功效，毒性和药代动力学。总体而言，该提案将解决三个特定目标，包括：（i）研究脂质体亚麻酸（Lipolla）对幽门螺杆菌的脂质体亚麻酸（Lipolla）的抗菌特异性和工作机制； （ii）设计一种对pH敏感的纳米颗粒稳定的脂质体系统，以“智能”药物递送到胃粘液衬里； （iii）测试 纳米颗粒稳定的Lipolla在小鼠模型中治疗幽门螺杆菌感染的治疗功效和毒性。该项目的成功将为新的，有效，安全， 和廉价的药物治疗幽门螺杆菌感染，这将使数百万患者受益。这项工作还将通过开发一种独特而强大的纳米颗粒稳定的脂质体系统来对推进生物工程和纳米技术研究产生重大影响，该系统可以耐受酸性胃环境并选择性地为胃粘液衬里提供有效载荷。此外，这项工作还将通过破坏细菌质膜的特性，从而避免诱导细菌耐药性来杀死细菌的基本理解。