A Surface Activable Nanoemulsion platform for Breast Cancer Diagnosis and Therapy

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妇女，仅在美国，每年诊断的病例总数约为19万，死亡率高达4万。这有力地推动了更有效治疗方法的发展。最近的流行病学和实验研究结果显示，乳腺癌与疏水他汀类药物治疗之间存在显著的有益关联。纳米乳液通过改善生物分布、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，为更好地处理疏水化合物提供了令人兴奋的新可能性。此外，它们还提供了靶向递送的可能性，更重要的是，整合了多种特性，例如，允许使用同一种药物进行治疗和诊断。在本项目中，我们提出开发一种独特的治疗性和表面可活化的纳米颗粒平台，可应用于乳腺癌的靶向性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其靶向循环中表达1v23的细胞：当纳米颗粒循环时，rgd -肽被长peg链积极屏蔽，以尽量减少其对血管生成血管系统和网状内皮系统细胞的暴露。一旦颗粒积聚在肿瘤间质空间，肿瘤内的基质金属蛋白酶-2活性就会切断peg链，rgd片段就可以被肿瘤细胞吸收。将进行全面的体外靶向和疗效研究。在体内，将对小鼠乳腺癌模型进行生物分布和分子成像研究，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。广泛的免疫荧光，组织学和分子生物学技术将应用于评估体内的发现和揭示作用机制。目标1：合成并表征用于靶向、可视化和治疗乳腺癌的表面开关纳米乳平台。目的2：研究纳米乳对不同类型细胞的体外靶向作用和治疗潜力。目的3：通过体内成像研究表面开关纳米乳剂在乳腺癌小鼠模型中的生物分布和靶向“捕获”。目的4：进行一项治疗研究，将携带他汀类药物的表面切换纳米乳液应用于乳腺癌小鼠模型。

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.