Targeted Nano-Chemosensitization of Breast Cancers

乳腺癌的靶向纳米化疗增敏

• 批准号: 9230196
• 负责人: Santosh Kumar
• 金额: $ 43.98万
• 依托单位: UNIVERSITY OF TENNESSEE HEALTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9230196
• 关键词: Academic Research Enhancement Awards; Address; Adverse effects; Antibodies; Antineoplastic Agents; Applications Grants; Attenuated; Autocrine Communication; Biocompatible Materials; Biological Availability; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Treatment; Breast Cancer therapy; Cancer Etiology; Cell Line; Cells; Cessation of life; Chemopreventive Agent; Chemosensitization; Cisplatin; Clinical; Clinical Trials; Course Content; Curcumin; Data; Deposition; Desmoplastic; Development; Doctor of Philosophy; Dose; Drug Delivery Systems; Drug Kinetics; Drug Transport; Drug resistance; ERBB2 gene; Engineering; Environment; Epithelial; Evaluation; Extracellular Matrix; Fibrosis; Formulation; In Vitro; Injection of therapeutic agent; Institution; Ions; Lead; Legal patent; Lipids; Magnetic nanoparticles; Malignant Neoplasms; Mammary Neoplasms; Membrane; Membrane Lipids; Mesenchymal; Metastatic breast cancer; Methodology; Methods; Modality; Modeling; Modification; Molecular; Mucin 1 protein; Multi-Drug Resistance; NF-kappa B; Nanotechnology; Neoplasm Metastasis; Nutritional; Oncogenes; Oncogenic; Organ; Outcome; Paracrine Communication; Pathway interactions; Peptide Vaccines; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Proteins; Publishing; Radiation-Sensitizing Agents; Radiosensitization; Research; Resistance; Resistance development; Role; SHH gene; Science; Signal Pathway; Solid Neoplasm; Stromal Cells; Students; Therapeutic; Therapeutic Agents; Toxic effect; Training; Transgenic Mice; Treatment Efficacy; United States; Woman; Xenograft procedure; cancer cell; chemotherapy; dosage; effective therapy; experimental study; graduate student; improved; innovation; malignant breast neoplasm; mouse model; nano; nanoformulation; nanoparticle; nanotherapeutic; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; resistance mechanism; response; smoothened signaling pathway; targeted treatment; therapy outcome; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression; uptake

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.

晚期乳腺癌 (BC)，尤其是三阴性 BC (TNBC) 的治疗尤为突出 由于对现有治疗方式的反应不佳，该治疗很困难。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药物输送和化疗耐药性不佳 （结缔组织增生）实体瘤。 NF-kappaB、Wnt 和 Sonic Hedgehog (SHH) 是关键的致癌信号 参与 BC 进展（包括结缔组织增生）和耐药性发展的途径 化疗药物方式。姜黄素是一种营养、抗癌和化学预防分子。最近的 研究表明姜黄素对上述致癌途径具有有效的抑制作用 诱导 BC 细胞（包括 TNBC）的化疗/放射增敏。然而，姜黄素的药代动力学较差 并且缺乏肿瘤靶向性。因此，为了成功的临床应用，需要对姜黄素进行修饰。我们的 初步数据表明姜黄素抑制 Wnt、NF-kappaB 和 SHH 信号传导以及姜黄素预处理 诱导化疗增敏并增强顺铂治疗癌细胞（包括 TNBC）的疗效 细胞。尽管在体外研究中很有希望，但游离姜黄素的药代动力学较差，并且对姜黄素有修饰作用。 成功的临床应用需要姜黄素。最近，我们设计了一种新型的姜黄素负载 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。我们发表的初步数据证明了抗体缀合能力 CUR 纳米制剂可有效靶向肿瘤并在肿瘤内注射后抑制肿瘤生长。因此， 我们假设我们的新型抗体引导的 MNP-CUR 将增强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 信号通路和减少促纤维增生反应。最近的研究表明串扰发挥着重要作用 BC 病理学中肿瘤和基质细胞之间的关系。最近的一项研究表明 MUC1 表达 94% 的基底样三阴性乳腺癌呈阳性。此外，MUC1肽疫苗用于TNBC 正在临床试验中。因此，MUC1 是经过充分研究和验证的 BC 和 TNBC 靶标。因此，我们将使用 MNP-CUR 缀合抗 MUC1 单克隆抗体可有效治疗 BC/TNBC。这种有针对性的方法将 由于姜黄素和顺铂的协同作用，提高了 BC 疗法的疗效，同时 通过降低有效治疗剂量来最大限度地减少这些方式的副作用。更重要的是， 该项目将支持竞争激烈的博士培训。学生并建立丰富的研究 主动开发癌症纳米疗法的环境。融入如此先进的理念 在药物科学中，课程设置中的实验是非常有必要的。这些努力将 最终导致开发出有效且安全的治疗乳腺癌的方法。

项目成果

Tannic Acid-Lung Fluid Assemblies Promote Interaction and Delivery of Drugs to Lung Cancer Cells.

• DOI: 10.3390/pharmaceutics10030111
• 发表时间: 2018-08-01
• 期刊: Pharmaceutics
• 影响因子: 5.4
• 作者: Hatami E;Nagesh PKB;Chowdhury P;Chauhan SC;Jaggi M;Samarasinghe AE;Yallapu MM
• 通讯作者: Yallapu MM