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

使用脂质体系统的治疗分子的有效细胞内递送多年来一直受到关注。然而，关于使用脂质体成功递送大分子仍然存在问题，这导致递送系统从血流中快速消除或诱导免疫应答，影响有效载荷的功效。使用非病毒载体可以解决这个问题，因为它们具有模拟病毒的能力，因此允许逃避单核吞噬细胞系统（MPS），这反过来允许循环时间长达一周以及增强靶向肿瘤的治疗（Geng et al.，2007; Niu等人，2013年）。Chen等人已经开发了模拟病毒融合肽活性的聚合物，其新奇在于pH响应性（Chen等人，2017年）。该小组进行的初步工作显示了成功的细胞内递送大分子如核酸和蛋白质的有希望的结果。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贮存期、增强靶向能力和改善此类脂质体药物递送系统的受控释放（Payton等人，2014年）。将这些递送系统储存更长时间而不损失稳定性和功能性的能力不仅对于保护有效载荷，而且对于在工业内商业化这些系统将是非常有益的。该项目的目的是使用Chen等人开发的pH响应性聚合物作为表面涂层来合成新型病毒模拟脂质体递送系统（Chen等人，2017年）的报告。该系统将进行优化，以更可控和更有针对性地将蛋白质和核酸等大分子细胞内递送到一系列不同的细胞类型中，包括癌细胞系。将评估系统穿过细胞膜、成功释放有效负载并最终触发细胞凋亡的能力。此外，这些输送系统的储存方法将得到优化，以允许在室温下储存更长时间，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.