Optimizing RNA nanoparticles size and shape for enhancing cancer targeting and treatment
优化 RNA 纳米粒子的大小和形状以增强癌症靶向和治疗
基本信息
- 批准号:9166825
- 负责人:
- 金额:$ 55.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-26 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse effectsAnimalsAntibodiesAntineoplastic AgentsAttributes of ChemicalsB-LymphocytesBehaviorBindingBiodistributionBiological SciencesBiotechnologyCatalytic RNACaveolinsCellsChemicalsClathrinClinicClinicalClinical TrialsDataDendritic CellsDrug KineticsEndocytosisEndosomesExcretory functionExhibitsGene SilencingGenerationsGoalsGuidelinesHourImmuneImmune responseImmune systemImmunotherapyIn VitroInjection of therapeutic agentInterferonsInvestigational DrugsInvestigational New Drug ApplicationLeadLigandsLiverLiver neoplasmsMalignant NeoplasmsMediatingMembrane MicrodomainsMetabolismMethodsMicroRNAsModificationMolecularMusNanotechnologyNatureNeoplasm MetastasisNucleic AcidsOrganPathway interactionsPhagocytosisPharmacodynamicsPharmacotherapyPinocytosisProcessRNARNA SequencesReactionReportingResearchSafetyShapesSmall Interfering RNAT-LymphocyteTherapeuticThermodynamicsTissuesToxic effectTranslationsTreatment EfficacyTumor EscapeValidationXenograft procedureabsorptionaptamerbasecancer immunotherapycancer therapyclinically relevantcytokinefunctional groupimprovedin vivolarge scale productionmacrophagemeetingsmouse modelnanonanoparticlepre-clinicalpreclinical studyscaffoldself assemblystoichiometrysubcutaneoustraffickingtumoruptake
项目摘要
PROJECT SUMMARY
RNA nanotechnology has progressed rapidly during the past several years. This nanotechnology includes
the integration of multiple functional modules into one nanoparticle, of which the scaffolds, ligands,
therapeutics, and regulators can be composed mainly or exclusively of RNA. We have constructed RNA
nanoparticles of diverse size, shape, and stoichiometry displaying high chemical and thermodynamic stability
and demonstrated their ability to harbor different functional groups, such as siRNA, miRNA, ribozyme, drug,
and cancer targeting RNA aptamer. All functional modules retain their authentic folding and independent
functionalities for specific cell binding, gene silencing, and cancer targeting in vivo. Upon systemic injection in
tumor bearing mice, RNA nanoparticles bind to xenograft and metastatic tumors specifically and strongly with
little to no accumulation in healthy vital organs and tissues 3-4 hours post-administration. The RNA
nanoparticles are non-toxic and display favorable biodistribution and pharmacokinetic profiles.
Our long-term goal is to promote RNA nanoparticles as a new generation of drug for the treatment of
cancers in the clinic. The short-term goal of this project is to characterize the behavior of RNA nanoparticles in
vitro and in vivo, with an aim to improve the efficiency for specific cell targeting, internalization and intracellular
trafficking, favorable biodistribution without entrapment in liver, endosome escape, and tumor regression.
These studies are based on three central hypotheses: (1) intracellular trafficking pathways and endosome
escape are critical for effective cancer therapy; (2) biodistribution and pharmacological profiles of RNA
nanoparticles are shape and size dependent; and, (3) immune responses elicited by RNA nanoparticles are
highly dependent on RNA sequence, chemical modifications, size, shape, and stoichiometry. To address our
goals, we will (1) systemically dissect the intracellular pathways taken by RNA nanoparticles and enhance
their endosome escape capabilities; (2) inspect the pharmacokinetics (PK); pharmacodynamics (PD); and
biodistribution of RNA nanoparticles with the goal of enhancing cancer targeting with minimal accumulation in
healthy organs; and, (3) evaluate the immune responses of RNA nanoparticles to minimize non-specific side
effects, as well as develop methods to stimulate the immune system by incorporating immuno-stimulatory
modules to RNA nanoparticles for cancer immunotherapy. Upon completion of these pre-clinical studies, we
will have identified several RNA nanoparticles with optimized shape, size, and stoichiometry displaying
favorable safety profiles and high therapeutic efficacy to comply with FDA Investigational New Drug guidelines
for initiating clinical trials.
项目总结
在过去的几年里,RNA纳米技术发展迅速。这种纳米技术包括
将多个功能模块集成到一个纳米颗粒中,其中的支架、配体、
治疗药物和调节剂可以主要或完全由RNA组成。我们已经构建了RNA
大小、形状和化学计量比不同的纳米颗粒,具有很高的化学和热力学稳定性
并展示了它们含有不同官能团的能力,如siRNA、miRNA、核酶、药物、
以及以RNA适体为靶标的癌症。所有功能模块保持原汁原味的折叠和独立
体内特定细胞结合、基因沉默和癌症靶向的功能。在全身注射时
荷瘤小鼠,RNA纳米颗粒与异种移植瘤和转移性肿瘤特异性强结合
给药后3-4小时,健康的重要器官和组织中几乎没有积聚。核糖核酸
纳米粒无毒,表现出良好的生物分布和药代动力学特征。
我们的长期目标是推动RNA纳米粒子成为治疗糖尿病的新一代药物
诊所里的癌症。该项目的短期目标是表征RNA纳米颗粒在体内的行为
体外和体内,旨在提高特定细胞靶向、内化和细胞内的效率
转运,良好的生物分布而不被困在肝脏,内吞逃逸,以及肿瘤消退。
这些研究基于三个中心假设:(1)细胞内转运途径和内体
逃逸对于有效的癌症治疗至关重要;(2)RNA的生物分布和药理学特征
纳米粒子是形状和大小相关的;以及,(3)由RNA纳米粒子引发的免疫反应
高度依赖于RNA序列、化学修饰、大小、形状和化学计量比。向我们的
目标,我们将(1)系统地剖析RNA纳米颗粒所走的细胞内途径,并增强
(2)检查药代动力学(PK)、药效学(PD);
RNA纳米粒的生物分布,目的是以最小的蓄积增强肿瘤靶向性
健康的器官;以及,(3)评估RNA纳米粒的免疫反应,以将非特异性方面降至最低
效果,以及开发通过结合免疫刺激剂来刺激免疫系统的方法
用于癌症免疫治疗的RNA纳米粒子的模块。在完成这些临床前研究后,我们
我将鉴定出几个形状、大小和化学计量比都经过优化的RNA纳米粒子
良好的安全性和高效的治疗效果符合FDA的新药研究指南
用于启动临床试验。
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 }}
WILLIAM E. CARSON其他文献
WILLIAM E. CARSON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('WILLIAM E. CARSON', 18)}}的其他基金
Dual-payload antibody-drug conjugate for chemo-immunotherapy of triple-negative breast cancers
用于三阴性乳腺癌化学免疫治疗的双有效负载抗体-药物偶联物
- 批准号:
10711488 - 财政年份:2023
- 资助金额:
$ 55.31万 - 项目类别:
Optimizing RNA nanoparticles size and shape for enhancing cancer targeting and treatment
优化 RNA 纳米粒子的大小和形状以增强癌症靶向和治疗
- 批准号:
9763480 - 财政年份:2016
- 资助金额:
$ 55.31万 - 项目类别:
Optimizing RNA nanoparticles size and shape for enhancing cancer targeting and treatment
优化 RNA 纳米粒子的大小和形状以增强癌症靶向和治疗
- 批准号:
10006088 - 财政年份:2016
- 资助金额:
$ 55.31万 - 项目类别:
Cetuximab Therapy of Pancreatic Cancer: Immune Modulation with IL-21
西妥昔单抗治疗胰腺癌:IL-21 的免疫调节
- 批准号:
7740058 - 财政年份:2009
- 资助金额:
$ 55.31万 - 项目类别:
ANTIBODY THERAPY FOR BREAST CANCER: INVESTIGATION OF IMMUNE MODULATION WITH IL-21
乳腺癌抗体治疗:IL-21 免疫调节研究
- 批准号:
7313944 - 财政年份:2007
- 资助金额:
$ 55.31万 - 项目类别:
Therapy of Melanoma with Bortezomib and Interferon-alpha
硼替佐米和干扰素-α 治疗黑色素瘤
- 批准号:
7418854 - 财政年份:2006
- 资助金额:
$ 55.31万 - 项目类别:
Therapy of Melanoma with Bortezomib and Interferon-alpha
硼替佐米和干扰素-α 治疗黑色素瘤
- 批准号:
7056407 - 财政年份:2006
- 资助金额:
$ 55.31万 - 项目类别:
Therapy of Melanoma with Bortezomib and Interferon-alpha
硼替佐米和干扰素-α 治疗黑色素瘤
- 批准号:
7230025 - 财政年份:2006
- 资助金额:
$ 55.31万 - 项目类别:
相似海外基金
Unraveling Adverse Effects of Checkpoint Inhibitors Using iPSC-derived Cardiac Organoids
使用 iPSC 衍生的心脏类器官揭示检查点抑制剂的副作用
- 批准号:
10591918 - 财政年份:2023
- 资助金额:
$ 55.31万 - 项目类别:
Optimization of mRNA-LNP vaccine for attenuating adverse effects and analysis of mechanism behind adverse effects
mRNA-LNP疫苗减轻不良反应的优化及不良反应机制分析
- 批准号:
23K15383 - 财政年份:2023
- 资助金额:
$ 55.31万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of adverse effects of combined exposure to low-dose chemicals in the living environment on allergic diseases and attempts to reduce allergy
阐明生活环境中低剂量化学品联合暴露对过敏性疾病的不良影响并尝试减少过敏
- 批准号:
23H03556 - 财政年份:2023
- 资助金额:
$ 55.31万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Green tea-based nano-enhancer as an adjuvant for amplified efficacy and reduced adverse effects in anti-angiogenic drug treatments
基于绿茶的纳米增强剂作为抗血管生成药物治疗中增强疗效并减少不良反应的佐剂
- 批准号:
23K17212 - 财政年份:2023
- 资助金额:
$ 55.31万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Effects of Tobacco Heating System on the male reproductive function and towards to the reduce of the adverse effects.
烟草加热系统对男性生殖功能的影响以及减少不利影响。
- 批准号:
22H03519 - 财政年份:2022
- 资助金额:
$ 55.31万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mitigating the Adverse Effects of Ultrafines in Pressure Filtration of Oil Sands Tailings
减轻油砂尾矿压力过滤中超细粉的不利影响
- 批准号:
563657-2021 - 财政年份:2022
- 资助金额:
$ 55.31万 - 项目类别:
Alliance Grants
1/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
1/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10521849 - 财政年份:2022
- 资助金额:
$ 55.31万 - 项目类别:
4/4-Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
4/4-破译ECT结果和不良反应的机制(DECODE)
- 批准号:
10671022 - 财政年份:2022
- 资助金额:
$ 55.31万 - 项目类别:
2/4 Deciphering Mechanisms of ECT Outcomes and Adverse Effects (DECODE)
2/4 ECT 结果和不良反应的破译机制(DECODE)
- 批准号:
10670918 - 财政年份:2022
- 资助金额:
$ 55.31万 - 项目类别:
Downsides of downhill: The adverse effects of head vibration associated with downhill mountain biking on visuomotor and cognitive function
速降的缺点:与速降山地自行车相关的头部振动对视觉运动和认知功能的不利影响
- 批准号:
2706416 - 财政年份:2022
- 资助金额:
$ 55.31万 - 项目类别:
Studentship