基于功能化石墨烯的靶向光热效应治疗皮肤创面多重耐药革兰阴性杆菌感染的研究

Multidrug-resistant Gram-negative bacterial infections of skin wounds have been a major challenge in the treatment of burns and trauma. As one of the alternative strategies, photothermal therapy (PTT) has become a research hotspot in recent years. However, the greatest defect for PTT could be the difficulty of heating the pathogenic bacteria directly and specially to avoid the undesirable increases in the temperature of ambient tissue, which commonly damages the surrounding healthy tissues. In the previous study, we have successfully prepared glycol chitosan conjugated carboxyl graphene (GCS-CG), which presents strong adherence to negatively charged bacteria surface in abscess, ensuring targeted heating and eradicating the bacteria, and controlling MRSA infection effectively in vivo. However, the materials developed with a single targeting strategy exhibits poor affinity to bacteria in vivo. In order to obtain satisfactory therapeutic effects, relatively high concentrations of the materials and laser intensities may be needed, which easily results in tissue toxicity and thermal damage. Taking these into consideration, in this study, a novel functionalized graphene nanomaterial will be prepared for targeted photothermal ablation of multidrug-resistant Gram-negative bacteria in infectious skin wounds. This novel nanomaterial will be safer, more efficient and dual-targeted. This study will not only provide a new treatment strategy for the multidrug-resistant Gram-negative bacterial infection of skin wounds; but also reach a breakthrough in the bacterial targeting of photothermal materials, which will provide experimental foundation for developing multifunctional nanoplatforms.

皮肤创面多重耐药革兰阴性杆菌感染一直是烧、创伤救治的重大挑战。光热治疗作为极具优势的替代疗法，成为近年的研究热点。其关键问题是光热剂无细菌靶向性，杀菌同时也造成周围正常组织热损伤。前期，我们合成了一种石墨烯-壳聚糖靶向杀菌光热材料。它通过静电作用与细菌紧密结合，直接对细菌加热杀灭，有效控制小鼠皮下MRSA感染。然而，单一靶向策略的材料与细菌亲和效率并不高，为获得满意疗效，材料应用浓度往往过大或激光强度采用过高而易出现材料毒性、组织副损伤等不良后果。本研究拟合成一种安全、高效、双重靶向的新型功能化石墨烯复合纳米材料，深入探讨其介导的靶向光热效应对皮肤创面多重耐药革兰阴性杆菌感染的治疗作用及机制。本研究为皮肤创面多重耐药革兰阴性杆菌感染提供一种新的、更高效、更安全的治疗方法，也在光热材料细菌靶向性问题上取得新的突破，为进一步探索设计应用于治疗多重耐药细菌感染的多功能纳米平台提供重要实验参考。

皮肤创面多重耐药革兰阴性杆菌感染一直是烧、创伤救治的重大挑战。光热治疗作为极具优势的替代疗法，成为近年的研究热点。其关键问题是光热剂无细菌靶向性，杀菌同时也造成周围正常组织热损伤。前期，我们合成了一种石墨烯-壳聚糖靶向杀菌光热材料。它通过静电作用与细菌紧密结合，直接对细菌加热杀灭，有效控制小鼠皮下MRSA感染。然而，单一靶向策略的材料与细菌亲和效率并不高，为获得满意疗效，材料应用浓度往往过大或激光强度采用过高而易出现材料毒性、组织副损伤等不良后果。 本研究合成了一种基于硼酸功能化石墨烯季铵盐（B-CG-QAS）的双靶向、化疗-光热联合抗菌平台。在革兰阴性杆菌相关感染部位，B-CG-QAS能通过静电吸附、共价偶联的双重效应特异地与细菌及其生物膜结合，从而展现出优于单一制剂（硼酸化石墨烯或石墨烯季铵盐）的靶向能力，显著提高的抗菌效率，较低的季铵盐剂量，以及极小的化疗/光热毒性。除了季铵盐介导的抗菌效应，近红外光照射可通过光热作用进一步提升抗菌作用。另一方面，季铵盐可破坏细菌细胞膜，提高细胞通透性和热敏感性。体内条件下，B-CG-QAS可通过化疗-光热联合有效控制多重耐药革兰阴性杆菌及其生物膜感染，并显著促进感染创面愈合。同时，B-CG-QAS具有突出的体内外生物安全性。因此，硼酸功能化石墨烯季铵盐（B-CG-QAS）在治疗多重耐药革兰阴性杆菌及其生物膜感染方面具有突出优势， 为皮肤创面多重耐药革兰阴性杆菌感染提供了一种新的、更高效、更安全的治疗方法，也在光热材料细菌靶向性问题上取得新的突破，为进一步探索设计应用于治疗多重耐药细菌感染的多功能纳米平台提供了重要实验参考。