Elucidating the effects of patient weight and metabolic state on circulating nanoparticle efficacy

阐明患者体重和代谢状态对循环纳米颗粒功效的影响

• 批准号: 8957960
• 负责人: Paul Dalhaimer
• 金额: $ 34.26万
• 依托单位: UNIVERSITY OF TENNESSEE KNOXVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-17 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8957960
• 关键词: Adipose tissue; Affect; Affinity; Animals; Antineoplastic Agents; Area; Arterial Fatty Streak; Arteries; Arteriosclerosis; Atherosclerosis; Attention; Behavior; Binding; Biodistribution; Biological Assay; Biomedical Engineering; Blood Circulation; Cancer Model; Cancer Patient; Cell Fraction; Charge; Chemistry; Clinic; Data; Dependence; Diet; Dimensions; Disease; Drug Delivery Systems; Dyes; Effectiveness; Fatty Liver; Fatty acid glycerol esters; Future; Geometry; Goals; Hepatic Mass; Hepatomegaly; Human; Image; In Vitro; Individual; Inflammation; Libraries; Life; Lipids; Lipoprotein Receptor; Lipoproteins; Liver; Low-Density Lipoproteins; Malignant Neoplasms; Measures; Metabolic; Metabolic Diseases; Metabolism; Methodology; Modeling; Mus; Mutation; Obese Mice; Obesity; Oncogenes; Organ; Overweight; Patients; Pharmaceutical Preparations; Physiological; Plasma; Play; Property; Rodent; Role; Scientist; Spleen; Technology; Testing; Trust; United States National Institutes of Health; Weight; Work; base; cancer therapy; chemotherapy; design; efficacy testing; improved; in vivo; insight; interest; macrophage; mouse model; nanoparticle; nanoscale; novel; particle; personalized medicine; public health relevance; research study; success; tumor

 DESCRIPTION: Nanoparticles carrying dyes and drugs that can be targeted to a wide variety of cancers have shown great promise in the treatment of this disease. However, most if not all of the mouse models that test the effectiveness of nanoparticles in eradicating cancers take place in lean, young mice whereas the vast majority of humans that will develop cancers and thus potentially be treated with nanoparticle technologies will be obese and have additional metabolic imbalances. We hypothesize that the metabolic condition of cancer patients will play a crucial role in the effectiveness of chemotherapies that are delivered via nanoparticles. In fact, we have compelling preliminary data showing that excessive white adipose tissue (WAT) is a major sink for nanoparticles in obese mice. We have created a unique nanoparticle library that spans both the geometries and chemistries of previously successful nanoparticles that we propose to administer to prescient mouse models of human metabolic conditions with a main focus on 1) excessive WAT, 2) fatty/enlarged livers, 3) varying lipoprotein levels, 4) atherosclerosis, and 5) the first-ever combinations of metabolic conditions and oncogene mutations. The dynamic biodistribution of the nanoparticles - the main assay for future efficacy in treating cancers - wil be assessed using cutting edge organ imaging. Results generated from in vivo experiments will be confirmed in reductionist in vitro experiments for the purpose of fleshing out nanoparticle localization mechanisms at the cellular level. The overall approach differs from the standard model of synthesis of a single nanoparticle and administration to lean rodents, which tends to provide nanoparticle-specific insights in idealized physiological settings. Instead, the proposed fundamental methodologies eliminate dependence upon the success of a single nanoparticle and provide a general and novel gateway toward complete understanding of nanoparticle-patient interactions that will be elucidated in enough detail as to drastically improve nanoparticl efficacy for a plethora of targeting applications with a special focus on cancer.

 描述：携带染料和可以针对各种癌症的染料和药物的纳米颗粒在治疗该疾病方面表现出了很大的希望。但是，大多数测试纳米颗粒在根除癌中有效性的小鼠模型都发生在瘦小的小鼠中，而绝大多数人类会发展癌症，因此可能会肥胖，并可能是肥胖的，并具有额外的代谢不足。我们假设癌症患者的代谢状况将在通过纳米颗粒传递的化学疗法的有效性中起关键作用。实际上，我们拥有引人注目的初步数据，表明超级白脂肪组织（WAT）是肥胖小鼠中纳米颗粒的主要水槽。 We have created a unique nanoparticle library that spans both the geometries and chemistries of previously successful nanoparticles that we propose to administer to prescient mouse models of human metabolic conditions with a main focus on 1) excessive WAT, 2) fatty/enlarged lives, 3) varying lipoprotein levels, 4) atherosclerosis, and 5) the first-ever combinations of metabolic conditions and oncogene mutations.纳米颗粒的动态生物分布 - 对治疗癌症的未来效率的主要评估 - 将使用尖端器官成像评估。体内实验产生的结果将在还原主义体外实验中得到证实，目的是在细胞水平上散发出纳米颗粒定位机制。总体方法与单个纳米颗粒和给药的合成的标准模型不同，该模型倾向于在理想化的物理环境中提供纳米颗粒特异性的见解。取而代之的是，提出的基本方法消除了对单个纳米颗粒的成功的依赖，并为纳米颗粒 - 患者相互作用提供了一个通用和新颖的门户，将以足够的细节阐明，以极大地提高纳米级效率，以提高针对特殊焦点癌症靶向癌症的靶向应用的多余效率。

项目成果

Elongated PEO-based nanoparticles bind the high-density lipoprotein (HDL) receptor scavenger receptor class B I (SR-BI)

• DOI: 10.1016/j.jconrel.2021.07.045
• 发表时间: 2021-08-06
• 期刊: JOURNAL OF CONTROLLED RELEASE
• 影响因子: 10.8
• 作者: Raith，Mitch;Kauffman，Sarah J.;Dalhaimer，Paul
• 通讯作者: Dalhaimer，Paul

Obesity and inflammation influence pharmacokinetic profiles of PEG-based nanoparticles.

肥胖和炎症影响基于 PEG 的纳米颗粒的药代动力学特征。

• DOI: 10.1016/j.jconrel.2023.02.007
• 发表时间: 2023
• 期刊: Journal of controlled release : official journal of the Controlled Release Society
• 作者: Raith,Mitch;Nguyen,Nicole;Kauffman,SarahJ;Kang,Namgoo;Mays,Jimmy;Dalhaimer,Paul
• 通讯作者: Dalhaimer,Paul