A Wholly Protein-based Self-assembly Nanoplatform for TNBC-specific Combination Therapy

用于 TNBC 特异性联合治疗的完全基于蛋白质的自组装纳米平台

• 批准号: 10668398
• 负责人: Rihe Liu
• 金额: $ 47.37万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668398
• 关键词: Address; Antigens; Binding; Biological Process; Body Temperature; Breast Cancer Cell; Breast Cancer cell line; Calmodulin; Chemoresistance; Chimeric Proteins; Combination immunotherapy; Combined Modality Therapy; Cysteine; Development; Docking; ERBB2 gene; ERBB3 gene; Elastin; Engineering; Epidermal Growth Factor Receptor; Estrogen Receptors; FZD7 gene; Genes; Genetic; Genetic Engineering; Histopathologic Grade; Homing; Human; Human body; Hydrolysis; Immunosuppression; Mediating; Micelles; Monoclonal Antibodies; Mus; Neoplasm Metastasis; Nucleosome Core Particle; PIK3CG gene; Pathway interactions; Peptides; Process; Progesterone Receptors; Proteins; Recombinant Proteins; Recombinants; Relapse; Side; Small Interfering RNA; Specificity; Surface; Surface Antigens; System; Temperature; Tertiary Protein Structure; Therapeutic; Therapeutic Agents; Therapeutic Studies; Toxic effect; Treatment Efficacy; WNT Signaling Pathway; antigen binding; cancer type; chemical conjugate; chemotherapy; ecto-nucleotidase; effective therapy; extracellular; high risk; hormone receptor-positive; immunogenicity; inhibitor; innovation; interest; malignant breast neoplasm; mouse model; nanobodies; nanometer; nanoparticle; nanotechnology platform; novel; overexpression; phosphatidylinositol 3-kinase gamma; polypeptide; programmed cell death ligand 1; receptor; self assembly; siRNA delivery; standard care; stemness; targeted delivery; targeted treatment; triple-negative invasive breast carcinoma; tumor; tumor initiation

Abstract Triple-negative breast cancer (TNBC) is a unique type of breast cancer that does not express or overexpress estrogen receptor (ER), progesterone receptor (PR), and HER2. During the past several decades, the standard care of TNBC remains the highly toxic chemotherapy with little progress in more effective treatments. To address the urgent unmet need to develop targeted therapies specific for TNBC, we developed a totally protein-based nanoplatform called ProNano that is composed of two recombinant proteins, including the first an elastin-like polypeptide (ELP) nanocore that displays multiple calmodulin-binding short peptides on the surface, and the second a recombinant calmodulin protein genetically fused with a highly stable and modular protein domain possessing either tumor homing or therapeutic features. The docking of the ELP nanocore with a TNBC- targeting module together with a functional module with therapeutic feature results in bifunctional ProNanos that can be used for tumor-homing delivery of therapeutic agents for the combination therapy for TNBC. Three specific aims will be pursued in this project. The first specific aim is to develop a ProNano platform that allows tunable targeting of TNBC cells based on their surface antigen expression profiles. The second specific aim is to develop a bifunctional ProNano platform that allows tumor-specific blockade of the aberrant Wnt signaling for the treatment of TNBC. The third specific aim is to develop a bifunctional ProNano platform that allows tumor- specific inhibition of the ENPP1-catalyzed hydrolysis of extracellular cGAMP for combination immunotherapy of TNBC. The bifunctional ProNano platforms developed in this project have several major advantages over conventional nanoplatforms, including all protein components each can be precisely and genetically engineered, oriented and self-assembled introduction of both tumor homing and/or therapeutic moieties at desired ratios without need of any chemical conjugation, and use of highly stable and easily expressed modular polypeptides with no or low immunogenicity. Although we focus on the targeted treatment for TNBC, the ProNano platforms developed in this project can be easily adapted to address other cancer types simply by changing the tumor targeting module.

抽象的 三阴性乳腺癌 (TNBC) 是一种独特的乳腺癌类型，不表达或不表达 过度表达雌激素受体 (ER)、孕激素受体 (PR) 和 HER2。在过去的几十年里， TNBC 的标准治疗仍然是高毒性化疗，在更有效的治疗方面几乎没有进展。 为了解决开发针对 TNBC 的靶向疗法的迫切未满足的需求，我们开发了一种完全 基于蛋白质的纳米平台称为 ProNano，由两种重组蛋白质组成，其中第一个是 弹性蛋白样多肽（ELP）纳米核心，在表面显示多个钙调蛋白结合短肽， 第二个是与高度稳定和模块化的蛋白质基因融合的重组钙调蛋白 具有肿瘤归巢或治疗特征的结构域。 ELP 纳米核心与 TNBC 的对接 靶向模块与具有治疗功能的功能模块一起形成双功能 ProNanos， 可用于TNBC联合疗法的治疗剂的肿瘤归巢递送。三 该项目将追求具体目标。第一个具体目标是开发一个 ProNano 平台，允许 基于 TNBC 细胞表面抗原表达谱的可调靶向。第二个具体目标是 开发双功能 ProNano 平台，允许肿瘤特异性阻断异常 Wnt 信号传导 TNBC 的治疗。第三个具体目标是开发一个双功能 ProNano 平台，允许肿瘤 特异性抑制 ENPP1 催化的细胞外 cGAMP 水解，用于联合免疫治疗 TNBC。该项目开发的双功能ProNano平台与其他平台相比具有几大优势 传统的纳米平台，包括所有蛋白质成分，每个都可以精确地进行基因工程， 以所需比例定向和自组装引入肿瘤归巢和/或治疗部分 无需任何化学缀合，使用高度稳定且易于表达的模块化多肽 没有或低免疫原性。虽然我们专注于TNBC的靶向治疗，但ProNano平台 该项目中开发的产品可以轻松地通过改变肿瘤来适应其他癌症类型 目标模块。