Nanoplatform-based combinational therapy against breast cancer

在成功的乳腺癌化疗的障碍中，有三个是关键的：药物问题 递送、耐药性和癌症干细胞（CSC）。到目前为止，还没有作出任何努力来解决所有问题， 三个问题在一个单一的方法。这项提案旨在通过一个纳米平台来应对挑战， 最近开发的，其由人血清白蛋白（HSA）涂层、富含胺的 中间涂层和氧化铁纳米颗粒（IONP）核。它在结构上类似于Abraxane， 商业紫杉醇-HSA复合物，但具有更小的流体动力学尺寸，因此具有更好的肿瘤蓄积 率和外渗率。这种有利的药代动力学可以通过添加外部药物来进一步改善。 这使得纳米平台成为一种有前途的药物输送载体。具有上级配体 由于外部HSA和中间富胺层提供的结合能力，这种纳米平台可以 装载了大量的药物分子在这个提议中，我们计划用阿霉素装载这样的纳米平台 (or紫杉醇）、盐霉素和tariquidar（或靶向MDR-1基因的siRNA）。阿霉素（或紫杉醇） 是一种常用于乳腺癌治疗的化学治疗剂，其目的是杀死 分化的肿瘤细胞占肿瘤块的大部分。盐霉素是最近发现的一种 具有选择性杀死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。希望随着 互补的癌症杀伤机制和有利的肿瘤靶向特征， 纳米平台，这种新的方法可能会导致显着改善的治疗效果。这将是第一 肿瘤治疗的研究，以解决药物递送，耐药性和CSC的问题，在一个单一的 approach.这项研究的成功可能是乳腺癌治疗的一个里程碑， 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.