Polymeric Nanomedicines of Small Molecules and miRNA for Treating Pancreatic Canc

用于治疗胰腺癌的小分子和 miRNA 聚合纳米药物

• 批准号: 8761405
• 负责人: Ram I. Mahato
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761405
• 关键词: Apoptosis; Biodistribution; Bypass; Cancer Model; Cancer Patient; Carbonates; Cell Line; Cell Proliferation; Cells; Cetuximab; Combined Modality Therapy; Complex; Desmoplastic; Development; Dodecanol; Dose; Down-Regulation; Drug Formulations; Drug Kinetics; Drug Stability; Drug resistance; Ensure; Epidermal Growth Factor Receptor; Ethylene Glycols; Exhibits; Genes; Half-Life; Human; In Vitro; Malignant Neoplasms; Malignant neoplasm of pancreas; Metabolism; Micelles; MicroRNAs; Mus; Neoplasm Metastasis; Pancreas; Pharmaceutical Preparations; Plasma; Play; Polymers; Recurrence; Relapse; Resistance; Role; Safety; Series; Time; Tissues; Toxic effect; Transfection; Tumor Tissue; base; cancer cell; cancer stem cell; cell growth; chemotherapy; clinical application; copolymer; cytotoxicity; drug metabolism; epithelial to mesenchymal transition; ethylene glycol; fetal bovine serum; gemcitabine; hydrophilicity; improved; in vivo; intravenous administration; mortality; nanocarrier; nanomedicine; nanosized; neoplastic cell; novel; overexpression; pancreatic neoplasm; propylene; public health relevance; receptor; residence; resistance mechanism; restoration; small molecule; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression; uptake; zeta potential

DESCRIPTION (provided by applicant): Successful treatment of pancreatic cancer remains a challenge due to the presence of pronounced desmoplastic tumor microenvironment and emergence of chemoresistance resulting in recurrence and metastatic spread. Gemcitabine shows only limited efficacy due to its inefficient delivery to tumor because of its hydrophilicity and rapid metabolism and also due to the activity of cancer stem cells (CSCs), which are regulated by miRNAs. In our preliminary studies, gemcitabine was conjugated to poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate) (PEG- PCC) and formulated into micelles which significantly inhibited tumor growth compared to free drug when injected intravenously into pancreatic tumor bearing NSG mice. To achieve complete tumor regression, we identified miR-205 among a series of dysregulated miRNAs from the CSCs isolated from gemcitabine resistant MIA PaCa-2R cells and human pancreatic cancer tissues, to be significantly downregulated and playing a predominant role in regulating cell growth, epithelial to mesenchymal transition (EMT) and resistance. Transfection of MIA PaCa-2R cells with miR-205 mimic resulted in the restoration of chemosensitivity to gemcitabine. Then, we synthesized gemcitabine conjugated poly(ethylene glycol)-block-poly(2-methyl-2-carboxyl-propylene carbonate-graft- dodecanol-graft-tetraethylenepentamine) copolymer having cationic chains for polyplex formation with miR-205 mimic which showed improved stability in fetal bovine serum and efficiently transfected and reversed chemoresistance, invasion and metastasis in gemcitabine resistant cells. Therefore, we hypothesize that co-formulation of miR-205 mimic with gemcitabine may effectively treat pancreatic cancer by reversing the chemo-resistance of CSCs and simultaneously target bulk tumor cells as well. Major focus of the project is to: a) discover suitable miRNAs to target chemo-resistance and EMT (like miR205) in pancreatic cancer and b) co-deliver this miRNA with gemcitabine to the tumor using a actively targeted nanocarrier which can protect both these molecules from plasma degradation and ensure enhanced uptake. Our specific aims are to i) identify the aberrantly expressed miRNAs and validate their role in chemoresistance, invasion and metastasis; ii) co- formulate miRNA and gemcitabine in polymeric micelles and assess their synergistic effect on the inhibition of pancreatic cancer and, iii) assess the synergistic action of micelles carrying gemcitabine and miRNA on the regression of human pancreatic tumor bearing mice. Significance of the project is to develop nanomedicines of miRNA mimic and gemcitabine that effectively increase local drug concentrations within the fibrotic stroma of these tumors and bypass the chemo-resistant mechanisms that allow tumor growth and inhibit the efficacy of current standard chemotherapies.

描述（由申请人提供）：由于存在明显的去肿瘤肿瘤微环境和化学耐药性的出现，导致复发和转移性扩散，因此成功治疗胰腺癌仍然是一个挑战。吉西他滨由于其亲水性和快速代谢以及由于受miRNA调节的癌症干细胞（CSC）的活性而显示出有限的疗效，因此其效率无效。在我们的初步研究中，将吉西他滨与聚（乙二醇）-Block-Poly（2-甲基-2-羧基 - 丙二醇）（PEG-PCC）共轭，并配制成与静脉内注射胰腺胰蛋白酶胰蛋白酶胰蛋白酶的乳腺药物相比，与肿瘤生长相比显着抑制肿瘤生长。为了实现完全的肿瘤回归，我们在从耐吉西他滨耐药的MIA PACA-2R细胞和人胰腺癌组织中分离的CSC中的一系列失调的miRNA中确定了miR-205，并显着下调，并在调节细胞生长中起主要作用，在调节细胞生长中起主要作用 间充质转变（EMT）和电阻。用miR-205模拟物将MIA PACA-2R细胞转染导致对吉西他滨的化学敏感性。然后，我们合成了吉西他滨共轭聚乙二醇（2-甲基-2-甲基-2-羧基 - 丙二醇 - 碳酸苯甲酸苯二甲酸 - 十二烷醇移植） - 乙醇 - 间接环氨基异氨基氨基异氨基），具有阳离子链，具有改进的Mim-205 Mimic and-205的共晶链，并在米型链中进行了良好的序列，并具有依赖型的bly-205吉西他滨耐药细胞中的化学抗性，侵袭和转移。因此，我们假设MiR-205与吉西他滨的共同成立可以通过逆转CSC的化学耐药性并同时靶向散装肿瘤细胞来有效治疗胰腺癌。该项目的主要重点是：a）在胰腺癌中发现合适的miRNA，以靶向化学耐药性和EMT（如miR205），b）b）使用主动靶向的纳米载盘将这种miRNA与吉西他滨共同给肿瘤，这些纳米载液可以使用这些分子脱离等化剂，并确保增强膨胀量。我们的具体目的是i）确定异常表达的miRNA并验证其在化学抗性，侵袭和转移中的作用； ii）在聚合物胶束中辅助miRNA和吉西他滨在聚合物胶束中，并评估其对胰腺癌抑制的协同作用，以及III）评估携带吉西他滨和miRNA对人胰腺肿瘤轴承小鼠回归的胶束的协同作用。该项目的重要性是开发miMNA模拟和吉西他滨的纳米药物，这些纳米药物有效地增加了这些肿瘤的纤维化基质内的局部药物浓度，并绕过化学耐药机制，从而允许肿瘤生长并抑制当前标准化疗的功效。