Collaborative Research: Integrative Adaptation of Dendrimer-peptide Conjugates for Cancer Immunotherapy

合作研究：树状聚合物-肽缀合物对癌症免疫治疗的综合适应

• 批准号: 2212123
• 负责人: Petr Kral
• 金额: $ 30万
• 依托单位: University of Illinois at Chicago
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2212123&HistoricalAwards=false
• 关键词: Collaborative; Research; Integrative; Adaptation; Dendrimer

Non-technical SummaryImmunotherapy, utilization of a patient’s own immune system to treat diseases, has revolutionized cancer treatment. Most of the immunotherapeutic drugs that are being used in the clinic are based on biologics, such as antibodies (proteins that bind to specific antigens only), that boost immune surveillance against tumor cells. However, such antibody-based drugs are expensive and often result in disappointing clinical outcomes, particularly when used alone. The use of peptides (macromolecules made from a chain of 20-30 amino acids) would be a promising alternative; however, their weaker binding than the corresponding antibodies has been recognized as a major weakness. Recently, the collaborative team proposing this work have demonstrated that small ball-shaped polymers (size of 1/10,000 of human hair thickness), called poly(amidoamine) (PAMAM) dendrimers, can be engineered to dramatically improve the binding strength of the peptides up to a million times. In this proposal, the team hypothesizes that dendrimers attached with computationally optimized peptides can boost up the immune system to attack tumor cells, thereby maximizing their immunotherapeutic effect. Upon successful completion of this project, the team will contribute to developing a new technology that would be compatible with various immunotherapeutic peptides. Integrated with the research effort, this project includes various educational activities that recruit graduate students, undergraduate students, and high school students. These activities will not only help advanced degree students be actively involved in cutting-edge science but also stimulate STEM interests of pre-college students, which will have profound impact on our nation to maintain the position as the world leader of science and engineering.Technical SummaryThe overarching goal of the research activities is to integrate computational and experimental methods to engineer a nanoparticle platform based on dendrimer-peptide conjugates for enhanced cancer immunotherapy. The collaborative team has demonstrated that poly(amidoamine) (PAMAM) dendrimers are excellent mediators for multivalent binding effects, as observed by dramatically enhanced binding avidities of small molecules, antibodies, and peptides. This nanoengineering approach for binding enhancement could be directly applicable for improving cancer immunotherapy that relies on efficient blocking of binding between immune and tumor cells. Given that strong binding to the target immune checkpoint proteins, such as programmed death-ligand 1 (PD-L1), programmed cell death protein-1 (PD-1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), is necessary to effectively induce the checkpoint blockade, all the FDA-approved immune checkpoint inhibitors (ICIs) to date are based on antibodies with strong binding affinities. Unfortunately, such antibody-based therapeutics are expensive and often result in disappointing clinical outcomes, particularly when used alone. The team hypothesizes that dendrimer conjugation with computationally optimized peptides that target multiple immune checkpoint receptors on T cells would substantially improve the binding strength of otherwise weakly binding peptides, which in turn would maximize their immunotherapeutic efficiency. The use of peptides would be advantageous, as they are cost-effective and amenable to various engineering strategies, in contrast to whole antibodies. The proposed dendrimer-peptide conjugate (DPC) systems, consisting of engineered PAMAM dendrimers functionalized with peptides, are relatively simple in comparison to other commonly used nanoparticle drug delivery systems. Yet, the DPC systems are unique and innovative in that: i) peptides can be adapted and optimized via a high-throughput computation; ii) dendrimers multimerize peptides to exploit strong multivalent binding effects (avidity); iii) folded peptides can be stabilized on the dendrimer surface, further contributing for binding enhancement; and iv) this approach is compatible with virtually any peptides, providing a modular platform for various combinations. Upon successful completion of this project, we will have obtained fundamental understanding in peptide design/synthesis, polymer engineering, and binding kinetics and biological behaviors of the DPCs. The project will broaden participation of underrepresented minorities and women in STEM research at various educational levels.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.

非技术摘要免疫疗法，使用患者自身的免疫疗法系统治疗疾病的利用已彻底改变了癌症治疗。临床中使用的大多数免疫治疗药物都是基于生物制剂的，例如抗体（仅与特定抗原结合的蛋白质），可增强对肿瘤细胞的免疫监视。但是，这种基于抗体的药物很昂贵，通常会导致令人失望的临床结果，尤其是单独使用时。使用Petides（由20-30个氨基酸链制成的大分子）是有希望的选择。但是，它们的结合比相应的抗体被认为是主要弱点。最近，提出这项工作的协作团队表明，小球形聚合物（1/10,000人的毛发厚度），称为poly（amidoamine）（Pamam）树枝状聚合物，可以设计以极大地提高宠物的约束力，高达一百万次。在此提案中，团队假设用计算优化的宠物附着的树枝状聚合物可以增强免疫系统以攻击肿瘤细胞，从而最大程度地发挥其免疫治疗作用。该项目成功完成后，该团队将为开发一种与各种免疫治疗性宠物兼容的新技术。该项目与研究工作集成在一起，包括各种教育活动，招募研究生，本科生和高中生。 These activities will not only help advanced degree students be actively involved in cutting-edge science but also stimulate STEM interests of pre-college students, which will have profound impact on our nation to maintain the position as the world leader of science and engineering.Technical SummaryThe overarching goal of the research activities is to integrate computational and experimental methods to engineer a nanoparticle platform based on dendrimer-peptide conjugates for enhanced cancer immunotherapy.该协作团队已经证明，通过动态增强的小分子，抗体和胡椒体的结合狂热观察到，聚（Amidoamine）（PAMAMINE）（PAMAM）（PAMAM）（PAMAM）是多价结合效应的出色介体。这种用于结合增强的纳米工程方法可能直接适用于改善癌症免疫疗法，该疗法依赖于有效阻断免疫细胞和肿瘤细胞之间结合的结合。鉴于与靶标免疫检查点蛋白（例如编程的死亡 - 指 - 指定）1（PD-L1），程序性细胞死亡蛋白1（PD-1）和细胞毒性T淋巴细胞相关蛋白4（CTLA-4）的结合是有效地诱导基于检查点封锁的所有fda-imuno topoint in in in in in in in in in in in in in in in in in in ICIS，ICIS in ICIS构成了ICIS，因此具有强结合亲和力的抗体。不幸的是，这种基于抗体的治疗剂很昂贵，并且通常会导致令人失望的临床结果，尤其是在单独使用时。团队假设树状聚合物与计算优化的petides结合，靶向T细胞上的多个免疫粘点受体将基本上提高原本弱结合的Petides的结合强度，从而最大程度地提高其免疫治疗效率。与整个抗体相比，使用Petides具有成本效益，并且对各种工程策略都是有利的。与其他常用的纳米粒子药物输送系统相比，由paTIDE功能化的工程PAMAM树状聚合物组成的拟议的树枝状聚合物肽共轭物（DPC）系统相对简单。但是，DPC系统是独特而创新的：i）可以通过高通量计算对Petides进行调整和优化； ii）树枝状聚合物多层次化宠物，以利用强大的多价结合效应（亲和力）； iii）折叠的宠物可以稳定在树枝状大分子表面，进一步有助于结合增强； iv）这种方法几乎与任何宠物兼容，为各种组合提供了模块化平台。成功完成该项目后，我们将获得DPC的肽设计/合成，聚合物工程以及结合动力学和生物学行为的基本理解。该项目将扩大代表性不足的少数群体和妇女在各种教育层面的STEM研究中的参与。该奖项反映了NSF的法定任务，并使用基金会的知识分子优点和更广泛的影响评估标准，被认为是珍贵的支持。