'Hide-and-Seek'- targeted drug delivery to intracellular pathogens

由细菌、病毒和真菌等病原体引起的传染病是全世界第二大死亡原因。许多致病菌能够通过隐藏和复制宿主免疫细胞（如巨噬细胞）来逃避宿主的防御机制。从治疗的角度来看，这种感染的治疗可能非常具有挑战性，因为目前许多抗菌药物分子不能有效地穿过感染宿主细胞的质膜，因此不能到达这些病原体所在的细胞内细胞器。因此，迫切需要更有效的策略来解决这一临床问题。该项目将通过设计药物递送纳米载体来解决这一治疗问题，纳米载体能够靶向受感染宿主细胞中的特定内吞受体，并向细胞内病原体递送抗菌剂。这种方法的一个显著优点是，它允许使用通常不会穿过受感染宿主细胞细胞膜的抗菌剂，从而可能扩大治疗这些感染的可用药物的范围，这在由于抗菌素耐药性而限制治疗选择时可能是关键。最初，这个项目将通过用一系列基于碳水化合物和/或短肽的配体装饰脂质体来设计靶向纳米载体——这些配体是市售的，或者是作为本研究的一部分合成的。这些纳米载体将结合荧光探针，以便在随后的生物医学分析中进行跟踪，并选择抗菌药物，这些药物将在体外模型中对现有的细胞内感染进行测试。在这个项目中，这些纳米载体的脂质组成，配体的化学性质，大小和拓扑结构，以及抗菌药物的类型将系统地改变，以获得这些新型靶向纳米药物的第一个结构-活性关系。项目与高级产品设计相一致

Infectious diseases caused by pathogens such as bacteria, viruses and fungi are the second leading cause of death worldwide. Many pathogenic bacteria are capable of evading host defence mechanisms by hiding and replicating host immune cells, such as macrophages. From a therapeutic viewpoint, treatment of such infections can be very challenging, as many of current antimicrobial drug molecules do not efficiently cross plasma membrane of infected host cells, and thus cannot reach intracellular organelles where these pathogens are located. Thus, more effective strategies to address this clinical issue are urgently needed.This project will address this therapeutic problem by engineering drug delivery nanovectors able to target specific endocytic receptors in infected host cells and deliver antimicrobial agents to intracellular pathogens. One of the significant advantages of this approach is that it allows for the use of antimicrobial agents which would not normally cross the cell membrane of infected host cells, thus potentially expanding the range of available drugs to treat these infections, which can be key when therapeutic options are restricted due to antimicrobial resistance.Initially, this project will engineer targeted nanovectors by decorating liposomes with a range of ligands based on carbohydrates and/or short peptides - commercially available, and/or synthesised as part of this study. These nanovectors will incorporate fluorescent probes to facilitate their tracking in subsequent biomedical assays, and selected antimicrobial agents which will be tested on existing intracellular infection in vitro models.In this project the lipid composition of these nanovectors, the chemical nature, size and topology of ligands, and type of antimicrobial drug will be systematically varied to gain a first structure-activity relationship for these novel targeted nanomedicines.Project aligned to Advanced Product Design