Next-generation PEGylation: antifouling and immunoevasive semi-randomized zwitterionic peptides

非技术摘要：该项目将探索使用计算设计的肽来增强药物递送系统，与NSF的使命“促进科学进步”和“促进国家健康繁荣和福利”保持一致。纳米颗粒具有巨大的潜力，可以将新的、非常有前途的治疗药物输送到体内的特定位置，增强药物效力，减少副作用。然而，血液蛋白吸附到纳米颗粒上，导致清除。蛋白质吸附降低了纳米颗粒到达组织靶器官和肿瘤的能力。控制纳米颗粒蛋白质吸附的现有材料在数量上是有限的。此外，它们在反复暴露后参与过敏样免疫系统反应，最近COVID 19的mRNA疫苗强调了这一点。该项目探索了计算设计的具有部分随机序列的肽，以制造一类新的多样化的抗蛋白质吸附选择，通过随机设计，将避免过敏反应和其他长期的免疫副作用。预计这些材料对于多个纳米颗粒系统是通用的，并且将能够改善药物递送。这些研究活动将与罗切斯特正在进行的K-12教育和外展工作，包括“教师教育”计划和研究生/本科生研究员mentorship.Technical摘要：非特异性蛋白吸附纳米颗粒（NP）药物输送系统（DDS）的挑战，通过减少靶组织积累和NP交付功能，并增加在单核吞噬细胞系统（MPS）的脱靶积累NP治疗的巨大前景。目前用于对抗蛋白质吸附的防污材料，如聚（乙二醇），具有有限的化学多样性，并且最近已被证明是抗原性的，如对COVID 19的PEG化mRNA疫苗方法的不良反应所强调的。该项目旨在开发具有半随机序列的计算设计的防污两性离子肽（ZIPs），以创建耐受适应性免疫的多样化的新型防污材料（srZIPs）。计算设计考虑了肽-肽和肽-蛋白质相互作用，并评估了具有最低相互作用潜力的潜在ZIP，以及保持总体相互作用特征以允许ZIP组成的半随机化以实现多样性的氨基酸取代。将在现有NP制剂中测试srZIP并直接与PEG化进行比较。通过研究设计参数、体外行为、生物分布、药代动力学和免疫原性之间的联系，该项目将进一步了解防污材料成分和临床相关NP性能参数之间的相互作用，同时建立一个新的防污材料类别，该奖项反映了NSF的法定使命，并被认为是值得通过使用基金会的知识产权进行评估的支持。优点和更广泛的影响审查标准。

Non-Technical Summary:This project will explore the use of computationally designed peptides to enhance drug delivery systems, aligning with NSF’s mission ‘To promote the progress of science’ and ‘to advance the national health prosperity, and welfare’. Nanoparticles have tremendous potential for delivering new, highly promising therapeutics to specific locations withing the body, enhancing drug potency, and reducing side-effects. However, blood proteins adsorb to nanoparticles, resulting in clearance. Protein adsorption reduces the ability of nanoparticles to reach tissue targets organs and tumors. Existing materials to control nanoparticle protein adsorption are limited in number. Furthermore, they are implicated in allergy-like immune system responses after repeated exposures, which has been highlighted recently by the mRNA vaccines for COVID19. This project explores computationally designed peptides with partially randomized sequences to make a new class of diverse anti-protein adsorption options, which, through randomized design, will avoid allergic reactions and other long-term immunological side effects. These materials are expected to be versatile for multiple nanoparticle systems and will enable improved drug delivery. The research activities will be integrated with Rochester’s ongoing K-12 education and outreach efforts, including the “Teach for Teachers” program and graduate/undergraduate researcher mentorship.Technical Summary:Non-specific protein adsorption to nanoparticle (NP) drug delivery systems (DDS) has challenged the tremendous promise of NP therapeutics by reducing target tissue accumulation and NP delivery function and increasing off-target accumulation in the mononuclear phagocyte system (MPS). Anti-fouling materials currently used to combat protein adsorption, such as poly(ethylene glycol), have limited chemical diversity and have been recently demonstrated to be antigenic, as highlighted by adverse reactions to PEGylated mRNA vaccine approaches for COVID19. This project seeks to develop computationally designed anti-fouling zwitterionic peptides (ZIPs) with semi-randomized sequences to create a diverse new class of anti-fouling materials (srZIPs) resistant to adaptive immunity. The computational design considers peptide-peptide and peptide-protein interactions and evaluates potential ZIPs with the lowest interaction potential, as well as amino acid substitutions that maintain overall interaction character to allow semi-randomization of ZIP composition for diversity. srZIPs will be tested in existing NP formulations and compared directly to PEGylation. By investigating links between design parameters, in vitro behavior, biodistribution, pharmacokinetics, and immunogenicity, this project will further the understanding of the interplay between anti-fouling material composition and clinically relevant NP performance parameters while establishing a new category of anti-fouling functionalities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.