Macrophage-specific nanotherapy for breast cancer

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。

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.