PDF(Pubmed)
Abstract：
A long-standing challenge is how to formulate proteins and vaccines to retain function during storage and transport and to remove the burdens of cold-chain management. Any solution must be practical to use, with the protein being released or applied using clinically relevant triggers. Advanced biologic therapies are distributed cold, using substantial energy, limiting equitable distribution in low-resource countries and placing responsibility on the user for correct storage and handling. Cold-chain management is the best solution at present for protein transport but requires substantial infrastructure and energy. For example, in research laboratories, a single freezer at -80 °C consumes as much energy per day as a small household1. Of biological (protein or cell) therapies and all vaccines, 75% require cold-chain management; the cost of cold-chain management in clinical trials has increased by about 20% since 2015, reflecting this complexity. Bespoke formulations and excipients are now required, with trehalose2, sucrose or polymers3 widely used, which stabilize proteins by replacing surface water molecules and thereby make denaturation thermodynamically less likely; this has enabled both freeze-dried proteins and frozen proteins. For example, the human papilloma virus vaccine requires aluminium salt adjuvants to function, but these render it unstable against freeze-thaw4, leading to a very complex and expensive supply chain. Other ideas involve ensilication5 and chemical modification of proteins6. In short, protein stabilization is a challenge with no universal solution7,8. Here we designed a stiff hydrogel that stabilizes proteins against thermal denaturation even at 50 °C, and that can, unlike present technologies, deliver pure, excipient-free protein by mechanically releasing it from a syringe. Macromolecules can be loaded at up to 10 wt% without affecting the mechanism of release. This unique stabilization and excipient-free release synergy offers a practical, scalable and versatile solution to enable the low-cost, cold-chain-free and equitable delivery of therapies worldwide.
摘要：
一个长期的挑战是如何配制蛋白质和疫苗以在储存和运输期间保持功能并消除冷链管理的负担。任何解决方案都必须实用，使用临床相关的触发剂释放或应用蛋白质。先进的生物疗法是冷分布的，使用大量的能量，限制低资源国家的公平分配，并由用户负责正确的储存和处理。冷链管理是目前蛋白质运输的最佳解决方案，但需要大量的基础设施和能源。例如,在研究实验室，-80°C的单个冰箱每天消耗的能量与小型家庭一样多1。生物（蛋白质或细胞）疗法和所有疫苗，75％需要冷链管理；自2015年以来，临床试验中的冷链管理成本增加了约20％，反映了这种复杂性。现在需要定制配方和赋形剂，与海藻糖2，蔗糖或聚合物3广泛使用，它通过取代表面水分子来稳定蛋白质，从而使热力学变性的可能性降低；这使得冷冻干燥的蛋白质和冷冻的蛋白质都成为可能。例如,人乳头瘤病毒疫苗需要铝盐佐剂才能发挥作用，但这些使其不稳定，以防止冻结4，导致一个非常复杂和昂贵的供应链。其他想法涉及硅化5和蛋白质6的化学修饰。总之,蛋白质稳定是一个挑战，没有通用的解决方案7,8.在这里，我们设计了一种硬水凝胶，即使在50°C下也能稳定蛋白质的热变性，这可以，与现有技术不同，交付纯净，通过从注射器中机械释放无赋形剂的蛋白质。大分子可以以高达10重量%的量加载而不影响释放机制。这种独特的稳定和无赋形剂的释放协同作用提供了一种实用的，可扩展且多功能的解决方案，以实现低成本、全球无冷链和公平地提供治疗。
