Nano Antibiotic Delivery for Treating MRSA Infections

用于治疗 MRSA 感染的纳米抗生素递送

• 批准号: 10212571
• 负责人: Arun Iyer
• 金额: $ 37.48万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-18 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212571
• 关键词: Address; Adverse event; Adverse reactions; Antibiotics; Applications Grants; Biodistribution; Clinical; Data; Development; Disease; Dose; Drug resistance; Drug usage; Engineering; Evaluation; Excipients; Exhibits; FDA approved; Folic Acid; Formulation; Goals; Healthcare; Hour; In Vitro; Infection; Kidney; Libraries; Liposomes; Liver; Modeling; Morbidity - disease rate; Mus; Nano delivery; Organ; Outcome; Patient-Focused Outcomes; Patients; Penetration; Pharmaceutical Preparations; Predisposition; Prodrugs; Rattus; Research Proposals; Resistance; Route; Safety; Site; Staphylococcus aureus; Staphylococcus aureus infection; Stimulus; Superbug; System; Technology; Testing; Therapeutic; Thigh structure; Time; Toxic effect; Translations; Treatment Efficacy; Vancomycin; Vancomycin Resistance; Variant; Work; bacterial resistance; bactericide; base; bench to bedside; clinical translation; drug preservation; improved; improved outcome; in vivo; in vivo evaluation; methicillin resistant Staphylococcus aureus; mortality; mouse model; nano; nanoformulation; nanoparticle; nephrotoxicity; novel; patient variability; pharmacokinetics and pharmacodynamics; resistant strain; response; scale up; side effect; success; targeted delivery; treatment response; uptake

PROJECT SUMMARY Superbugs such as Methicillin-resistant Staphylococcus aureus (MRSA) is a global healthcare problem which exhibits high rates of morbidity and mortality amongst patients. While variant strains of bacterial resistance continue to emerge, the development of newer and more potent antibiotics has not kept pace, with urgent and burgeoning unmet need for several resistant infections including MRSA. It is thus imperative to find alternative solutions, such as to package current antibiotics into novel targeted delivery systems that can selectively deliver antibiotics at the site of the infection and smartly evade the bacterial barriers and for better therapeutic response with high safety. We for the first time, developed a folate decorated VAN nano-antibiotic (LVAN) that showed pronounced accumulation at the site of infection, leading to enhanced killing of MRSA strains in vitro and in vivo as compared to the commercially available VAN that forms the basis for further exploration. The goal of this project is to further develop and optimize a library of folate containing stimuli responsive nano-antibiotics with very high vancomycin (VAN) loading (~50% wt/wt) that will yield significant bactericidal activity against strains of MRSA while demonstrating high safety. Specifically, we will develop bacterial colony-responsive nano-antibiotic library synthesis for optimized killing of MRSA and selective delivery/release to improve infection treatment followed by determining the most optimal nano-antibiotic formulation by susceptibility testing and use of a validated PK/PD model against MRSA strains. These select few (1-2) nano-antibiotic formulation containing VAN will then be tested in vivo using a mouse thigh infection model against validated strains of MRSA followed by evaluation of biodistribution and kidney toxicity using a well characterized rat model. It is expected that the targeted nano-antibiotic formulation of VAN developed herein on systemic administration will show selective accumulation at the site of MRSA infection and exhibit controlled antibiotic release over an extended period of at least 72 hours improving efficacy. In addition, the liposomal formulation will be safer than commercially available VAN because of the expected lower dose exposure and the alternative route of elimination by the liver. With respect to positive outcomes, the work proposed in this application is expected to yield a safe and robust stimuli-responsive targeted nano-antibiotic formulation with high VAN loading that will have a major impact on improving the lives of MRSA infected patients. Since the formulation has a high drug loading with minimum side effects, the patient can be administered with therapeutic doses of VAN without any major adverse reactions or events. Furthermore, since the formulation utilizes FDA-approved excipients we do not see any outward difficulty in scale up and translation of the technology from the bench to the bedside.

项目摘要 超级细菌，例如耐甲氧西林金黄色葡萄球菌（MRSA）是一个全球医疗保健问题， 患者的发病率和死亡率很高。而细菌抗性的变异菌株 继续出现，更新，更有效的抗生素的发展并没有保持紧急和 不满意的几种抗性感染的需求包括MRSA。因此，必须找到替代方案 解决方案，例如将当前抗生素包装到新的目标输送系统中 在感染部位的抗生素，并巧妙地避免细菌屏障和更好的治疗反应 具有高安全性。 我们第一次开发了叶酸装饰的范纳诺抗生素（LVAN），显示出明显的 在感染部位积聚，导致MRSA菌株在体外和体内的杀死增强 到构成进一步探索基础的市售货车。该项目的目标是进一步 开发并优化含有非常高的万古霉素的刺激反应式纳米抗生素的叶酸库 （van）加载（〜50％wt/wt），将对MRSA菌株产生明显的杀菌活性 证明高安全性。具体而言，我们将开发细菌菌落响应性纳米抗生素库 合成用于优化MRSA和选择性输送/释放以改善感染治疗的合成，然后 通过易感性测试和使用经过验证的PK/PD来确定最佳的纳米抗生素配方 针对MRSA菌株的模型。这些选择的少数（1-2）纳米抗生素配方含有货车将是 使用小鼠大腿感染模型在体内测试，以针对经过验证的MRSA菌株进行评估 使用良好的大鼠模型的生物分布和肾脏毒性。 预计本文中开发的货车的靶向纳米抗生素公式 将在MRSA感染部位显示选择性积累，并在 至少72小时的长期提高了功效。此外，脂质体配方将比 由于预期的下剂量暴露和替代路线，可商购的面包车 肝脏消除。 关于积极的结果，预计本申请中提出的工作将产生安全稳固 刺激响应的靶向纳米抗生素配方具有高货车载荷，这将对 改善MRSA感染患者的生活。由于该配方具有最小的药物载荷 效果，可以用治疗剂量的货车给药而没有任何重大不良反应或 事件。此外，由于该配方利用了FDA批准的赋形剂，因此我们看不到任何外部困难 从规模上进行扩展，并将技术从长凳转换为床边。

项目成果

Novel approaches for the treatment of methicillin-resistant Staphylococcus aureus: Using nanoparticles to overcome multidrug resistance.

治疗耐甲氧西林金黄色葡萄球菌的新方法：使用纳米颗粒克服多重耐药性。

• DOI: 10.1016/j.drudis.2020.10.011
• 发表时间: 2021-01
• 期刊: Drug discovery today
• 影响因子: 7.4
• 作者: Vanamala K;Tatiparti K;Bhise K;Sau S;Scheetz MH;Rybak MJ;Andes D;Iyer AK
• 通讯作者: Iyer AK

Nanomedicine approaches to reduce cytokine storms in severe infections.

• DOI: 10.1016/j.drudis.2022.103355
• 发表时间: 2022-11
• 期刊: DRUG DISCOVERY TODAY
• 影响因子: 7.4
• 作者: Rauf, Mohd Ahmar;Nisar, Maryam;Abdelhady, Hosam;Gavande, Navnath;Iyer, Arun K.
• 通讯作者: Iyer, Arun K.