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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

基本信息

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
项目类别：
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

项目摘要

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.

摘要