Self-immolative prodrug/miRNA nanoparticle combinations for cancer treatment
用于癌症治疗的自毁前药/miRNA纳米颗粒组合
基本信息
- 批准号:10084282
- 负责人:
- 金额:$ 45.66万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-11 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAnabolismApoptoticArtificial nanoparticlesBiodistributionCancer ModelCell DeathCellsChargeClinical TrialsColonColon CarcinomaCombined Modality TherapyDNA DamageDataDown-RegulationDrug Delivery SystemsDrug KineticsEncapsulatedEvaluationFaceFormulationGene MutationGoalsHumanImmunocompetentIn VitroInduction of ApoptosisInterventionLigandsMalignant NeoplasmsMetabolismMicroRNAsMicrofluidicsModelingModificationMutationNanotechnologyNatureNucleic AcidsOncogenicPathway interactionsPenetrationPeptidesPerformancePharmaceutical PreparationsPharmacologic SubstancePlasmaPolyamine CatabolismPolyaminesPolymersProdrugsProductionPropertyPublishingReactive Oxygen SpeciesResearchSchemeSystemSystemic TherapyTP53 geneTestingTherapeuticToxic effectTumor Suppressor GenesUp-RegulationWomanWorkXenograft Modelanaloganti-canceranti-cancer therapeuticanti-tumor immune responseanticancer activityantitumor effectbasecancer cellcancer heterogeneitycancer therapycancer typecell growthclinical translationcolon cancer treatmentdesignefficacious treatmenthuman diseaseimmunogenicityimprovedin vivoin vivo evaluationinnovationlipophobicitymennanomaterialsnanoparticlenanoparticle deliveryneoplastic cellparticlepreclinical safetyresponserestorationsmall moleculetherapeutic miRNAtraffickingtumortumor progressiontumor xenografttumorigenesis
项目摘要
The goal of this proposal is to improve systemic therapies of colon cancer using self-assembled nanomaterials
that can deliver potent anticancer miRNA and then degrade in cancer cells to active small molecule modulators
of dysregulated polyamine metabolism. Despite tremendous therapeutic potential, clinical translation of miRNA
faces major unsolved pharmaceutical delivery challenges. Due to the involvement of multiple mutations in
tumorigenesis and tumor progression, combination of miRNAs with modulators of polyamine metabolism has
significant therapeutic potential. The fact that polyamine metabolism is downstream from many oncogenes and
tumor suppressor pathways make it a logical target for such combination miRNA therapy approaches. Our
objective is to develop polyamine prodrugs (PaPs) that can modulate dysregulated polyamine metabolism and
encapsulate and systemically deliver anticancer miR-34a. The hypothesis is that self-immolative PaPs based on
modulators of polyamine metabolism will deliver miR-34a to the tumors, which will result in enhanced
combination effect due to the downregulation of tumor polyamine biosynthesis and upregulation of polyamine catabolism
and restoration of important cell growth and death-regulatory functions due to miR-34a. We will accomplish the
objectives in three specific aims: (1) we will optimize formulation of tumor-penetrating PaP/miR-34a
nanoparticles that deliver miRNA and modulate polyamine metabolism. Based on encouraging anticancer in vivo activity
in our preliminary studies, we hypothesize that particle modification with tumor-penetrating iRGD peptide and
with stabilizing superhydrophobic fluorinated moieties will result in efficient systemic delivery. (2) we will
determine the mechanism of action of PaP/miR-34a nanoparticles in vitro. Our results indicate that PaPs are effective
in reducing tumor cell growth and induction of apoptosis, but the precise mechanism of action of the
nanoparticles and how it relates to their intracellular trafficking, disassembly and rate of polyamine analog release is
unknown. We will ascertain the mechanisms of action and determine which composition strategies are most
effective in producing strong antitumor effect. (3) we will test the in vivo efficacy of the particles in colon cancer
using human tumor xenografts and syngeneic immune competent tumor models. We will conduct comprehensive
evaluation of anticancer activity and survival advantage of PaP/miR-34a in models relevant for human disease.
Contribution of the antitumor immunogenicity to the efficacy will be also studied due to known effects of
polyamine analogs on increasing the antitumor immune response. We predict that we will be able to prepare
nanoparticles with improved anticancer activity and prolonged survival. The proposed integrative approach is innovative
because of the dual-function design of the PaP polymers as modulators of polyamine metabolism and miRNA
carriers. The research is significant because it will address major barriers in developing drug/nucleic acid
nanotechnology for systemic treatment of cancer and establish a widely applicable and versatile platform for
combination delivery systems that target polyamine metabolism as a way of improving anticancer therapies.
该提案的目标是利用自组装纳米材料改善结肠癌的全身治疗
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 }}
Robert A. Casero其他文献
Polyamines: the pivotal amines in influencing the tumor microenvironment
- DOI:
10.1007/s12672-024-01034-9 - 发表时间:
2024-05-18 - 期刊:
- 影响因子:2.900
- 作者:
Cassandra E. Holbert;Robert A. Casero;Tracy Murray Stewart - 通讯作者:
Tracy Murray Stewart
Ornithine decarboxylase and polyamines as biomarkers in colorectal neoplasia: Correlation between polyamine pathway metabolites and polyp development in familial adenomatous polyposis
- DOI:
10.1016/s0016-5085(00)83180-7 - 发表时间:
2000-04-01 - 期刊:
- 影响因子:
- 作者:
Francis M. Giardiello;Linda M. Hylind;Jill D. Brensinger;Wendy Devereux;Vincent Yang;Robert A. Casero - 通讯作者:
Robert A. Casero
99 Polyamines Mediate <em>Helicobacter</em> priori-Induced Gastric Carcinogenesis in Gerbils
- DOI:
10.1016/s0016-5085(13)60079-7 - 发表时间:
2013-05-01 - 期刊:
- 影响因子:
- 作者:
Thibaut de Sablet;Rupesh Chaturvedi;Mohammad Asim;Daniel P. Barry;Alain P. Gobert;M. Blanca Piazuelo;Robert A. Casero;Patrick M. Woster;Pelayo Correa;Keith T. Wilson - 通讯作者:
Keith T. Wilson
Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases
针对癌症和其他过度增殖性疾病中的多胺代谢和功能
- DOI:
10.1038/nrd2243 - 发表时间:
2007-05-01 - 期刊:
- 影响因子:101.800
- 作者:
Robert A. Casero;Laurence J. Marton - 通讯作者:
Laurence J. Marton
Robert A. Casero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('Robert A. Casero', 18)}}的其他基金
Self-immolative prodrug/miRNA nanoparticle combinations for cancer treatment
用于癌症治疗的自毁前药/miRNA纳米颗粒组合
- 批准号:
10334440 - 财政年份:2019
- 资助金额:
$ 45.66万 - 项目类别:
Self-immolative prodrug/miRNA nanoparticle combinations for cancer treatment
用于癌症治疗的自毁前药/miRNA纳米颗粒组合
- 批准号:
10672877 - 财政年份:2019
- 资助金额:
$ 45.66万 - 项目类别:
Self-immolative prodrug/miRNA nanoparticle combinations for cancer treatment
用于癌症治疗的自毁前药/miRNA纳米颗粒组合
- 批准号:
9760967 - 财政年份:2019
- 资助金额:
$ 45.66万 - 项目类别:
Identification of novel spermine oxidase (SMOX) inhibitors as probes for an emerging chemoprevention target
鉴定新型精胺氧化酶 (SMOX) 抑制剂作为新兴化学预防靶标的探针
- 批准号:
9288140 - 财政年份:2016
- 资助金额:
$ 45.66万 - 项目类别:
Identification of novel spermine oxidase (SMOX) inhibitors as probes for an emerging chemoprevention target
鉴定新型精胺氧化酶 (SMOX) 抑制剂作为新兴化学预防靶标的探针
- 批准号:
9924482 - 财政年份:2016
- 资助金额:
$ 45.66万 - 项目类别:
Identification of novel spermine oxidase (SMOX) inhibitors as probes for an emerging chemoprevention target
鉴定新型精胺氧化酶 (SMOX) 抑制剂作为新兴化学预防靶标的探针
- 批准号:
9193210 - 财政年份:2016
- 资助金额:
$ 45.66万 - 项目类别:
Identification of novel spermine oxidase (SMOX) inhibitors as probes for an emerging chemoprevention target
鉴定新型精胺氧化酶 (SMOX) 抑制剂作为新兴化学预防靶标的探针
- 批准号:
9392356 - 财政年份:2016
- 资助金额:
$ 45.66万 - 项目类别:
The role of polyamine oxidase in antitumor drug response
多胺氧化酶在抗肿瘤药物反应中的作用
- 批准号:
6899831 - 财政年份:2003
- 资助金额:
$ 45.66万 - 项目类别:
The role of polyamine oxidase in antitumor drug response
多胺氧化酶在抗肿瘤药物反应中的作用
- 批准号:
6679649 - 财政年份:2003
- 资助金额:
$ 45.66万 - 项目类别:
The role of polyamine oxidase in antitumor drug response
多胺氧化酶在抗肿瘤药物反应中的作用
- 批准号:
7076829 - 财政年份:2003
- 资助金额:
$ 45.66万 - 项目类别:
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 45.66万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 45.66万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 45.66万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 45.66万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 45.66万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 45.66万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 45.66万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 45.66万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 45.66万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 45.66万 - 项目类别:
Studentship