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:
- 金额:$ 49.8万
- 依托单位:
- 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:
- 关键词:3-DimensionalAdjuvant TherapyBindingCD47 geneCancer BiologyCellsCessation of lifeCirculationDNADataDevelopmentDiagnosticDiseaseDrug CarriersDrug Delivery SystemsEatingEngineeringEpidermal Growth Factor ReceptorExhibitsFutureGene DeliveryGenetic EngineeringGenetically Engineered MouseGoalsHeterogeneityHomingHumanIn VitroIntegrinsKnowledgeLeadLipidsLiposomesLiverMacrophageMalignant NeoplasmsMalignant neoplasm of pancreasMedicineMetabolic Clearance RateModelingMononuclearNanodeliveryOperative Surgical ProceduresOutcomePancreatic Ductal AdenocarcinomaPatientsPenetrationPeptidesPhagocytesPhagocytosisPharmaceutical PreparationsPropertyProteinsRNARegimenResearchSHPS-1 proteinSignal TransductionSiteSolidSpleenSurfaceSystemTechniquesTechnologyTestingTherapeuticTherapeutic EffectTumor EscapeUnited StatesWorkbiomaterial compatibilitycancer cellcancer therapychemotherapyclinically relevantcytotoxicdelivery vehicleefficacy evaluationefficacy validationengineered exosomesexosomeextracellularextracellular vesiclesimmunogenicityimprovedin vitro Modelin vivoin vivo Modelinnovationmacromoleculemouse modelnanocarriernanoparticlenanoscaleneoplastic cellnovelnovel therapeutic interventionoverexpressionpancreas xenograftpancreatic PDX modelspancreatic cancer cellspancreatic ductal adenocarcinoma cellpreventreceptor bindingsmall moleculesuccesstargeted cancer therapytargeted treatmenttranslational potentialtumoruptake
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 v3-
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,
在美国的相关死亡。胰腺癌的治疗在很大程度上受到缺乏有效治疗的阻碍。
有效的交付系统。外泌体正在成为一种有前途的药物/基因递送纳米载体,
这些天然衍生的纳米级细胞外囊泡的独特性质及其固有的能力,
穿梭蛋白、脂质和细胞间的DNA/RNA。然而,仍然存在重大挑战,包括它们无法
靶向肿瘤细胞及其被单核吞噬细胞系统(MPS)清除的高比例
肝脏和脾脏。我们的长期目标是开发具有低免疫原性、高免疫原性和高免疫原性的创新纳米载体。
生物相容性、增加的稳定性、更长的循环时间和高度活性的肿瘤细胞靶向。使用新颖
外泌体工程技术,我们最近发现(a)掺入肿瘤归巢肽(RGD),
外泌体表面标记物CD 9(ExoCD 9-RGD)上的结合导致与整合素CD 3- 1特异性结合并被其摄取。
表达癌细胞的外泌体,和(B)过表达CD 47(一种“不要吃我”信号)的外泌体,通过其最小的自我调节,
肽(CD 47 p110 -130),与巨噬细胞上的信号调节蛋白(SIRP β,CD 172 A)相互作用,
减少肝脏和脾脏对外来体的清除。这些发现引出了我们的核心假设,
通过CD 9工程化在外来体上的RGD和CD 47 p110 -130将允许外来体在体内靶向PDAC,
从而使外来体逃避MPS清除。为了实现这一假设,我们通过以下方式开发了“智能外泌体”:
在外泌体表面共展示RGD和CD 47 p110 -130(ExoSmart)。这导致增强的受体结合,
从而增加3D富含基质的PDAC球状体肿瘤中的积累和细胞毒性治疗效果
模型有了这些强有力的初步数据,我们建议追求三个具体目标来表征ExoSmart
并验证ExoSmart在药物输送中的应用。(1)为了评估共表达CD 9-CD 8的智能外泌体,
RGD和CD 9-CD 47 p110 -130(ExoSmart)用于使用人PDAC基质的独家主动PDAC靶向治疗-
丰富的3D球体模型,包括体外和体内。(2)验证ExoSmart PDAC靶向的有效性
基因工程小鼠PDAC肿瘤模型(KPC)和临床相关患者中的化疗-
衍生的异种移植(PDX)胰腺癌小鼠模型。(3)将ExoSmart扩展到个性化PDAC
通过优化CD 9和肿瘤靶向肽的多个插入位点进行靶向,以实现最佳PDAC靶向。
总的来说,我们提出的研究将通过开发创新的纳米载体来广泛影响该领域,
优化的货物和表面,以实现精确的PDAC目标。该项目具有巨大的翻译潜力,
癌症治疗,同时为未来利用新型肽工程化外泌体的工作提供坚实的基础
战略布局
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Shi-He Liu其他文献
Shi-He Liu的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
Countering sympathetic vasoconstriction during skeletal muscle exercise as an adjuvant therapy for DMD
骨骼肌运动期间对抗交感血管收缩作为 DMD 的辅助治疗
- 批准号:
10735090 - 财政年份:2023
- 资助金额:
$ 49.8万 - 项目类别:
The ESCAPE clinical trial of circulating tumor DNA to guide adjuvant therapy in chemo-resistant triple negative breast cancer
循环肿瘤 DNA 指导化疗耐药三阴性乳腺癌辅助治疗的 ESCAPE 临床试验
- 批准号:
494901 - 财政年份:2023
- 资助金额:
$ 49.8万 - 项目类别:
Operating Grants
A Type I Hybrid Effectiveness-Implementation Trial to Evaluate a Navigation-Based Multilevel Intervention to Decrease Delays Starting Adjuvant Therapy Among Patients with Head and Neck Cancer
一项 I 型混合有效性实施试验,用于评估基于导航的多级干预措施,以减少头颈癌患者开始辅助治疗的延迟
- 批准号:
10714537 - 财政年份:2023
- 资助金额:
$ 49.8万 - 项目类别:
Multi-modal machine learning to guide adjuvant therapy in surgically resectable colorectal cancer
多模式机器学习指导可手术切除结直肠癌的辅助治疗
- 批准号:
10588103 - 财政年份:2023
- 资助金额:
$ 49.8万 - 项目类别:
Efficacy of ethanol adjuvant therapy after resection of malignant soft tissue tumors
恶性软组织肿瘤切除术后乙醇辅助治疗的疗效
- 批准号:
22K09407 - 财政年份:2022
- 资助金额:
$ 49.8万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Identification of immune response cells and development of novel adjuvant therapy for sublingual immunotherapy
免疫应答细胞的鉴定和舌下免疫治疗新型辅助疗法的开发
- 批准号:
21KK0287 - 财政年份:2022
- 资助金额:
$ 49.8万 - 项目类别:
Fund for the Promotion of Joint International Research (Fostering Joint International Research (A))
Pursuing molecular biomarkers to guide adjuvant therapy for HPV+ head and neck cancers after transoral robotic surgery
寻找分子生物标志物来指导经口机器人手术后 HPV 头颈癌的辅助治疗
- 批准号:
10357120 - 财政年份:2022
- 资助金额:
$ 49.8万 - 项目类别:
Biomarker research using two prospective studies on preoperative and postoperative adjuvant therapy for pancreatic cancer
使用两项关于胰腺癌术前和术后辅助治疗的前瞻性研究进行生物标志物研究
- 批准号:
21K08700 - 财政年份:2021
- 资助金额:
$ 49.8万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Personalized Resistant Starch as an Adjuvant Therapy for Pediatric Inflammatory Bowel Disease
个性化抗性淀粉作为小儿炎症性肠病的辅助治疗
- 批准号:
437315 - 财政年份:2020
- 资助金额:
$ 49.8万 - 项目类别:
Studentship Programs
Tailored adjuvant therapy in POLE-mutated and p53-wildtype early stage endometrial cancer (TAPER)
POLE 突变和 p53 野生型早期子宫内膜癌 (TAPER) 的定制辅助治疗
- 批准号:
435603 - 财政年份:2020
- 资助金额:
$ 49.8万 - 项目类别:
Operating Grants