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.

晚期乳腺癌的治疗，特别是三阴性乳腺癌(TNBC)的治疗是例外的 由于对现有治疗方法的反应不佳，因此很难做到这一点。生存不佳的主要原因是 由于过度纤维化和细胞外基质沉积而导致的次优药物传递和化疗耐药性 (结缔组织增生症)在实体瘤中。核因子-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)和抗药性发展的途径 化疗药物模式。姜黄素是一种营养、抗癌和化学预防分子。近期 研究表明，姜黄素对上述致癌途径有很强的抑制作用 诱导包括TNBCs在内的BC细胞的化疗/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，需要对姜黄素进行修饰才能成功地应用于临床。我们的 初步数据表明，姜黄素抑制Wnt、NF-kappaB和SHH信号转导及姜黄素预处理 在包括TNBC在内的癌细胞中诱导化疗增敏并增强顺铂治疗的疗效 细胞。尽管在体外研究中前景看好，但游离姜黄素的药代动力学和修饰作用都很差。 姜黄素是临床成功使用所必需的。最近，我们设计了一种新型的姜黄素 治疗癌症的多层磁性纳米颗粒(MNP-CUR)配方(专利#PCT/US2011/063723) 治疗应用。我们已发表的和初步的数据表明，抗体偶联能力 Cur纳米制剂(S)瘤内注射可有效靶向肿瘤并抑制肿瘤生长。因此， 我们推测，我们的新型抗体导向的MNP-CUR将提高姜黄素在肿瘤中的生物利用度。 通过抑制癌基因抑制肿瘤生长并增强BC细胞对治疗药物(顺铂)的敏感性 信号通路和减少促结缔组织反应。最近的研究表明，相声在其中起着重要作用 在BC的病理生物学中，肿瘤和间质细胞之间的关系。最近的一项研究表明，MUC1的表达 在94%的基底细胞样三阴性乳腺癌中呈阳性。此外，MUC1多肽疫苗用于TNBC 正在进行临床试验。因此，MUC1是BC和TNBC经过充分研究和验证的目标。因此，我们将使用 MNP-Cur偶联抗MUC1单抗有效治疗BC/TNBC这种有针对性的方法将 通过姜黄素和顺铂的协同作用提高BC疗法的疗效 通过降低有效治疗剂量来最大限度地减少这些方法的副作用。更重要的是， 该项目将为博士生的高竞争力培养提供支持，并建立丰富的研究 环境与发展癌症纳米疗法的倡议。融入这些先进的概念 在药学中，将实验纳入课程课程是非常必要的。这些努力将 最终导致开发出有效和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