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Macrophage-specific nanotherapy for breast cancer

乳腺癌巨噬细胞特异性纳米疗法

基本信息

批准号：
10441570
负责人：
Bryan Ronain Smith
金额：
$ 45.49万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-04 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10441570
关键词：
4T1 Address Anemia Animals Anti-CD47 Antibodies Apoptotic Beds Binding Biological Assay Blocking Antibodies Blood Breast Cancer Model CD47 gene CD47-SIRPα Cell Survival Cell surface Cells Charge Chemicals Clinical Dangerousness Data Dendritic Cells Drug Delivery Systems Eating Endocytic Vesicle Endosomes Enzyme Inhibitor Drugs Equus caballus Excision Fluorescence Microscopy Frequencies High Pressure Liquid Chromatography Homing Human Hyperbilirubinemia Immune Immune mediated destruction Immune system In Vitro Incubated Inflammatory Inflammatory Infiltrate Kinetics Leukocytes Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Measures Mediating Membrane Methods Mus NR0B2 gene Oncology PTPN6 gene Pathway interactions Peptides Phagocyte Bactericidal Dysfunction Phagocytes Phagocytosis Pharmaceutical Preparations Physiological Process Protein Tyrosine Phosphatase Protocols documentation Reticulocytosis Rodent Safety Signal Pathway Signal Transduction Solid Neoplasm Spectrum Analysis Surface Testing Therapeutic Toxic effect Translating Translations Treatment Efficacy Tumor Burden Tumor-infiltrating immune cells anti-cancer base cancer cell cancer immunotherapy cell growth cell type clinical translation cytokine design dosage in vivo in vivo evaluation inhibitor innovation intravital microscopy macrophage malignant breast neoplasm monocyte mouse model nanoparticle nanoparticle delivery nanotherapy neoplastic cell nonhuman primate novel overexpression patient derived xenograft model prevent receptor receptor binding side effect single walled carbon nanotube small molecule small molecule inhibitor spatiotemporal trafficking translational therapeutics tumor tumor growth tumor progression uptake

项目摘要

PROJECT SUMMARY/ABSTRACT Healthy ‘phagocytosis’ — a process by which foreign cells such as tumor cells and apoptotic debris are engulfed and removed by inflammatory monocytes and macrophages — is a defense against cancer, including breast cancer. However, phagocytosis against cancer can become inhibited by ‘don’t eat me’ signaling caused by overexpression of CD47 on the surface of solid tumor cells. Remarkably, anti-CD47 antibodies can restore phagocytosis of tumor cells, causing tumors to shrink or stabilize. Unfortunately, these antibodies may also sometimes have severe side effects, especially anemia and reticulocytosis. This project addresses the challenge of restoring phagocytosis against solid tumors via the CD47 pathway without the side effects of anti-CD47 antibodies. We will do this by testing nanoparticles we developed to selectively deliver small molecule inhibitors of the enzyme SHP1 intracellularly into inflammatory monocytes and macrophages within breast tumors. SHP1 is part of the CD47 signaling pathway within macrophages and an excellent target for restoring phagocytosis without side effects. Strong evidence indicates our nanoparticles can act as a kind of Trojan horse to deliver small molecule drugs selectively into inflammatory monocytes and macrophages that infiltrate solid tumors. We will reveal the mechanisms of: A) selective nanoparticle uptake; and B) in vivo nanoparticle delivery of SHP1 inhibitors in 2 murine breast cancer models. Aim 1 will identify the nanoparticle uptake receptor and elucidate the mechanisms of nanoparticle uptake and persistence in tumors. Aim 2 will test nanoparticles for selectively releasing SHP1 inhibitors inside inflammatory macrophages, then restoring phagocytosis and shrinking tumors in vivo without causing anemia and reticulocytosis. Impact: This project will advance understanding of the CD47 pathway in cancer, develop an intracellular therapeutic approach to inhibit CD47-related signaling, help remove a major barrier to progress in oncology — the lack of selective drug delivery into inflammatory monocytes and macrophages, and advance design principles for translational therapies based on in vivo immune cell selectivity.

项目摘要/摘要健康的“吞噬”--外来细胞，如肿瘤细胞和凋亡碎片 -被炎性单核细胞和巨噬细胞吞噬和清除-是抗癌的一种防御措施，包括乳腺癌。然而，对癌症的吞噬作用可能会受到“不要吃我”信号的抑制 CD47在实体瘤细胞表面过表达。值得注意的是，抗CD47抗体可以恢复肿瘤细胞的吞噬功能，导致肿瘤缩小或稳定下来。不幸的是，这些抗体有时也可能有严重的副作用，特别是贫血和网织红细胞增多症。这个项目解决了通过CD47途径恢复对实体瘤的吞噬功能的挑战没有抗CD47抗体的副作用。我们将通过测试我们开发的纳米颗粒来实现这一点选择性地将SHP1酶的小分子抑制剂输送到炎性单核细胞内乳腺肿瘤内的巨噬细胞。SHP1是巨噬细胞内CD47信号通路的一部分恢复吞噬功能的极佳靶点，且无副作用。强有力的证据表明，我们的纳米颗粒可以充当一种特洛伊木马来运送小分子药物选择性地进入浸润性实体瘤的炎性单核细胞和巨噬细胞。我们将揭晓机制：A)选择性纳米颗粒摄取；以及B)SHP1抑制剂在体内的纳米颗粒在2 小鼠乳腺癌模型。目标1将鉴定纳米颗粒摄取受体并阐明肿瘤中纳米颗粒摄取和持续存在的机制。AIM 2将有选择地测试纳米颗粒在炎性巨噬细胞内释放SHP1抑制物，恢复吞噬功能，缩小肿瘤体内不会引起贫血和网织红细胞增多症。影响：该项目将促进对CD47途径在癌症中的理解，开发一种细胞内抑制CD47相关信号的治疗方法，有助于消除肿瘤学进展的主要障碍- 缺乏对炎性单核细胞和巨噬细胞的选择性药物输送，以及先进的设计基于体内免疫细胞选择性的转化性治疗原则。