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：携带染料和药物的纳米颗粒可以针对多种癌症，在治疗这种疾病方面显示出巨大的前景。然而，大多数（如果不是全部）测试纳米颗粒消除癌症有效性的小鼠模型都是在瘦小的年轻小鼠身上进行的，而绝大多数将患上癌症并因此可能接受纳米颗粒技术治疗的人类将是肥胖的，并且有额外的代谢失衡。我们假设癌症患者的代谢状况将在通过纳米粒子递送的化疗的有效性中发挥至关重要的作用。事实上，我们有令人信服的初步数据表明，过多的白色脂肪组织（WAT）是肥胖小鼠体内纳米颗粒的主要吸收库。我们创建了一个独特的纳米颗粒库，涵盖了先前成功的纳米颗粒的几何形状和化学成分，我们建议将其用于人类代谢状况的有先见之明的小鼠模型，主要关注1）过量的WAT，2）脂肪/肝脏增大，3）不同的脂蛋白水平，4）动脉粥样硬化，以及5）代谢状况和癌基因突变的首次组合。纳米粒子的动态生物分布（未来治疗癌症功效的主要测定方法）将使用尖端器官成像进行评估。体内实验产生的结果将在体外还原实验中得到证实，以充实细胞水平上的纳米颗粒定位机制。整体方法不同于合成单个纳米颗粒并给予瘦啮齿动物的标准模型，后者往往在理想的生理环境中提供纳米颗粒特定的见解。相反，所提出的基本方法消除了对单个纳米颗粒成功的依赖，并为完全理解纳米颗粒与患者的相互作用提供了一种通用的、新颖的途径，这种相互作用将得到足够详细的阐明，从而大大提高纳米颗粒在大量靶向应用（特别是癌症）中的功效。

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