Engineering Exosome for Pancreatic Cancer Targeting Therapies

用于胰腺癌靶向治疗的外泌体工程

基本信息

批准号：
10803020
负责人：
Shi-He Liu
金额：
$ 49.8万
依托单位：
UNIVERSITY OF TOLEDO HEALTH SCI CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-21 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10803020
关键词：
3-Dimensional Adjuvant Therapy Binding CD47 gene Cancer Biology Cells Cessation of life Circulation DNA Data Development Diagnostic Disease Drug Carriers Drug Delivery Systems Eating Engineering Epidermal Growth Factor Receptor Exhibits Future Gene Delivery Genetic Engineering Genetically Engineered Mouse Goals Heterogeneity Homing Human In Vitro Integrins Knowledge Lead Lipids Liposomes Liver Macrophage Malignant Neoplasms Malignant neoplasm of pancreas Medicine Metabolic Clearance Rate Modeling Mononuclear Nanodelivery Operative Surgical Procedures Outcome Pancreatic Ductal Adenocarcinoma Patients Penetration Peptides Phagocytes Phagocytosis Pharmaceutical Preparations Property Proteins RNA Regimen Research SHPS-1 protein Signal Transduction Site Solid Spleen Surface System Techniques Technology Testing Therapeutic Therapeutic Effect Tumor Escape United States Work biomaterial compatibility cancer cell cancer therapy chemotherapy clinically relevant cytotoxic delivery vehicle efficacy evaluation efficacy validation engineered exosomes exosome extracellular extracellular vesicles immunogenicity improved in vitro Model in vivo in vivo Model innovation macromolecule mouse model nanocarrier nanoparticle nanoscale neoplastic cell novel novel therapeutic intervention overexpression pancreas xenograft pancreatic PDX models pancreatic cancer cells pancreatic ductal adenocarcinoma cell prevent receptor binding small molecule success targeted cancer therapy targeted treatment translational potential tumor uptake

项目摘要

Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest cancers and ranks fourth in cancer- related deaths in the United States. Therapies for pancreatic cancer are largely hindered by the lack of an effective delivery system. Exosomes are emerging as a promising type of nanocarrier for drug/gene delivery due to the unique properties of these naturally derived, nanoscale extracellular vesicles and their innate ability to shuttle proteins, lipids and DNA/RNA between cells. However, major challenges exist, including their inability to target tumor cells and their high proportion of clearance by the mononuclear phagocyte system (MPS) of the liver and spleen. Our long-term goal is to develop innovative nanocarriers with low immunogenicity, high biocompatibility, increased stability, longer circulation times, and highly active tumor cell targeting. Using novel exosomal engineering techniques, we recently found that (a) incorporation of a tumor-homing peptide (RGD) onto exosomal surface marker CD9 (ExoCD9-RGD) results in specific binding to and uptake by integrin v3- expressing cancer cells, and (b) exosomes overexpressing CD47, a “don’t eat me” signal, via its minimal self- peptide (CD47p110-130), interact with signal regulatory proteins (SIRP, CD172A) on macrophages to significantly reduce liver and spleen clearance of exosomes. These findings lead to our central hypothesis that displaying RGD and CD47p110-130 on exosomes through CD9 engineering will permit exosomes to target PDAC in vivo while allowing exosomes to evade MPS clearance. Toward this hypothesis, we have developed “smart exosomes” by co-displaying RGD and CD47p110-130 on the exosome surface (ExoSmart). This results in enhanced receptor binding, thereby increasing accumulation and cytotoxic therapeutic effects in 3D stroma-rich PDAC spheroid tumor models. With these strong preliminary data, we propose to pursue three Specific Aims to characterize ExoSmart and validate the application of ExoSmart in drug delivery. (1) To evaluate smart exosomes co-expressing CD9- RGD and CD9-CD47p110-130 (ExoSmart) for exclusive active PDAC targeting therapy using human PDAC stroma- rich 3D spheroid models, both in vitro and in vivo. (2) To validate the efficacy of ExoSmart PDAC targeting chemotherapies in a genetically engineered mouse PDAC tumor model (KPC) and clinically relevant patient- derived xenografted (PDX) pancreatic cancer mice models. (3) To extend ExoSmart to personalized PDAC targeting by optimizing multiple insertion sites of CD9 and tumor-targeting peptides for optimal PDAC targeting. Collectively, our proposed research will broadly impact the field by developing innovative nanocarriers with optimized cargos and surfaces for precision PDAC targeting. This project holds great translational potential for cancer therapy while providing a solid basis for future work utilizing novel peptide-engineered exosome strategies.

胰腺导管腺癌（PDAC）是最致命的癌症之一，在癌症中排名第四美国相关死亡。缺乏胰腺癌的疗法很大程有效的交付系统。外泌体正在作为用于药物/基因递送的纳米载体的承诺类型这些天然衍生的纳米级细胞外蔬菜的独特特性及其先天的能力穿梭蛋白，脂质和细胞之间的DNA/RNA。但是，存在主要挑战，包括无法靶向肿瘤细胞及其通过单核吞噬细胞系统（MPS）的高比例清除率肝脏和脾脏。我们的长期目标是开发具有低免疫原性的创新纳米载体，高生物相容性，稳定性提高，循环时间更长和高度活性的肿瘤细胞靶向。使用小说外泌体工程技术，我们最近发现（a）掺入肿瘤的肽（RGD）进入外泌体表面标记CD9（EXOCD9-RGD）会导致整合素v3-的特异性结合并摄取表达癌细胞和（b）外泌体过表达CD47，即“不要吃我”信号，通过其最小的自我自我信号 Pepperide（CD47P110-130），与巨噬细胞上的信号调节蛋白（SIRP，CD172A）相互作用，以显着减少肝脏和脾外泌体清除。这些发现导致我们的中心假设表明 RGD和CD47P110-130通过CD9工程进行外泌体上允许外泌体逃避MPS间隙。为了这一假设，我们开发了“智能外来” 外泌体表面上的共同播放RGD和CD47P110-130（ExoSmart）。这导致增强的接收器结合，从而增加富3D基质PDAC球体肿瘤的积累和细胞毒性疗法的影响型号。有了这些强大的初步数据，我们建议追求三个特定的目标来表征外部并验证Exosmart在药物输送中的应用。（1）评估智能外泌体共表达CD9- RGD和CD9-CD47P110-130（EXOSMART）用于使用人PDAC基质 - 体外和体内富3D球体模型。（2）验证Exosmart PDAC靶向的效率一般设计的小鼠PDAC肿瘤模型（KPC）和临床相关的患者中的化学疗法衍生的异种移植（PDX）胰腺癌小鼠模型。（3）将EXOSMART扩展到个性化的PDAC 通过优化CD9的多个插入位点和靶向肿瘤的肽来靶向，以实现最佳PDAC靶向。总的来说，我们拟议的研究将通过与优化的尺骨和表面可用于精确的PDAC靶向。该项目具有巨大的翻译潜力癌症疗法同时为未来的工作提供了良好的基础，利用新型肽工程外泌体策略。