Molecular strategy for developing instant nanomedicine

背景：英国和全球都迫切需要制定战略，在临床设施内或靠近临床设施的地方产生治疗药物，以便及时交付给患者，即护理点(POC)制造。这一概念包括药物、疫苗、细胞和核酸疗法的生产(例如，基因疗法、信使核糖核酸疫苗、纳米药物等)。用于治疗各种疾病，从罕见疾病到更常见的疾病，如癌症、感染、严重烧伤或糖尿病。英国药品和保健产品监管机构(MHRA)最近提出了一个专门针对医院内POC疗法制造的新监管框架。这项计划将缓解使用保质期有限的疗法和供应链问题(如低温储存(例如，信使核糖核酸纳米疫苗))的现有挑战，并将扩大NHS.CHALLENGES新创新疗法的范围和可获得性。该项目涉及：纳米医学尽管在Doxil®、Abraxane®、MarQibo®、Stimuvax®等产品上取得了初步成功和有效性，但尚未充分发挥其潜力。使用固体脂质纳米制剂(如辉瑞/生物技术和莫德纳)的新冠肺炎疫苗面临制造复杂性、配方复杂、放大困难、低溶解度、储存过程中胶体稳定性损失、有限的货架期和严格的储存条件(例如-80°C)等挑战，是限制其全面效果的促成因素。因此，更简单的制造和配方策略以及长期储存稳定性是无法满足的关键需求。AIMS&目标：本项目的主要目标是：合理设计一种分子策略来开发一种可用于即时药物制剂的自组装肽：我们将开发一个设计合理的用于自组装的多肽库，并能够简单快速地将药物包封用于护理点(POC)生产。WP2(9-18个月)：筛选FDA批准的药物和核酸的包封率。建立不同化学结构的信息库：信息库将进行优化，以实现即时协同保存，通过简单的方法，如混合、pH值的微小变化、离子强度、热、氧化还原电位、超声波、涡流等，通过操纵共激活和自组装过程，将包装和自组装成容易的配方，从而实现简单快速的药物配方。建议的INFORM项目与EPSRC的这一呼吁完美地结合在一起，以解决未来药品生产流水线中的关键瓶颈。INFORM建议将通过可能提供高额回报的投机性、高风险的想法来服务于这次呼吁的目的。潜在影响：INFORM方法将解决现有纳米医学和即时护理点制造的主要瓶颈问题之一。将开发一个多肽纳米构造库，用于凝聚和药物和核酸的即时包装。利用所提出的策略设计和使用这种凝聚肽作为特定的纳米配方，从未被开发和测试过。因此，这种创新的方法可以为未来的研究产生重大的改变结果，IP，并可能在临床和商业上对纳米医学和护理点疗法的未来步骤产生重大影响。INFORM的成功将对模块化制造(如医院、全科医生、门诊、药房)、移动制造、POC制造以及潜在的基于家庭的制造产生重大影响，以完成英国的使命。

CONTEXT: There exists a pressing clinical need in the UK and globally to make strategy for generating therapeutics within or in close proximity to clinical facilities for timely delivery to patients, i.e., point-of-care (POC) manufacturing. This concept encompasses the production of drugs, vaccines, cell, and nucleic acid therapies (e.g., gene therapies, mRNA vaccines, nanomedicines, etc.) for the treatment of a diverse array of diseases, ranging from rare conditions to more prevalent ones such as cancer, infections, severe burns, or diabetes.The UK Medicines and Healthcare products Regulatory Agency (MHRA) has recently brought forth a new regulatory framework specifically designed for the in-hospital POC manufacturing of therapies. This initiative will alleviate the existing challenges of using therapeutics with a limited shelf-life and supply-chain issues such as low-temperature storage (e.g., mRNA nanovaccines) and will expand the range and availability of new innovative therapies in the NHS.CHALLENGES THE PROJECT ADDRESSES: Nanomedicine despite its initial successes and effectiveness with products like Doxil®, Abraxane®, Marqibo®, Stimuvax®, etc., it has not fully realized its potential. Challenges such as manufacturing complexity, formulation intricacies, upscaling difficulties, low solubility, colloidal stability loss during storage, limited shelf-life, and stringent storage conditions (e.g., -80 °C), as encountered with COVID-19 vaccines using solid-lipid nano formulations (e.g., Pfizer/BioNTech and Moderna), are contributory factors that limit its full impact.Therefore, a simpler manufacturing and formulation strategy together with long-term stability for storage are unmet crucial needs. We propose to develop an innovative molecular platform for a point-of-care instant nano formulation (inFORM) to address the principal bottleneck of manufacturing therapeutics on-site.AIMS & OBJECTIVES: The focused aims of this project are to:WP1(1-9months) Rationally design a molecular strategy to develop a self-assembled peptide for making instant drug formulation: We will develop a rationally designed peptide library for self-assembly and capable of simple and quick drug encapsulation for point-of-care (POC) manufacturing.WP2(9-18months): Screening encapsulation efficiency for selected FDA approved drugs and nucleic acids with different chemical structure to build inFORM library: The inFORM library will be optimised for instant co-acervation, packaging and self-assembling to an easy formulation by manipulating the co-acervation and self-assembly process by simple methods such as by mixing, small change in pH, ionic strength, heat, redox potential, sonication, vortexing etc for simple and quick drug formulation.The proposed inFORM project is perfectly aligned with this EPSRC call 'to address key bottlenecks in future medicines manufacturing pipeline'. The inFORM proposals will serve the purpose of this call 'through speculative, high-risk ideas that could potentially offer high reward'.POTENTIAL IMPACT: The inFORM approach will address one of the principal bottleneck issues of existing nanomedicine and point-of-care instant manufacturing. A library of peptide nanoarchitectures will be developed for coacervation and instant packaging of drugs and nucleic acids. Designing and employing such coacervating peptides to serve as a specific nano formulation with the proposed strategy has never been developed and tested. Therefore, this innovative approach can generate significant step-change results for future study, IPs, and can have significant impacts on future steps in nanomedicine and point-of care therapy both clinically and commercially. The success of inFORM will have a significant impact on modular manufacture (e.g., hospital, GP, OPD, pharmacies), mobile manufacture, POC manufacture and potentially home-based manufacture to fulfil the UK mission.