Non-invasive magnetic nanothermotherapy for resolution of wound biofilm infection

 描述(申请人提供)：来自人类慢性创面的临床数据显示，随着创面的慢性发作，细菌生物膜的形成导致了长时间的住院和截肢。目前治疗伤口感染的方法包括局部或全身应用抗生素治疗，以及伤口清创、引流和手术干预。然而，治疗生物被膜感染的一个关键挑战是它们对抗生素具有耐药性，并且很容易逃避先天免疫攻击。因此，迫切需要以生物膜为目标的新战略来管理不可愈合的慢性伤口。为了应对这一挑战，我们最近开发了一种非侵入性、抗菌的磁热疗法平台，其中使用高频交变磁场(AMF)来快速加热与细菌病原体结合的磁性纳米颗粒(MNP)。这是第一次证明使用靶向MNP热疗作为一种非侵入性抗菌疗法来管理和加速伤口感染愈合的可行性。尽管这项技术前景看好，类似的MNPs用于热疗的研究已经在癌症治疗应用中得到了相当广泛的研究，但仍有几个关键问题需要解决，以成功地将 这项治疗伤口感染的技术。拟议研究的目标是提供临床前研究 磁性纳米颗粒热疗与先天免疫反应合作，与常规抗生素治疗协同工作，在治疗革兰氏+菌和革兰氏-菌种的多菌生物被膜感染方面有效，并确保了技术的安全性。为了达到这一目标，我们提出(1)在体外优化氧化铁颗粒结合物的结构，以有效地靶向细菌细胞内 (2)检测MNP/AMF热疗对细菌吞噬的先天免疫反应的影响(Aim 2)，以及(3)使用临床相关的糖尿病小鼠皮肤生物被膜感染模型对MNP/AMF热疗系统进行体内评估(Aim 3)。这项研究的成功完成可能为治疗不能耐受全身抗生素的脆弱患者提供必要的工具，并可能为抗生素耐药的慢性伤口感染的“智能”治疗建立一个新的非侵入性平台。

 DESCRIPTION (provided by applicant): Clinical data from human chronic wounds implicates bacterial biofilm formation with the onset of wound chronicity that leads to prolonged hospitalization and limb amputation. Current approaches for the treatment of wound infections include the application of topical or systemic antibiotic treatments along with wound debridement, drainage, and surgical intervention. However, a critical challenge in treatment of biofilm infection is that they are antibiotic resistant and readily evade innate immune attacks. Thus, there is a dire need for new strategy that targets biofilms in the management of non-healing chronic wounds. To address this challenge, we have recently developed a non-invasive, antimicrobial, magnetic thermotherapy platform in which a high-frequency alternating magnetic field (AMF) is used to rapidly heat magnetic nanoparticles (MNPs) that are bound to a bacterial pathogen. This has been the first application that demonstrates a feasibility of using a targeted MNP hyperthermia as a non-invasive antimicrobial therapeutic for management and accelerated healing of wound infection. Although this technology holds promise, and the use of similar MNPs for hyperthermia has been studied quite extensively in cancer treatment application, there remain several key issues that need to be resolved for the successful clinical translation of this technology to treat wound infections. The goal of the proposed study is to provide preclinical validation of magnetic nanoparticle thermotherapy that cooperates with the innate immune response, works synergistically with conventional antibiotic treatment, is effective in the treatment of polymicrobial biofilm infection with both Gram + and Gram - bacterial species, and ensures safety of the technology. To achieve the goal, we propose (1) to optimize the structure of iron oxide particles conjugates in vitro to effectively target bacterial cells for intracellular heating (Aim 1), (2) to examine the impact of MNP/AMF hyperthermia on innate immune response for bacterial phagocytosis (Aim 2), and (3) to proceed to an in vivo assessment of the MNP/AMF hyperthermia system using clinically relevant diabetic mouse models of cutaneous biofilm infection (Aim 3). The successful completion of this study may provide a needed tool for treatment of fragile patients who cannot tolerate systemic antibiotics and this could establish a novel non-invasive platform for "smart" treatments of antibiotic-resistant chronic wound infection.