Nanoplatform-based combinational therapy against breast cancer

在乳腺癌化疗成功的障碍中，有三个是至关重要的：药物问题 传递、耐药和癌症干细胞(CSCs)。到目前为止，还没有做出任何努力来解决所有 一种方法解决了三个问题。这项提议寻求通过一个纳米平台来应对挑战，我们 最近开发的，它由人血清白蛋白(HSA)涂层组成，富含胺 中间涂层和氧化铁纳米颗粒(1ONP)芯。它的结构类似于Abraxane，一种 商业紫杉醇-人血清白蛋白复合体，但流体力学尺寸较小，因此肿瘤聚集较好 外渗率和外渗率。这种良好的药代动力学可以通过添加外部的 这使得纳米平台成为一种很有前途的药物输送载体。具有上位配体 由外部HSA和富胺中间层两者提供的结合能力，这样的纳米平台可以 装载范围广泛的药物分子。在这项提案中，我们计划将阿霉素负载到这样的纳米平台上 (或紫杉醇)、盐霉素和达奎达(或靶向mdr-1基因的siRNA)。阿霉素(或紫杉醇) 是一种通常用于乳腺癌治疗的化疗药物，旨在杀死 分化的肿瘤细胞，占肿瘤块的大部分。盐霉素是一种新近发现的 具有选择性杀伤CSC能力的治疗剂。Tariquidar和siRNA都可以作为mdr-1发挥作用 抑制剂及其调节作用可能导致药物蓄积增加。人们希望，有了 提供互补的肿瘤杀伤机制和良好的肿瘤靶向特征 纳米平台，这一新的方法可能导致显著改善的治疗效果。这将是第一次 研究肿瘤治疗以解决药物输送、耐药性和肿瘤干细胞的单一问题 接近。这项研究的成功可能是乳腺癌治疗的一个里程碑，为乳腺癌治疗提供了一种强大的、一体化的、 乳腺癌治疗方案。

Among the obstacles to successful breast cancer chemotherapy, three have been critical: problems of drug delivery, drug resistance, and cancer stem cells (CSCs). Until now, no effort has been made to address all three issues in a single approach. This proposal seeks to meet the challenge through a nanoplatform that we recently developed, which is comprised of a human serum albumin (HSA) coating, an amine-rich intermediate coating, and an iron oxide nanoparticle (lONP) core. It structurally resembles Abraxane, a commercial paclitaxel-HSA complex, but has smaller hydrodynamic size therefore better tumor accumulation rate and extravasation rate. Such favorable pharmacokinetics can be further improved by adding an external field at the tumor sites, making the nanoplatform a promising drug delivery vehicle. With superior ligand binding capability afforded by both the outer HSA and intermediate amine-rich layers, such nanoplatform can load a broad range of drug molecules. In this proposal, we plan to load such a nanoplatform with doxorubicin (or paclitaxel), salinomycin and tariquidar (or siRNA that targets the MDR-1 gene). Doxorubicin (or paclitaxel) is a chemotherapeutic agent that is commonly used in breast cancer therapy, directed toward killing the differentiated tumor cells that account for most of a tumor mass. Salinomycin is a recently identified therapeutic agent with selective CSC killing capability. Both tariquidar and siRNA can function as MDR-1 inhibitors and their modulating effects may lead to increased drug accumulation. It is hoped that, with complementary cancer killing mechanisms and favorable tumor targeting profile provided by the nanoplatform, this novel approach may lead to dramatically improved therapeutic effects. This will be the first investigation on tumor therapy to address problems of drug delivery, drug resistance, and CSCs in a single approach. Success of this study may be a milestone in breast cancer therapy for providing a powerful, all-inone, breast cancer therapeutic regimen.