Reagents for the Design of Targeted Multifunctional Nanomaterials

用于设计靶向多功能纳米材料的试剂

基本信息

批准号：
8270576
负责人：
LEE JOSEPHSON
金额：
$ 37.85万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8270576
关键词：
Animals Antibodies Binding Bombesin Cells Charge Chelating Agents Chemistry Clinic Clinical Cultured Cells Detection Development Diagnostic Drug Delivery Systems Esters Fluorochrome GRP gene Glioma Goals Haptens Image Immunohistochemistry Kidney Kinetics Lead Liver Magnetism Maleimides Malignant neoplasm of prostate Methods Modality Modeling Organ Penetration Peptides Polymers Property Prostate Proteins Reaction Reagent Reporter Research Solutions Spatial Distribution Structure Therapeutic Tissues Translations Xenograft Model anti-CEA scFv base biological systems bombesin like peptide cancer cell chemical property chromophore colon cancer cell line design functional group hydrophilicity imaging modality improved nanomaterials nanoparticle neoplastic cell next generation physical property public health relevance receptor scaffold single photon emission computed tomography stoichiometry tumor uptake

项目摘要

DESCRIPTION (provided by applicant): The need to maximize tumor uptake, and minimize uptake by other organs, is a common and formidable hurdle for many drug delivery and imaging applications. To attain this goal, new chemistries are required that attach multiple functional groups to substrates (substrates = nanoparticles, proteins, peptides), so a single probe's fate in biological systems can be easily detected by the different modalities needed to ascertain probe disposition at the cellular, tissue and whole animal levels. In addition, these chemistries need to simultaneously alter the physical properties of the probe (e.g., hydrophilicity, charge), to maximize tumor targeting. Finally, it is essential that these new chemistries provide probes with the rigorously defined chemical properties needed for the clinical translation. A solution to these three problems in multifunctional materials design lies in a new class of reagents termed Multifunctional Single Attachment Point or MSAP's. MSAP's consist of a short peptide scaffolds to which multiple functional groups and a single reactive group, such an NHS ester or maleimide, are attached. The RG of the MSAP then attaches the MSAP (and its multiple functional groups) to a substrate in a single reaction, to yield a multifunctional probe. (Note: MSAP reagent + substrate = multifunctional probe). The functional groups employed in an MSAP reagent (i) permit the disposition of the resulting probe to be determined in biological systems (functional groups can be chromophores, fluorochromes, chelating groups or immunoreactive haptens) and, (ii) permit the physical properties of the resulting probe to be controlled and optimized (functional groups = hydrophilic polymers or a small charged structures). Multifiunctional MSAP based probes achieve a stoichiometry between multiple functional groups based on the MSAP reagent, a feature essential for the eventual clinical use of multifunctional materials. We shall expand MSAP chemistry by synthesizing MSAP reagent panels and demonstrate their broad applicability with three different types of substrates: (i) a NP substrate, obtaining enhanced glioma targeting), (ii) an anti-CEA scFv antibody substrate (enhanced tumor CEA targeting) and, (iii) a bombesin (BN) peptide substrate (enhanced tumor GRP receptor targeting). PUBLIC HEALTH RELEVANCE: Our goal is the development of a new type of reagent for designing multifunctional nanomaterials that will enable materials to be detected by different imaging modalities and which will enable them to target tumors more effectively.

描述（由申请人提供）：对于许多药物输送和成像应用，需要最大程度地提高肿瘤吸收并最大程度地减少其他器官的吸收。为了实现这一目标，需要新的化学分子将多个官能团附加到底物（底物=纳米颗粒，蛋白质，肽）上，因此可以通过确定在细胞，组织和整个动物水平上确定概率处置所需的不同方式来轻松检测生物系统中的单个探针命运。此外，这些化学物质需要同时改变探针的物理特性（例如亲水性，电荷），以最大程度地提高肿瘤靶向。最后，这些新化学物质必须提供临床翻译所需的严格定义的化学特性，这一点至关重要。多功能材料设计中这三个问题的解决方案在于一类新的试用的试剂单个附件或MSAP的试剂。 MSAP由短肽支架组成，该支架附着多个官能团和单个反应组，例如NHS酯或马来酰亚胺。然后，MSAP的RG将MSAP（及其多个函数组）连接到单个反应中的底物上，以产生多功能探针。（注意：MSAP试剂 +底物=多功能探针）。 The functional groups employed in an MSAP reagent (i) permit the disposition of the resulting probe to be determined in biological systems (functional groups can be chromophores, fluorochromes, chelating groups or immunoreactive haptens) and, (ii) permit the physical properties of the resulting probe to be controlled and optimized (functional groups = hydrophilic polymers or a small charged structures).基于MSAP的多功能基于MSAP的探针基于MSAP试剂在多个功能组之间实现了化学计量，这是最终临床使用多功能材料所必需的特征。 We shall expand MSAP chemistry by synthesizing MSAP reagent panels and demonstrate their broad applicability with three different types of substrates: (i) a NP substrate, obtaining enhanced glioma targeting), (ii) an anti-CEA scFv antibody substrate (enhanced tumor CEA targeting) and, (iii) a bombesin (BN) peptide substrate (enhanced tumor GRP receptor targeting). 公共卫生相关性：我们的目标是开发一种新型试剂，用于设计多功能纳米材料，这些纳米材料将使材料能够通过不同的成像方式检测到材料，并使它们能够更有效地靶向肿瘤。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Fluorochrome-functionalized nanoparticles for imaging DNA in biological systems.

DOI：
10.1021/nn305962n
发表时间：
2013-03-26
期刊：
ACS NANO
影响因子：
17.1
作者：
Cho, Hoonsung;Alcantara, David;Yuan, Hushan;Sheth, Rahul A.;Chen, Howard H.;Huang, Peng;Andersson, Sean B.;Sosnovik, David E.;Mahmood, Umar;Josephson, Lee
通讯作者：
Josephson, Lee

The PEG-fluorochrome shielding approach for targeted probe design.

DOI：
10.1021/ja309085b
发表时间：
2012-11-28
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Guo, Yanyan;Yuan, Hushan;Rice, William L.;Kumar, Anand T. N.;Goergen, Craig J.;Jokivarsi, Kimmo;Josephson, Lee
通讯作者：
Josephson, Lee

Imaging PEG-like nanoprobes in tumor, transient ischemia, and inflammatory disease models.

肿瘤、短暂性缺血和炎症疾病模型中的类 PEG 纳米探针成像。

DOI：
10.1021/acs.bioconjchem.5b00213
发表时间：
2015
期刊：
Bioconjugate chemistry
影响因子：
4.7
作者：
Wilks,MosesQ;Normandin,MarcD;Yuan,Hushan;Cho,Hoonsung;Guo,Yanyan;Herisson,Fanny;Ayata,Cenk;Wooten,DustinW;ElFakhri,Georges;Josephson,Lee
通讯作者：
Josephson,Lee

Cytoprotective nanoparticles by conjugation of a polyhis tagged annexin V to a nanoparticle drug.

通过将多聚组氨酸标记的膜联蛋白 V 与纳米颗粒药物缀合来提供细胞保护纳米颗粒。