Exosomes as carriers of cancer therapeutics

外泌体作为癌症治疗的载体

基本信息

项目摘要

Effective treatment of lung cancer remains a formidable clinical challenge. The advent of molecularly- targeted therapies and immune checkpoint inhibitors has shown promise in lung cancer treatment. However, only a subset of lung cancer patients benefit from these therapies. Further, inefficient delivery and accumulation of anticancer drugs in tumor depots combined with dose-limiting toxicity contributes to disease relapse, drug resistance, and metastasis culminating in patient death. As a result, the overall survival rate of lung cancer patients is <16%. Thus, testing of new therapeutics and novel drug delivery systems that can efficiently transport anticancer drugs to tumor depots and kill cancer cells are necessary for improving treatment outcomes. In the present application, we propose testing “exosomes” as drug carriers for cancer therapy. The exosomes derived from normal human lung fibroblast and murine fibroblast cell-derived exosomes (Exo) are loaded with iron-oxide nanoparticles (IONP) carrying an anticancer drug [Doxorubicin (Dox), Cisplatin (CDDP)]. The release of the chemodrug from the IONP is controlled by a pH responsive linker thereby minimizing drug- related toxicity to normal cells. Further, the drug-IONP loaded exosome is decorated with a tumor-targeted ligand for enhancing tumor-specific drug delivery and reducing cytotoxicity to normal cells. Finally, inclusion of IONP enables monitoring tumor growth and treatment response by magnetic resonance imaging (MRI). Pilot studies demonstrated exosomes could be successfully loaded with Dox-, and CDDP-conjugated IONP. Further, excellent drug loading efficiency and drug release kinetics was demonstrated from the exosomes. In vitro studies showed chemodrug-loaded exosomes exerted significant cytotoxicity towards cancer cells but not normal cells. MRI and SQUID studies showed drug-loaded exosomes provided good contrast image without losing the superparamagnetic properties of IONP. Furthermore, tumor-targeted (tt) exosomes directed towards transferrin receptor (TfR) overexpressing lung cancer cells exhibited greater cytotoxicity compared to non- targeted exosomes and accumulated in the tumor xenograft resulting in in vivo efficacy. Based on our compelling preliminary data, we hypothesize that tt-exosomes will efficiently deliver chemotherapeutics to tumor cells and concurrently enable measurement of treatment response by MRI with minimal toxicity to normal cell when tested both, in vitro and in vivo. We will conduct the proposed studies under the following two specific aims. Aim 1a. Physico-biological characterization of tt-exosome as drug carriers for use in in vitro and in vivo studies. Aim 1b. Determine the efficacy of tt-exosome against human and mouse lung cancer and normal cells, spheroids and organoids in vitro. Aim 2. Investigate the in vivo antitumor activity of tt-exosome against lung tumor models.
肺癌的有效治疗仍然是一个艰巨的临床挑战。分子学的出现- 靶向疗法和免疫检查点抑制剂在肺癌治疗中显示出前景。然而,在这方面, 只有一部分肺癌患者受益于这些疗法。此外,交付效率低下, 抗癌药物在肿瘤贮库中的积累结合剂量限制性毒性有助于疾病 复发、耐药性和转移,最终导致患者死亡。因此, 肺癌患者<16%。因此,测试新的治疗剂和新的药物递送系统, 有效地将抗癌药物运输到肿瘤库并杀死癌细胞是改善肿瘤的必要条件。 治疗结果。 在本申请中,我们提出测试“外来体”作为癌症治疗的药物载体。的 来源于正常人肺成纤维细胞的外泌体和来源于鼠成纤维细胞的外泌体(Exo), 装载有携带抗癌药物[多柔比星(Dox)、顺铂(CDDP)]的氧化铁纳米颗粒(IONP)。 化学药物从IONP的释放由pH响应性连接体控制,从而使药物释放最小化。 对正常细胞的毒性。此外,负载药物-IONP的外泌体用肿瘤靶向的寡核苷酸修饰。 用于增强肿瘤特异性药物递送和降低对正常细胞的细胞毒性的配体。最后,包括 IONP能够通过磁共振成像(MRI)监测肿瘤生长和治疗反应。 初步研究表明,外泌体可以成功地负载Dox-和CDDP-缀合的IONP。 此外,从外来体证明了优异的药物装载效率和药物释放动力学。在 体外研究表明,装载化学药物的外泌体对癌细胞具有显著的细胞毒性, 正常细胞MRI和SQUID研究显示,载药外泌体提供了良好的对比度图像, 失去了IONP的超顺磁性。此外,肿瘤靶向(tt)外泌体针对 转铁蛋白受体(TfR)过表达的肺癌细胞表现出更大的细胞毒性相比,非 靶向外泌体并在肿瘤异种移植物中积累,从而产生体内功效。基于我们 令人信服的初步数据,我们假设TT-外泌体将有效地递送化疗药物, 肿瘤细胞,同时能够通过MRI测量治疗反应,对肿瘤细胞的毒性最小, 在体外和体内测试时,正常细胞。我们会根据以下两项建议进行研究 具体目标。 目标1a。tt-外泌体作为药物载体在体内外研究中的物理生物学特性。 目标1b。确定tt-外泌体对人和小鼠肺癌和正常细胞的功效, 类球体和类器官。 目标二。研究tt-外泌体对肺肿瘤模型的体内抗肿瘤活性。

项目成果

期刊论文数量(0)
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 }}

Rajagopal Ramesh其他文献

Rajagopal Ramesh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 }}

{{ truncateString('Rajagopal Ramesh', 18)}}的其他基金

Engineered Nanoformulation for Immune-modulation in Cancer
用于癌症免疫调节的工程纳米制剂
  • 批准号:
    10719487
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
ShEEP Request for CytoViva 3D Darkfield Hyperspectral Microscope
ShEEP 请求 CytoViva 3D 暗场高光谱显微镜
  • 批准号:
    9906462
  • 财政年份:
    2019
  • 资助金额:
    $ 57.62万
  • 项目类别:
An improved IL-24 gene-based therapeutic for cancer
改进的基于 IL-24 基因的癌症疗法
  • 批准号:
    10326352
  • 财政年份:
    2019
  • 资助金额:
    $ 57.62万
  • 项目类别:
An improved IL-24 gene-based therapeutic for cancer
改进的基于 IL-24 基因的癌症疗法
  • 批准号:
    10544003
  • 财政年份:
    2019
  • 资助金额:
    $ 57.62万
  • 项目类别:
Cancer Research Training and Education Coordination
癌症研究培训和教育协调
  • 批准号:
    10627028
  • 财政年份:
    2018
  • 资助金额:
    $ 57.62万
  • 项目类别:
Molecular Impact of Platinum Drugs on the Proteasome and SQSTM1_P62 Complexes_A Paradigm Shift in Resistance
铂类药物对蛋白酶体和 SQSTM1_P62 复合物的分子影响_耐药范式转变
  • 批准号:
    10051382
  • 财政年份:
    2017
  • 资助金额:
    $ 57.62万
  • 项目类别:
Molecular Impact of Platinum Drugs on the Proteasome and SQSTM1_P62 Complexes_A Paradigm Shift in Resistance
铂类药物对蛋白酶体和 SQSTM1_P62 复合物的分子影响_耐药范式转变
  • 批准号:
    9478535
  • 财政年份:
    2017
  • 资助金额:
    $ 57.62万
  • 项目类别:
HuR Targeted Nanotherapy for Lung Cancer
HuR 靶向纳米疗法治疗肺癌
  • 批准号:
    8601528
  • 财政年份:
    2013
  • 资助金额:
    $ 57.62万
  • 项目类别:
HuR Targeted Nanotherapy for Lung Cancer
HuR 靶向纳米疗法治疗肺癌
  • 批准号:
    8785610
  • 财政年份:
    2013
  • 资助金额:
    $ 57.62万
  • 项目类别:
HuR Targeted Nanotherapy for Lung Cancer
HuR 靶向纳米疗法治疗肺癌
  • 批准号:
    8440451
  • 财政年份:
    2013
  • 资助金额:
    $ 57.62万
  • 项目类别:

相似海外基金

Quantification of Neurovasculature Changes in a Post-Hemorrhagic Stroke Animal-Model
出血性中风后动物模型中神经血管变化的量化
  • 批准号:
    495434
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
Small animal model for evaluating the impacts of cleft lip repairing scar on craniofacial growth and development
评价唇裂修复疤痕对颅面生长发育影响的小动物模型
  • 批准号:
    10642519
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
Bioactive Injectable Cell Scaffold for Meniscus Injury Repair in a Large Animal Model
用于大型动物模型半月板损伤修复的生物活性可注射细胞支架
  • 批准号:
    10586596
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
A Comparison of Treatment Strategies for Recovery of Swallow and Swallow-Respiratory Coupling Following a Prolonged Liquid Diet in a Young Animal Model
幼年动物模型中长期流质饮食后吞咽恢复和吞咽呼吸耦合治疗策略的比较
  • 批准号:
    10590479
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
Diurnal grass rats as a novel animal model of seasonal affective disorder
昼夜草鼠作为季节性情感障碍的新型动物模型
  • 批准号:
    23K06011
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Longitudinal Ocular Changes in Naturally Occurring Glaucoma Animal Model
自然发生的青光眼动物模型的纵向眼部变化
  • 批准号:
    10682117
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
A whole animal model for investigation of ingested nanoplastic mixtures and effects on genomic integrity and health
用于研究摄入的纳米塑料混合物及其对基因组完整性和健康影响的整体动物模型
  • 批准号:
    10708517
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
A Novel Large Animal Model for Studying the Developmental Potential and Function of LGR5 Stem Cells in Vivo and in Vitro
用于研究 LGR5 干细胞体内外发育潜力和功能的新型大型动物模型
  • 批准号:
    10575566
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
Elucidating the pathogenesis of a novel animal model mimicking chronic entrapment neuropathy
阐明模拟慢性卡压性神经病的新型动物模型的发病机制
  • 批准号:
    23K15696
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
The effect of anti-oxidant on swallowing function in an animal model of dysphagia
抗氧化剂对吞咽困难动物模型吞咽功能的影响
  • 批准号:
    23K15867
  • 财政年份:
    2023
  • 资助金额:
    $ 57.62万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了