Multifunctional nanoparticles for targeting aberrant tumorigenic pathways

针对异常致瘤途径的多功能纳米粒子

• 批准号: 7889328
• 负责人: Shiladitya Sengupta
• 金额: $ 36.94万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-19 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7889328
• 关键词: Address; Adverse effects; Apoptosis; Avastin; Biomedical Engineering; Breast Cancer Model; Cancer Model; Cancer cell line; Cell Proliferation; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Cisplatin; Clinic; Combination Drug Therapy; Cytotoxic agent; Development; Doxorubicin; Drug Combinations; Drug Delivery Systems; Drug or chemical Tissue Distribution; Engineering; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Exhibits; Gefitinib; Goals; Homing; Hospitals; In Vitro; Institutes; Luciferases; MEKs; Malignant Neoplasms; Medicine; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mutation; Nanotechnology; Oncogenic; Outcome; Ovarian; Pathway interactions; Patients; Peptides; Permeability; Pharmaceutical Preparations; Phosphorylation; Polyglycolic Acid; Polymer Chemistry; Polymers; Positioning Attribute; Receptor Protein-Tyrosine Kinases; Reporting; Resistance; Role; S-Phase Fraction; Signal Pathway; Signal Transduction; Signal Transduction Inhibitor; System; Testing; Therapeutic Index; Tissues; Toxic effect; Transgenic Mice; Trastuzumab; Tumor Angiogenesis; United States; Woman; Work; base; cancer pharmacology; cancer therapy; chemotherapeutic agent; cytotoxic; editorial; efficacy testing; improved; in vivo; inhibitor/antagonist; insight; instructor; medical schools; melanoma; mortality; mouse model; nanoparticle; next generation; poly(lactide); professor; public health relevance; small molecule; standard of care; targeted delivery; tool; treatment effect; tumor; tumorigenic

DESCRIPTION (provided by applicant): Traditional cancer chemotherapy has primarily been based on highly cytotoxic drugs that nonspecifically target any dividing cell, thereby inducing global systemic toxicity with only a modest improvement in patient survival. Indeed, cancer is still the second leading cause of mortality in the United States, with 1,444,920 new cases and 559,650 deaths in 2007. There is clearly an urgent need for a new paradigm in the management of cancer. The goal of this project is to engineer a next generation nanoparticle that can deploy a combination of a signal transduction inhibitor of an aberrant oncogenic pathway along with a cytotoxic chemotherapeutic agent to exert a superior antitumor outcome with reduced adverse effects. Specifically, we will engineer a multifunctional nanoparticle that can inhibit the mitogen activated protein kinase (MAPK) pathway, a critical oncogenic pathway, and additionally deliver doxorubicin after homing into the tumor. The specific aims are: Aim 1: To engineer a tumor 'targeted' multifunctional nanoparticle from a defined ratio of polylactide polyglycolide (PLGA)-doxorubicin and PLGA-PD98059, a MAPK (MEK) inhibitor. Additionally, we will integrate a targeting peptide to the nanoparticle, which has already been optimized for targeting nanoparticles to tumors, to test the hypothesis that 'targeted' nanoparticles result in superior antitumor outcome as compared to homing by enhanced permeability and retention (EPR) effect. Aim 2: To test the efficacy of the multifunctional nanoparticle in vitro and in vivo. We have identified cancer cell lines that exhibit activated MAPK status, and are susceptible or resistant to doxorubicin, which would serve as powerful tools to test and optimize the multifunctional nanoparticles. Furthermore, we have established a luciferase-expressing RAS-activated ovarian mouse transgenic cancer model, a 4T1 breast cancer model and a B16/F10 melanoma syngeneic model with activated MAPK signaling, which will be used in this study. Aim 3. To elucidate the mechanisms underlying the activity of the multifunctional nanoparticle. At a tissue level, we will test the tissue distribution of the nanoparticles with the anticipation that enhanced delivery to the tumor could be the mechanism underlying improved therapeutic index. At a molecular level, we will dissect the effect of treatment on the phosphorylation status of ERK, and its correlation with cell proliferation index, apoptosis and tumor angiogenesis. We anticipate that achieving these goals will enable the development of a mechanistically-inspired multifunctional nanoparticle for the treatment of cancers driven by the MAPK signaling pathway. Additionally, it will shed insights into the rational combination of two active agents in a nanoparticle, thereby opening up the possibility of engineering next generation nanoparticles. PUBLIC HEALTH RELEVANCE: Cancer is still the second leading cause of mortality in the United States, with 1,444,920 new cases and 559,650 deaths in 2007. There is clearly an urgent need for a new paradigm in the management of cancer. The goal of this project is to engineer a next generation nanoparticle that can deploy a combination of a signal transduction inhibitor of an aberrant oncogenic pathway along with a cytotoxic chemotherapeutic agent to exert a superior antitumor outcome with reduced adverse effects. We anticipate that achieving these goals will enable the development of a mechanistically-inspired multifunctional nanoparticle for the treatment of cancers driven by the MAPK signaling pathway. Additionally, it will shed insights into the rational combination of two active agents in a nanoparticle, thereby opening up the possibility of engineering next generation nanoparticles.

描述（由申请人提供）：传统的癌症化学疗法主要基于高度细胞毒性药物，非特异性地针对任何分裂细胞，从而诱导全球全身毒性，只有适度的改善患者的生存率。实际上，癌症仍然是美国死亡率的第二大原因，2007年有1,444,920例新病例和559,650例死亡。显然，迫切需要在癌症治疗中建立新的范式。该项目的目的是设计一种下一代纳米颗粒，该纳米颗粒可以组合一个异常的致癌途径的信号转导抑制剂以及细胞毒性化学治疗剂，以发挥出色的抗肿瘤结果和减少的不良影响。 具体而言，我们将设计一种多功能纳米颗粒，该纳米颗粒可以抑制有丝分裂激活的蛋白激酶（MAPK）途径，这是一种关键的致癌途径，并在将阿霉素送入肿瘤后递送阿霉素。具体目的是：目标1：从polylactide polylactide聚乙酰醇（PLGA） - 多氧霉素和PLGA-PD98059（MAPK）（MAPK）抑制剂的定义比例中，以肿瘤为“靶向”多功能纳米颗粒。此外，我们将将靶向肽集成到纳米颗粒上，该纳米颗粒已经对纳米颗粒靶向肿瘤进行了优化，以检验以下假设：“靶向”纳米颗粒会导致与通过增强的渗透性和保留（EPR）效应相比，与归巢相比，与归巢相比，抗性结果具有优势。目标2：测试多功能纳米颗粒在体外和体内的功效。我们已经确定了表现出激活的MAPK状态的癌细胞系，并且对阿霉素易感或耐药，这将是测试和优化多功能纳米颗粒的强大工具。此外，我们已经建立了一种表达荧光素酶的RAS激活的卵巢小鼠转基因癌模型，一个4T1乳腺癌模型和带有活化的MAPK信号的B16/F10黑色素瘤合成模型，该模型将在本研究中使用。目标3。阐明多功能纳米颗粒活性的机制。在组织水平上，我们将测试纳米颗粒的组织分布，并预期增强向肿瘤的递送可能是改善治疗指数的机制。在分子水平上，我们将剖析治疗对ERK磷酸化状态的影响，及其与细胞增殖指数，凋亡和肿瘤血管生成的相关性。我们预计实现这些目标将使机械启发的多功能纳米颗粒能够开发用于由MAPK信号通路驱动的癌症的处理。 此外，它将洞悉纳米颗粒中两种活性剂的合理组合，从而开辟了工程下一代纳米颗粒的可能性。 公共卫生相关性：癌症仍然是美国死亡率的第二大主要原因，2007年有1,444,920例新病例和559,650例死亡。显然，迫切需要在癌症管理中建立新的范式。 该项目的目的是设计一种下一代纳米颗粒，该纳米颗粒可以组合一个异常的致癌途径的信号转导抑制剂以及细胞毒性化学治疗剂，以发挥出色的抗肿瘤结果和减少的不良影响。我们预计实现这些目标将使机械启发的多功能纳米颗粒能够开发用于由MAPK信号通路驱动的癌症的处理。 此外，它将洞悉纳米颗粒中两种活性剂的合理组合，从而开辟了工程下一代纳米颗粒的可能性。