Targeted delivery of macromolecules using a novel virus-mimicking liposomal system

利用脂质体系统有效地在细胞内递送治疗性分子已引起人们多年的兴趣。然而，关于使用脂质体成功递送大分子的问题仍然存在，这会导致递送系统从血液中快速消除或诱导免疫反应，影响有效载荷的有效性。使用非病毒载体可以解决这一问题，因为它们具有模拟病毒的能力，因此可以避开单核吞噬细胞系统（MPS），从而允许循环时间长达一周，并增强对靶向肿瘤的治疗（耿等人，2007；Niu等人，2013）。Chen等人开发了模拟病毒融合肽活性的聚合物，具有ph响应的新颖性（Chen等人，2017）。该小组进行的初步工作显示，在核酸和蛋白质等大分子的细胞内成功递送方面，结果很有希望。这可能有利于更有针对性地递送药物和治疗分子，以治疗癌症等疾病。另一个感兴趣的领域是延长保质期，增强靶向能力和改善这种脂质体药物递送系统的控释（佩顿等人，2014）。在不失去稳定性和功能的情况下，将这些输送系统储存更长时间的能力，不仅有利于保护有效载荷，而且在经济上有利于这些系统在工业上的商业化。该项目的目的是利用Chen等人开发的ph响应聚合物作为表面涂层，合成一种新型病毒模拟脂质体递送系统（Chen et al., 2017）。该系统将被优化为更可控和靶向的细胞内递送大分子，如蛋白质和核酸，进入一系列不同的细胞类型，包括癌细胞系。该系统穿越细胞膜、成功释放有效载荷并最终引发细胞凋亡的能力将被评估。此外，这些输送系统的存储方法将被优化，以允许在室温下更长的存储时间，而不会损害系统的完整性。

The efficient intracellular delivery of therapeutic molecules using liposomal systems has been of interest for many years. However, issues remain with regards to the successful delivery of macromolecules using liposomes, which cause quick elimination of the delivery system from the bloodstream or induction of an immune response, affecting the efficacy of the payload. The use of non-viral vectors can address this issue as they have the ability to mimic viruses, hence allowing evasion of the mononuclear phagocyte system (MPS), which in turn allows circulation times of up to one week as well as enhanced treatment of the targeted tumour (Geng et al., 2007; Niu et al., 2013). Chen et al. have developed polymers that mimic the activity of viral fusogenic peptides with the novelty of being pH-responsive (Chen et al., 2017). Preliminary work carried out by the group shows promising results with regards to the successful intracellular delivery of macromolecules such as nucleic acids and proteins. This could be beneficial for more targeted delivery of drugs and therapeutic molecules to treat diseases such as cancer. Another area of interest is to prolong the shelf life, enhance targeting capacity and improve controlled release of such liposomal drug delivery systems (Payton et al., 2014). The ability to store these delivery systems for a longer amount of time, without the loss of stability and functionality, would be very beneficial not only to protect the payload, but also economically, to commercialize these systems within industry.The aim of this project is to synthesise a novel virus-mimicking liposomal delivery system using pH-responsive polymers developed by Chen et al. as the surface coating (Chen et al., 2017). The system will be optimised for more controllable and targeted intracellular delivery of macromolecules such as proteins and nucleic acids into a range of different cell types, including cancer cell lines. The ability for the system to cross the cell membrane, successfully release the payload, and ultimately trigger apoptosis will be assessed. Moreover, the storage method of these delivery systems will be optimised to allow for longer storage at room temperature without compromising the integrity of the system.