Targeted Nano-Chemosensitization of Breast Cancers

晚期乳腺癌（BC），特别是三阴性BC（TNBC）的管理是非常困难的。 由于对现有治疗方式的反应较差，因此很难。生存率低主要是因为 由于过度纤维化和细胞外基质沉积导致的次优药物递送和化学抗性 （结缔组织增生）。NF-κ B、Wnt和Sonic Hedgehog（SHH）是关键的致癌信号传导 参与BC进展（包括结缔组织增生）和对 化疗药物模式。姜黄素是一种营养、抗癌和化学预防分子。最近 研究表明姜黄素对上述致癌途径具有有效的抑制作用， 在包括TNBC的BC细胞中诱导化学/放射敏化。然而，姜黄素具有较差的药代动力学 并且缺乏肿瘤靶向。因此，需要对姜黄素进行修饰以用于成功的临床应用。我们 初步数据表明，姜黄素抑制Wnt，NF-κ B和SHH信号传导和姜黄素预处理 诱导化疗增敏并增强顺铂治疗在癌细胞（包括TNBC）中的功效 细胞尽管在体外研究中有希望，但游离姜黄素具有差的药代动力学和修饰， 姜黄素是成功的临床应用所必需的。最近，我们设计了一种新的姜黄素负载 用于癌症的多层磁性纳米颗粒（MNP-CUR）制剂（专利号PCT/US2011/063723） 治疗应用。我们公开的和初步的数据表明， CUR纳米制剂在肿瘤内注射后有效靶向肿瘤并抑制肿瘤生长。因此，我们认为， 我们假设我们的新型抗体引导的MNP-CUR将提高姜黄素在肿瘤中的生物利用度 通过抑制癌基因来减弱肿瘤生长并使BC细胞对治疗药物（顺铂）敏感 信号通路和结缔组织增生反应减少。最近的研究表明， 肿瘤和基质细胞之间的关系。最近的一项研究表明，MUC1表达 在94%的基底细胞样三阴性乳腺癌中呈阳性。此外，MUC1肽疫苗用于TNBC 正在进行临床试验因此，MUC1是BC和TNBC的充分研究和验证的靶标。因此，我们将使用 用于有效治疗BC/TNBC的MNP-CUR缀合的抗MUC1 MAb。这种有针对性的方法将 由于姜黄素和顺铂提供的协同作用而提高BC治疗剂的功效， 通过降低其有效治疗剂量使这些方式的副作用最小化。更重要的是， 该项目将支持竞争激烈的博士培养。学生和建立丰富的研究 环境与发展癌症纳米疗法的倡议。融入这些先进理念 将实验纳入课程设置是药学专业发展的必然要求。这些努力将 最终导致有效和安全的方法来治疗乳腺癌的发展。

The management of advanced stage breast cancer (BC), especially, triple negative BC (TNBC) is exceptionally difficult due to the poor response to available therapeutic modalities. Poor survival is primarily because of suboptimal drug delivery and chemo-resistance due to excessive fibrosis and extracellular matrix deposition (desmoplasia) in solid tumors. NF-kappaB, Wnt and Sonic Hedgehog (SHH) are key oncogenic signaling pathways that are involved in BC progression (including desmoplasia) and the development of resistance to chemotherapeutic drug modalities. Curcumin is a nutritional, anticancer and chemopreventive molecule. Recent studies demonstrate that curcumin has potent inhibitory effects on aforementioned oncogenic pathways and induces chemo/radio-sensitization in BC cells including TNBCs. However, curcumin has poor pharmacokinetics and lack tumor targeting. Therefore modifications to curcumin are needed for successful clinical use. Our preliminary data suggest that curcumin inhibits Wnt, NF-kappaB and SHH signaling and curcumin pre-treatment induces chemo-sensitization and enhances the efficacy of cisplatin treatment in cancer cells, including TNBC cells. Although promising in in vitro studies, free curcumin has poor pharmacokinetics and modifications to curcumin are needed for successful clinical use. Recently, we have engineered a novel curcumin loaded multi-layered magnetic nanoparticle (MNP-CUR) formulation (Patent # PCT/US2011/063723) for cancer therapeutic applications. Our published and preliminary data demonstrate antibody conjugation capability of CUR nanoformulations(s) effectively target tumors and inhibit tumor growth upon intra-tumoral injection. Hence, we hypothesize that our novel antibody-guided MNP-CUR will enhance the bioavailability of curcumin in tumors to attenuate tumor growth and sensitize BC cells to therapeutic drug (cisplatin) via suppression of oncogene signaling pathways and decreased desmoplastic reaction. Recent studies suggest a major role for cross-talk between tumor and stromal cells in the pathobiology of BC. A recent study demonstrates that MUC1 expression is positive in 94% of basal-like triple-negative breast cancers. Additionally, MUC1 peptide vaccine use for TNBC is in clinical trial. Thus, MUC1 is a well-studied and validated target for BC and TNBC. Therefore, we will use MNP-CUR conjugated anti-MUC1 MAbs for effective treatment of BC/TNBC. This targeted approach will improve the efficacy of BC therapeutics due to the synergistic action provided by curcumin and cisplatin while minimizing the side effects of these modalities by lowering their effective therapeutic dose. More importantly, this project will support highly competitive training for Ph.D. students and establish a rich research environment with the initiative to develop cancer nano-therapeutics. Incorporation of such advanced concepts and experiments into course curriculum is highly warranted in pharmaceutical science. These efforts will eventually lead to the development of effective and safe methods to treat breast cancer.