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（植物油中的天然化合物）与创新的纳米递送技术相结合，开发一种新的纳米疗法，以消除幽门螺杆菌（H. pylori）感染负担。这项工作是由我们最近的发现推动的，即亚麻酸的脂质体制剂可以有效、快速地杀死复制型（也称为螺旋型）和休眠型（也称为球状型）幽门螺杆菌以及临床分离的幽门螺杆菌菌株。通常对现有抗生素具有耐药性。目前幽门螺杆菌感染的标准治疗称为三联疗法，包括使用质子泵抑制剂 (PPI) 和两种抗生素（克拉霉素）。然而，三联疗法与患者的依从性差、抗生素的副作用和高成本有关，此外，对其中一些抗生素产生耐药性的幽门螺杆菌菌株的不断出现导致了病情的进展。近年来，幽门螺杆菌的根除率下降到令人无法接受的低水平，从 60% 到 75% 不等。在此，我们的目标是开发一种独特且强大的纳米疗法来治疗幽门螺杆菌感染，高效且无副作用。影响。我们将测试所提出的纳米疗法的理化和生物学特性以及工作机制。使用幽门螺杆菌悉尼株（SS1）小鼠模型，我们还将彻底评估纳米疗法针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，该提案将解决三个具体目标，包括：（i）研究脂质体亚麻酸（LipoLLA）对幽门螺杆菌的抗菌特异性和作用机制； (ii) 设计一种 pH 敏感的纳米颗粒稳定的脂质体系统，用于“智能”地将药物输送到胃粘液内层； (iii) 测试 纳米颗粒稳定的 LipoLLA 在治疗小鼠模型中的幽门螺杆菌感染时的疗效和毒性。该项目的成功将为人们提供一种新的、有效的、安全的、 治疗幽门螺杆菌感染的廉价药物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将有效负载传递到胃粘液内层。此外，这项工作还将提高人们对如何通过破坏细菌质膜的特性来杀死细菌的基本认识，从而避免诱导细菌耐药性。