Multipurpose targeted nano-antibiotic therapy to fight tough infection in bones

项目摘要/摘要 描述。我们的目标是开发一种针对生物膜引起的骨髓炎而量身定做的多功能纳米疗法- 形成耐药细菌，这些细菌往往存在于成骨细胞内。骨髓炎经常持续或 尽管进行了几周积极的抗生素治疗，但还是复发了。治疗失败通常是由药物输送引起的。 相关问题，如抗生素骨内水平不足，难以根除生物被膜形成 细菌菌株，特别是耐甲氧西林金黄色葡萄球菌(MRSA)，要求更高 与过量用药相关的治疗性抗生素水平和剂量限制药物毒性的表现 分布于非骨组织。这一组相互关联的问题可以用我们的骨骼同时解决- 靶向杂交纳米载体(BTN)。BTN是为提供新一代抗生素而量身定做的，如利奈唑胺 和利福平以骨骼特异和受控的方式。我们对BTN原型的初步研究 证明了这种新的纳米系统可以实质上结合、分布和穿透各种骨骼 在体外和体内均可直接暴露、局部注射或全身注射，并实现受控 释放linzolid有效载荷几天。这导致利奈唑胺的骨内水平增加了8倍以上。 与游离利奈唑胺相比，显著提高了根除MRSA生物被膜的效果。在此应用程序中，我们 将专注于进一步探索这种先进的纳米抗生素疗法，并增强其翻译潜力 作为一种通用的治疗方法，可以通过全身或局部治疗不同的骨髓炎情况 可注射形式。具体来说，我们将(1)研究利奈唑胺-BTN的参数，以优化药物治疗- 引起骨髓炎的耐药细菌，(2)确定骨靶向和药代动力学特性 局部或全身应用利奈唑胺-BTN，以及(3)评估利奈唑胺-BTNS的治疗效果和毒性 利奈唑胺-BTN在骨髓炎模型中的应用。 与公共卫生的相关性。骨感染，通常被称为骨髓炎，发生在儿童和 成人，尤其是在创伤后。目前，多达三分之一的创伤后患者面临着 骨髓炎。这是最困难和最昂贵的治疗感染之一，因为几周或几个月的侵袭性 需要抗生素治疗来慢慢根除隐藏在受感染的骨组织和骨细胞中的细菌。 如果得不到有效的治疗，骨髓炎很容易持续下去，成为一种慢性病，导致疼痛， 使病人感到虚弱的发病率。该项目的成功完成将验证和优化一个新的 纳米技术可以大幅提高抗生素对骨骼的选择性，延长他们的 治疗作用，并将健康的非骨组织中的药物水平降至最低。因此，一个 在抗生素治疗这种具有挑战性的疾病的有效性和安全性方面可以取得重大进展。

PROJECT SUMMARY/ABSTRACT Description. Our goal is to develop a multi-purpose nanotherapy tailored for osteomyelitis caused by biofilm- forming, drug-resistant bacteria that tend to reside inside osteoblasts. Osteomyelitis frequently persists or recurs despite several weeks of aggressive antibiotic therapy. Treatment failure is often caused by drug delivery related issues such as inadequate intra-bone levels of antibiotics, difficulty in eradicating biofilm-forming bacterial strains especially methicillin-resistant Staphylococcus aureus (MRSA) that require much higher therapeutic antibiotic levels, and manifestation of dose-limiting drug toxicity associated with excessive drug distribution to non-bone tissues. This set of inter-related issues can be simultaneously tackled with our bone- targeting hybrid nanocarriers (BTNs). BTNs are tailored to deliver new generation antibiotics such as linezolid and rifampin in a bone-specific and controlled manner. Our preliminary studies of the BTN prototype demonstrated that this new nanosystem could substantially bind, distribute and penetrate to various bones both in vitro and in vivo after direct exposure, local injection or systemic injection, and achieve controlled release of the linezolid payload for several days. This led to over 8-fold increase in linezolid intra-bone level versus free linezolid and significantly improved efficacy in eradicating MRSA biofilms. In this application, we will focus on further exploring this advanced nano-antibiotic therapy and enhancing its translational potential as a versatile treatment that can deal with different osteomyelitis conditions by serving as a systemic or local injectable form. Specifically, we will (1) study the parameters of linezolid-BTN for optimal treatment of drug- resistant bacteria that cause osteomyelitis, (2) determine the bone-targeting and pharmacokinetic properties of locally or systemically administered linezolid-BTNs, and (3) evaluate the therapeutic outcomes and toxicity of linezolid-BTNs in osteomyelitis models. Relevance to Public Health. Bone infection, frequently known as osteomyelitis, occurs to both children and adults especially after traumatic injuries. Currently, up to one third of post-traumatic patients face the risk of osteomyelitis. This is one of the most difficult and costly-to-treat infections as weeks or months of aggressive antibiotic therapy is required to slowly eradicate the bacteria hidden in the infected bone tissue and bone cells. Without effective treatment, osteomyelitis can easily persist and become a chronic disease and cause painful, debilitating morbidity to the patients. Successful completion of this project will validate and optimize a new nanotechnology that can substantially increase the selectivity of antibiotics for the bones, prolong their therapeutic action there and minimize the drug levels in the healthy, non-bone tissues. Consequently, a significant advance in the efficacy and safety of antibiotic treatment of this challenging disease can be achieved.