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，乳腺癌影响多达十分之一的妇女，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。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，乳腺癌和疏水性他汀类药物治疗之间存在显著的有益关联。纳米乳剂通过改善生物分布、循环半衰期以及通过减少与血浆蛋白或其他血浆成分的相互作用，为疏水化合物的更好治疗策略提供了令人兴奋的新可能性。此外，它们还提供了靶向特异性递送的可能性，并且重要的是，提供了多种特性的整合，例如，允许使用相同的试剂进行治疗和诊断。 在本项目中，我们提出开发一种独特的治疗诊断和表面可活化的纳米颗粒平台，可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1v 23的乳腺癌细胞，但通过以下策略防止靶向循环中的表达1v 23的细胞：当纳米颗粒循环时，RGD肽被长PEG链主动屏蔽，以最大限度地减少其暴露于血管生成血管系统和网状内皮系统的细胞。一旦颗粒积聚在肿瘤间质空间中，PEG链就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。 将进行完整的体外靶向和疗效研究。将在小鼠乳腺癌模型上进行体内生物分布和分子成像研究，以评价靶向效率。最后，将在相同的小鼠模型中研究疗效。广泛的免疫荧光，组织学和分子生物学技术将被应用于评估在体内的结果，并解开的作用机制。 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液平台。目的2：检测纳米乳对不同类型细胞的靶向性和治疗潜力。目的3：通过体内成像研究表面转换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，其中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。

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.