构建递送两性霉素B的聚丝氨酸脂质纳米粒用于增强抗真菌感染治疗效果的研究

两性霉素B(AmB)自1958年获批以来，一直作为治疗全身或深部真菌感染的优势药物和“金标准”。由于AmB不溶于水、肾毒性大等问题，需要采用脂质体进行药物递送。但现有的AmB脂质体不具备理想的血液长循环和免疫逃逸功能，导致疗效不佳并伴随毒副作用。AmB脂质药物的发展近20多年来一直没有突破瓶颈，而临床中亟需增强药物疗效，解决通常超过50%死亡率的侵袭性真菌感染难题。突破瓶颈的难点在于很难获得低免疫原性的材料并合理构建稳定性好、药物利用度高的AmB递送系统。针对这一技术瓶颈背后的核心科学问题，本项目基于申请人前期研究中发现的超亲水性和低免疫原性的丝氨酸类聚合物，系统性研究和构建递送AmB的聚丝氨酸脂质纳米粒(LNPs)，赋予其免疫逃逸功能，实现水溶性高、毒性低、稳定性好、血液半衰期长的性能。本项目以增强抗真菌感染治疗效果为目标，努力突破抗真菌药物研究的瓶颈，并深入探索递送系统的作用机制。

Amphotericin B (AmB) has been the dominant drug and “gold standard” for the treatment of systemic or deep fungal infections since it was approved in 1958. Liposomes are required for AmB delivery because of the poor water solubility and high nephrotoxicity of AmB. However, the existing AmB liposomes cannot escape from the immune system and do not have long blood circulation half-life, causing poor therapeutic efficacy and toxicity. The development of AmB liposome drugs has not broken the bottleneck in the past 20 years. Therefore, it is urgent to improve the efficacy of AmB to treat the current invasive fungal infections, which often exceed 50% of mortality. The challenge to break the bottleneck lies in obtaining low-immunogenic materials and reasonably constructing AmB delivery systems with good stability and bioavailability. To resolve the core scientific problem behind this technological bottleneck, this project will systematically investigate and construct the AmB lipid nanoparticles (LNPs), which based on the super-hydrophilic and low immunogenic polyserine material that found in our previous research, endow the LNPs with immune escape function, and achieve the properties of high water solubility, low toxicity, good stability and prolonged residence time in blood. The purpose of this project is to improve the therapeutic efficacy against fungal infection, making efforts to break through the bottleneck of current antifungal drugs, and deeply exploring the mechanism of the delivery system.