A Surface Activable Nanoemulsion platform for Breast Cancer Diagnosis and Therapy

用于乳腺癌诊断和治疗的表面活性纳米乳平台

• 批准号: 8917868
• 负责人: Willem Mulder
• 金额: $ 35.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8917868
• 关键词: Adverse effects; Affect; Apoptotic; Biodistribution; Biological; Biological Assay; Blood; Blood Circulation; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Treatment; Breast Cancer therapy; Cancer Model; Cell Proliferation; Cell Survival; Cells; Chemistry; Cleaved cell; Confocal Microscopy; Data; Detection; Developed Countries; Development; Diagnosis; Diagnostic; Dose; Drug Formulations; Drug Kinetics; Electron Microscopy; Encapsulated; Endothelial Cells; Ensure; Epidemiologic Studies; Exhibits; Exposure to; Fatty acid glycerol esters; Gelatinase A; Growth; Half-Life; Histological Techniques; Imagery; Imaging Phantoms; In Vitro; Integrins; Life; Ligands; Lipids; Magnetic Resonance Imaging; Malignant Neoplasms; Measures; Microscopic; Molecular; Molecular Biology; Mus; Near-infrared optical imaging; Oils; Patients; Permeability; Pharmaceutical Preparations; Phospholipids; Plasma; Plasma Proteins; Polyethylene Glycols; Polymers; Property; RGD (sequence); Research Personnel; Surface; System; Techniques; Testing; Therapeutic; Treatment Efficacy; United States; Woman; base; bioluminescence imaging; breast cancer diagnosis; cancer therapy; cell type; density; design; drug efficacy; effective therapy; imaging modality; improved; in vitro testing; in vivo; in vivo imaging; interstitial; iron oxide; macrophage; malignant breast neoplasm; molecular imaging; mortality; mouse model; nanocrystal; nanoemulsion; nanoparticle; nanotherapy; neoplastic cell; optical imaging; particle; prevent; research study; response; theranostics; treatment strategy; tumor; tumor growth; uptake

DESCRIPTION (provided by applicant): Breast cancer affects up to one in 10 women in Western and industrialized countries and the total number of cases diagnosed are about 190,000 each year in the United States alone, with a considerable mortality rate of 40,000. This strongly motivates the development of more effective treatments. Results from recent epidemiological and experimental studies have revealed significant beneficial association between breast cancer and hydrophobic statin therapy. Nanoemulsions offer exciting new possibilities for better treatment strategies of hydrophobic compounds by improving the biodistribution, the circulation half-life, and by diminishing interactions with plasma proteins or other plasma constituents. In addition, they also offer the possibility for target-specific delivery and, importantly, the integration of multiple properties, e.g. to allow therapy and diagnostics with the same agent. In this project we propose to develop a unique theranostic and surface activatable nanoparticle platform, which can be applied for target-specific MRI and anti-tumor therapy of breast cancer. The nanoparticles are targeted to 1v23-expressing breast cancer cells via RGD-peptides, but are prevented from targeting 1v23-expressing cells in the circulation through the following strategy: When the nanoparticles circulate, the RGD-peptides are actively shielded by long PEG-chains to minimize their exposure to the angiogenic vasculature and the cells of the reticulo-endothelial system. Once the particles accumulate in the tumor interstitial space, the PEG-chains are cleaved off by matrix metalloproteinase-2 activity inside the tumor and the RGD-moieties become available to facilitate uptake by tumor cells. Full in vitro targeting and efficacy studies will be performed. In vivo, biodistribution and molecular imaging studies will be performed on mouse breast cancer models in order to evaluate targeting efficiency. Lastly, therapeutic efficacy will be investigated in the same mouse models. Extensive immunofluorescent, histological, and molecular biological techniques will be applied to evaluate the in vivo findings and to unravel the mechanism of action. The specific aims are: Aim 1: To synthesize and characterize a surface-switching nanoemulsion platform for targeting, visualizing and treating breast cancer. Aim 2: To test the targeting efficacy and therapeutic potential of nanoemulsions in vitro on different cell types. Aim 3: To study the biodistribution and targeted 'trapping' of surface-switching nanoemulsions in a breast cancer mouse model via in vivo imaging. Aim 4: To conduct a therapy study where surface-switching nanoemulsions, that carry statins, are applied to a breast cancer mouse model.

描述（由申请人提供）：在西方和工业化国家，乳腺癌影响到十分之一的女性，仅在美国每年诊断的病例总数约为 190,000 例，死亡率高达 40,000 例。这强烈推动了更有效治疗方法的开发。最近的流行病学和实验研究的结果揭示了乳腺癌和疏水性他汀类药物治疗之间的显着有益关联。纳米乳剂通过改善生物分布、循环半衰期以及减少与血浆蛋白或其他血浆成分的相互作用，为疏水性化合物的更好治疗策略提供了令人兴奋的新可能性。此外，它们还提供了针对特定目标的交付的可能性，重要的是，还提供了多种属性的集成，例如允许使用相同的试剂进行治疗和诊断。 在这个项目中，我们建议开发一种独特的治疗诊断和表面可激活纳米颗粒平台，可应用于乳腺癌的靶向特异性MRI和抗肿瘤治疗。纳米颗粒通过 RGD 肽靶向表达 1v23 的乳腺癌细胞，但通过以下策略阻止靶向循环中表达 1v23 的细胞：当纳米颗粒循环时，RGD 肽被长 PEG 链主动屏蔽尽量减少它们与血管生成血管系统和网状内皮系统细胞的接触。一旦颗粒在肿瘤间隙中积累，PEG-链就会被肿瘤内的基质金属蛋白酶-2活性裂解，并且RGD-部分变得可用于促进肿瘤细胞的摄取。 将进行全面的体外靶向和功效研究。体内生物分布和分子成像研究将在小鼠乳腺癌模型上进行，以评估靶向效率。最后，将在相同的小鼠模型中研究治疗效果。将应用广泛的免疫荧光、组织学和分子生物学技术来评估体内研究结果并揭示作用机制。 具体目标是： 目标 1：合成和表征用于靶向、可视化和治疗乳腺癌的表面转换纳米乳剂平台。目标2：测试纳米乳剂对不同细胞类型的体外靶向功效和治疗潜力。目标 3：通过体内成像研究乳腺癌小鼠模型中表面转换纳米乳剂的生物分布和靶向“捕获”。目标 4：进行一项治疗研究，将携带他汀类药物的表面转换纳米乳剂应用于乳腺癌小鼠模型。

项目成果

A modular labeling strategy for in vivo PET and near-infrared fluorescence imaging of nanoparticle tumor targeting.

• DOI: 10.2967/jnumed.114.141861
• 发表时间: 2014-10
• 期刊: Journal of nuclear medicine : official publication, Society of Nuclear Medicine
• 作者: Pérez-Medina C;Abdel-Atti D;Zhang Y;Longo VA;Irwin CP;Binderup T;Ruiz-Cabello J;Fayad ZA;Lewis JS;Mulder WJ;Reiner T
• 通讯作者: Reiner T

The effect of nanoparticle polyethylene glycol surface density on ligand-directed tumor targeting studied in vivo by dual modality imaging.

• DOI: 10.1021/nn301630n
• 发表时间: 2012-06-26
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Hak, Sjoerd;Helgesen, Emily;Hektoen, Helga H.;Huuse, Else Marie;Jarzyna, Peter A.;Mulder, Willem J. M.;Haraldseth, Olav;Davies, Catharina de Lange
• 通讯作者: Davies, Catharina de Lange

Periodicity in tumor vasculature targeting kinetics of ligand-functionalized nanoparticles studied by dynamic contrast enhanced magnetic resonance imaging and intravital microscopy.

• DOI: 10.1007/s10456-013-9380-7
• 发表时间: 2014-01
• 期刊: ANGIOGENESIS
• 影响因子: 9.8
• 作者: Hak, Sjoerd;Cebulla, Jana;Huuse, Else Marie;Davies, Catharina de L.;Mulder, Willem J. M.;Larsson, Henrik B. W.;Haraldseth, Olav
• 通讯作者: Haraldseth, Olav

A Comprehensive Procedure to Evaluate the In Vivo Performance of Cancer Nanomedicines.

评估癌症纳米药物体内性能的综合程序。

• DOI: 10.3791/55271
• 发表时间: 2017
• 期刊: Journal of visualized experiments : JoVE
• 作者: Tang,Jun;Pérez-Medina,Carlos;Zhao,Yiming;Sadique,Ahmad;Mulder,WillemJM;Reiner,Thomas
• 通讯作者: Reiner,Thomas