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）的管理，特别是三阴性BC （TNBC）是例外的

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