Polymeric Nanoparticles for Delivery of Ribonucleic Acids: Overcoming the Endosomal Barrier and Going Beyond the Liver
用于传递核糖核酸的聚合物纳米颗粒:克服内体屏障并超越肝脏
基本信息
- 批准号:RGPIN-2019-07243
- 负责人:
- 金额:$ 2.04万
- 依托单位:
- 依托单位国家:加拿大
- 项目类别:Discovery Grants Program - Individual
- 财政年份:2019
- 资助国家:加拿大
- 起止时间:2019-01-01 至 2020-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Ribonucleic acid (RNA) packaged into nanoparticles (NPs) or included in molecular conjugates for delivery to cells can knock-down gene expression, elucidate gene function, express proteins, upregulate genes and edit the genome and is poised to revolutionize the field of medicine. Extensive research has been published for NP delivery systems where RNA is packaged with cationic polymers or cationic lipids. Despite significant progress achieved in the field, delivery is still the main challenge that faces RNA-based systems. Delivery systems are internalized into cells in vesicles (endosome) and entrapment in these vesicles constitutes a major intracellular barrier and a central current research problem. Additionally, delivery of RNA following intravenous administration is currently almost exclusively targeted to the liver.******The applicant has an established expertise in the production and characterization of chitosan, a positively charged biopolymer composed of glucosamine that is derived from crustacean shells. Chitosan is biocompatible and is used extensively in biomedical applications. The applicant has formed NPs of chitosan with RNA and showed that these NPs are efficient in vitro and specifically accumulate in kidneys following their intravenous administration. Although these results are promising, the ability to escape the endosome, the efficacy and the biodistribution following intravenous injection of these nanosystems must be further examined and improved.******A long-term objective of this research program is to develop a novel family of chitosan-based systems with increased ability to escape the endosome for improved delivery of RNA and that biodistribute to organs other than liver following intravenous administration. Another long-term objective is to further our understanding of cellular internalization and endosomal escape fundamental mechanisms. This proposal aims to extend our previous work by synthesizing a large library of chemically modified chitosans that will be used in combination with moieties facilitating endosomal release to produce entirely new delivery systems. These nanosystems will be characterized for their physicochemical and structural properties and their cellular internalization, intracellular trafficking, efficacy and biodistribution. For the first 5 years of this research program, 4 PhD students with background in polymer chemistry, colloidal science, and cell/molecular biology and 1 undergraduate student/year will be recruited.******This work will provide design principles, structure-activity relationships and identify intracellular mechanisms of biological function for efficient chitosan-based RNA delivery systems and will create a knowledge base that will allow for a tremendous expansion in the applicability of these nanosystems for gene expression, gene knockdown and in vivo applications. The outcomes of this research program will be significant for the fields of gene therapy, nanotechnology and cell biology.**
核糖核酸(RNA)包装成纳米颗粒(NP)或包含在分子缀合物中以递送到细胞中,可以敲低基因表达、阐明基因功能、表达蛋白质、上调基因和编辑基因组,并且有望彻底改变医学领域。已经发表了对NP递送系统的广泛研究,其中RNA与阳离子聚合物或阳离子脂质一起包装。尽管在该领域取得了重大进展,但递送仍然是基于RNA的系统面临的主要挑战。递送系统在囊泡(内体)中内化到细胞中,并且在这些囊泡中的包封构成主要的细胞内屏障和当前的中心研究问题。此外,静脉内给药后RNA的递送目前几乎完全靶向肝脏。申请人在壳聚糖的生产和表征方面拥有成熟的专业知识,壳聚糖是一种由甲壳类动物壳中的葡萄糖胺组成的带正电荷的生物聚合物。壳聚糖具有生物相容性,广泛应用于生物医学领域。申请人已经形成了具有RNA的壳聚糖的NP,并且表明这些NP在体外是有效的,并且在静脉内施用后特异性地在肾脏中积累。虽然这些结果是有希望的,但必须进一步检查和改进静脉注射这些纳米系统后逃逸内体的能力、功效和生物分布。该研究计划的长期目标是开发一种新型的基于壳聚糖的系统家族,其具有增加的逃逸内体的能力,以改善RNA的递送,并且在静脉内给药后生物分布到肝脏以外的器官。另一个长期目标是进一步了解细胞内化和内体逃逸的基本机制。该提案旨在通过合成化学修饰的壳聚糖的大型库来扩展我们先前的工作,所述化学修饰的壳聚糖将与促进内体释放的部分组合使用以产生全新的递送系统。这些纳米系统将表征其物理化学和结构特性及其细胞内化,细胞内运输,功效和生物分布。对于本研究计划的前5年,将招募4名具有高分子化学,胶体科学和细胞/分子生物学背景的博士生和1名本科生/年。这项工作将提供设计原则,结构-活性关系,并确定有效的基于壳聚糖的RNA递送系统的生物功能的细胞内机制,并将创建一个知识库,将允许这些纳米系统的基因表达,基因敲低和体内应用的适用性的巨大扩展。这项研究计划的成果将对基因治疗,纳米技术和细胞生物学领域具有重要意义。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lavertu, Marc其他文献
Heat-induced transfer of protons from chitosan to glycerol phosphate produces chitosan precipitation and gelation
- DOI:
10.1021/bm700745d - 发表时间:
2008-02-01 - 期刊:
- 影响因子:6.2
- 作者:
Lavertu, Marc;Filion, Dominic;Buschmann, Michael D. - 通讯作者:
Buschmann, Michael D.
Robust Segmentation-Free Algorithm for Homogeneity Quantification in Images
- DOI:
10.1109/tip.2021.3086053 - 发表时间:
2021-01-01 - 期刊:
- 影响因子:10.6
- 作者:
Milano, Fiona;Chevrier, Anik;Lavertu, Marc - 通讯作者:
Lavertu, Marc
Stability and binding affinity of DNA/chitosan complexes by polyanion competition
- DOI:
10.1016/j.carbpol.2017.08.002 - 发表时间:
2017-11-15 - 期刊:
- 影响因子:11.2
- 作者:
Ma, Pei Lian;Lavertu, Marc;Buschmann, Michael D. - 通讯作者:
Buschmann, Michael D.
Kinetics and efficiency of chitosan reacetylation
- DOI:
10.1016/j.carbpol.2011.08.096 - 发表时间:
2012-01-15 - 期刊:
- 影响因子:11.2
- 作者:
Lavertu, Marc;Darras, Vincent;Buschmann, Michael D. - 通讯作者:
Buschmann, Michael D.
High efficiency gene transfer using chitosan/DNA nanoparticles with specific combinations of molecular weight and degree of deacetylation
- DOI:
10.1016/j.biomaterials.2006.04.029 - 发表时间:
2006-09-01 - 期刊:
- 影响因子:14
- 作者:
Lavertu, Marc;Methot, Stephane;Buschmann, Michael D. - 通讯作者:
Buschmann, Michael D.
Lavertu, Marc的其他文献
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{{ truncateString('Lavertu, Marc', 18)}}的其他基金
Polymeric Nanoparticles for Delivery of Ribonucleic Acids: Overcoming the Endosomal Barrier and Going Beyond the Liver
用于传递核糖核酸的聚合物纳米颗粒:克服内体屏障并超越肝脏
- 批准号:
RGPIN-2019-07243 - 财政年份:2022
- 资助金额:
$ 2.04万 - 项目类别:
Discovery Grants Program - Individual
Polymeric Nanoparticles for Delivery of Ribonucleic Acids: Overcoming the Endosomal Barrier and Going Beyond the Liver
用于传递核糖核酸的聚合物纳米颗粒:克服内体屏障并超越肝脏
- 批准号:
RGPIN-2019-07243 - 财政年份:2021
- 资助金额:
$ 2.04万 - 项目类别:
Discovery Grants Program - Individual
Polymeric Nanoparticles for Delivery of Ribonucleic Acids: Overcoming the Endosomal Barrier and Going Beyond the Liver
用于传递核糖核酸的聚合物纳米颗粒:克服内体屏障并超越肝脏
- 批准号:
RGPIN-2019-07243 - 财政年份:2020
- 资助金额:
$ 2.04万 - 项目类别:
Discovery Grants Program - Individual
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用于传递核糖核酸的聚合物纳米颗粒:克服内体屏障并超越肝脏
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