Systemic RNA Delivery to Tumors

全身性 RNA 递送至肿瘤

基本信息

  • 批准号:
    10447166
  • 负责人:
  • 金额:
    $ 53.52万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-12-21 至 2026-06-30
  • 项目状态:
    未结题

项目摘要

ABSTRACT The use of RNA technologies to specifically target genetic alterations in tumor cells has shown great potential of becoming a novel therapy modality for cancer treatment. Nevertheless, systemic delivery of RNA agents such as messenger RNA (mRNA) to tumor cells in vivo commonly faces multiple barriers, including low stability, rapid elimination by renal excretion, insufficient cellular uptake, poor endosomal escape, and transient activities. Our long-term objective is to develop robust nanoparticle (NP) platforms for effective and safe RNA delivery to solid tumors, and along with cancer target validation in vivo, to eventually transition the RNA nanomedicines into clinical development. In the last funding cycle, a lipid-polymer hybrid RNA NP system has been engineered with favorable features, such as small size, high RNA encapsulation, efficient cytosolic translocation, and relatively long blood circulation. We have also pioneered the application of these hybrid NPs for mRNA delivery to restore tumor suppressors (e.g., PTEN) in different cancer types including prostate cancer (PCa) and non-small cell lung cancer, which represents a novel approach to cancer treatment that is independent of oncogene antagonism. In our latest work, we further reveal that PTEN restoration in PTEN-null/mutated murine tumor cell lines can induce immunogenic cell death (ICD). Preliminary in vivo studies show that PTEN mRNA NP treatment triggers cytotoxic T cell responses, modulates the immunosuppressive tumor microenvironment, and improves the responses of immune checkpoint blockade therapy. In this renewal application, we propose to i) address the unique challenge of transient bioactivity in mRNA delivery by developing a new generation of hybrid mRNA NPs, and ii) apply the new hybrid mRNA NPs to explore PTEN restoration-induced ICD and evaluate the anti-tumor efficacy of PTEN restoration along with immune checkpoint blockade. Specifically, the three Aims underlying the proposal are: 1) To optimize the new generation of hybrid NPs and study the NP-mediated long duration of mRNA bioactivity with the goal of achieving prolonged PTEN expression in PCa tumors using as infrequent injections as possible; 2) To apply the optimized mRNA NPs to investigate the mechanisms underlying PTEN-mediated ICD and anti- tumor immune responses and to evaluate the therapeutic effect and safety in subcutaneously grafted, orthotopic, and transgenic models of PCa; and 3) To expand the new hybrid mRNA NPs to systemic co-delivery of PTEN mRNA and CpG oligodeoxynucleotide (a toll-like receptor-9 agonist) for stronger ICD and to test the co-delivery NPs for PCa treatment together with immune checkpoint inhibitors. We expect that successful completion of this project will lead to development of a novel synthetic mRNA nanotherapy that could benefit cancer patients with loss/mutation of PTEN. Moreover, this NP delivery strategy could be readily expanded to other tumor suppressor- encoding mRNAs for various malignancies.
摘要 使用RNA技术特异性靶向肿瘤细胞中的遗传改变已经显示出巨大的潜力, 成为癌症治疗的一种新的治疗方式。然而,RNA试剂的全身递送, 作为信使RNA(mRNA)在体内进入肿瘤细胞通常面临着多重障碍,包括稳定性低、快速 通过肾排泄消除、细胞摄取不足、内体逃逸差和瞬时活性。我们 长期目标是开发强大的纳米颗粒(NP)平台,用于有效和安全的RNA递送到固体 肿瘤,并沿着体内癌症靶点验证,最终将RNA纳米药物转化为 临床发展。在上一个资助周期中,脂质-聚合物杂交RNA NP系统已经被工程化, 有利的特征,如小尺寸、高RNA包封、有效的胞质易位,以及相对 长时间的血液循环。我们还开创了将这些混合纳米颗粒用于mRNA递送以恢复 肿瘤抑制剂(例如,在不同的癌症类型中,包括前列腺癌(PCa)和非小细胞肺癌(NSCLC), 它代表了一种新的癌症治疗方法,不依赖于癌基因拮抗作用。在 我们的最新工作,我们进一步揭示了PTEN缺失/突变的小鼠肿瘤细胞系中的PTEN恢复可以诱导 免疫原性细胞死亡(ICD)。初步的体内研究表明,PTEN mRNA NP处理触发细胞毒性, T细胞应答,调节免疫抑制性肿瘤微环境,并改善免疫应答。 免疫检查点阻断疗法。在此更新申请中,我们建议i)解决独特的挑战 通过开发新一代杂交mRNA NP来实现mRNA递送中的瞬时生物活性,以及ii)应用 新的杂交mRNA NPs用于探索PTEN诱导的ICD并评估PTEN的抗肿瘤功效 恢复沿着免疫检查点阻断。具体而言,该建议的三个基本目标是: 为了优化新一代的杂合纳米粒,并研究纳米粒介导的长持续mRNA生物活性, 使用尽可能少的注射实现PCa肿瘤中延长的PTEN表达的目标; 2) 应用优化的mRNA纳米颗粒研究PTEN介导的ICD和抗- 肿瘤免疫应答,并评估皮下移植,原位, 以及PCa的转基因模型;以及3)将新的杂交mRNA NP扩展到系统性共递送PTEN mRNA和CpG寡脱氧核苷酸(一种toll样受体-9激动剂)用于更强的ICD,并测试共同递送 用于PCa治疗的NP与免疫检查点抑制剂一起。我们期待这一工作的顺利完成, 该项目将导致开发一种新的合成mRNA纳米疗法,可以使癌症患者受益, PTEN缺失/突变。此外,这种NP递送策略可以容易地扩展到其他肿瘤抑制剂- 编码各种恶性肿瘤的mRNA。

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(2)

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 }}

Jinjun Shi其他文献

Jinjun Shi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('Jinjun Shi', 18)}}的其他基金

A New Lipid Nanoparticle Technology Enabling Long-acting mRNA Therapy
新型脂质纳米颗粒技术实现长效 mRNA 治疗
  • 批准号:
    10669826
  • 财政年份:
    2023
  • 资助金额:
    $ 53.52万
  • 项目类别:
Long-Acting RNAi Therapy for Atherosclerosis and Insulin Resistance
长效 RNAi 治疗动脉粥样硬化和胰岛素抵抗
  • 批准号:
    10424582
  • 财政年份:
    2021
  • 资助金额:
    $ 53.52万
  • 项目类别:
Long-Acting RNAi Therapy for Atherosclerosis and Insulin Resistance
长效 RNAi 治疗动脉粥样硬化和胰岛素抵抗
  • 批准号:
    10631236
  • 财政年份:
    2021
  • 资助金额:
    $ 53.52万
  • 项目类别:
Long-Acting RNAi Therapy for Atherosclerosis and Insulin Resistance
长效 RNAi 治疗动脉粥样硬化和胰岛素抵抗
  • 批准号:
    10277786
  • 财政年份:
    2021
  • 资助金额:
    $ 53.52万
  • 项目类别:
Systemic RNA Delivery to Tumors
全身性 RNA 递送至肿瘤
  • 批准号:
    10297216
  • 财政年份:
    2015
  • 资助金额:
    $ 53.52万
  • 项目类别:
Systemic RNA Delivery to Tumors
全身性 RNA 递送至肿瘤
  • 批准号:
    10659129
  • 财政年份:
    2015
  • 资助金额:
    $ 53.52万
  • 项目类别:
Systemic RNA Delivery to Tumors
全身性 RNA 递送至肿瘤
  • 批准号:
    9197972
  • 财政年份:
    2015
  • 资助金额:
    $ 53.52万
  • 项目类别:
Nanoparticle Co-delivery of RNAi and Chemotherapy for Multidrug Resistant Cancers
纳米粒子联合递送 RNAi 和化疗治疗多重耐药癌症
  • 批准号:
    8689250
  • 财政年份:
    2013
  • 资助金额:
    $ 53.52万
  • 项目类别:
Nanoparticle Co-delivery of RNAi and Chemotherapy for Multidrug Resistant Cancers
纳米粒子联合递送 RNAi 和化疗治疗多重耐药癌症
  • 批准号:
    8707222
  • 财政年份:
    2013
  • 资助金额:
    $ 53.52万
  • 项目类别:
Nanoparticle Co-delivery of RNAi and Chemotherapy for Multidrug Resistant Cancers
纳米粒子联合递送 RNAi 和化疗治疗多重耐药癌症
  • 批准号:
    8916630
  • 财政年份:
    2013
  • 资助金额:
    $ 53.52万
  • 项目类别:

相似海外基金

Metachronous synergistic effects of preoperative viral therapy and postoperative adjuvant immunotherapy via long-term antitumor immunity
术前病毒治疗和术后辅助免疫治疗通过长期抗肿瘤免疫产生异时协同效应
  • 批准号:
    23K08213
  • 财政年份:
    2023
  • 资助金额:
    $ 53.52万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Improving the therapeutic immunity of cancer vaccine with multi-adjuvant polymeric nanoparticles
多佐剂聚合物纳米粒子提高癌症疫苗的治疗免疫力
  • 批准号:
    2881726
  • 财政年份:
    2023
  • 资助金额:
    $ 53.52万
  • 项目类别:
    Studentship
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:
    $ 53.52万
  • 项目类别:
Evaluation of the Sensitivity to Endocrine Therapy (SET ER/PR) Assay to predict benefit from extended duration of adjuvant endocrine therapy in the NSABP B-42 trial
NSABP B-42 试验中内分泌治疗敏感性 (SET ER/PR) 测定的评估,用于预测延长辅助内分泌治疗持续时间的益处
  • 批准号:
    10722146
  • 财政年份:
    2023
  • 资助金额:
    $ 53.52万
  • 项目类别:
AUGMENTING THE QUALITY AND DURATION OF THE IMMUNE RESPONSE WITH A NOVEL TLR2 AGONIST-ALUMINUM COMBINATION ADJUVANT
使用新型 TLR2 激动剂-铝组合佐剂增强免疫反应的质量和持续时间
  • 批准号:
    10933287
  • 财政年份:
    2023
  • 资助金额:
    $ 53.52万
  • 项目类别:
DEVELOPMENT OF SAS A SYNTHETIC AS01-LIKE ADJUVANT SYSTEM FOR INFLUENZA VACCINES
流感疫苗类 AS01 合成佐剂系统 SAS 的开发
  • 批准号:
    10935776
  • 财政年份:
    2023
  • 资助金额:
    $ 53.52万
  • 项目类别:
DEVELOPMENT OF SMALL-MOLECULE DUAL ADJUVANT SYSTEM FOR INFLUENZA VIRUS VACCINE
流感病毒疫苗小分子双佐剂体系的研制
  • 批准号:
    10935796
  • 财政年份:
    2023
  • 资助金额:
    $ 53.52万
  • 项目类别:
A GLYCOLIPID ADJUVANT 7DW8-5 FOR MALARIA VACCINES
用于疟疾疫苗的糖脂佐剂 7DW8-5
  • 批准号:
    10935775
  • 财政年份:
    2023
  • 资助金额:
    $ 53.52万
  • 项目类别:
Adjuvant strategies for universal and multiseasonal influenza vaccine candidates in the context of pre-existing immunity
在已有免疫力的情况下通用和多季节流感候选疫苗的辅助策略
  • 批准号:
    10649041
  • 财政年份:
    2023
  • 资助金额:
    $ 53.52万
  • 项目类别:
Adjuvant Photodynamic Therapy to Reduce Bacterial Bioburden in High-Energy Contaminated Open Fractures
辅助光动力疗法可减少高能污染开放性骨折中的细菌生物负载
  • 批准号:
    10735964
  • 财政年份:
    2023
  • 资助金额:
    $ 53.52万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了