Multifunctional nanoparticles for targeting aberrant tumorigenic pathways

描述（由申请人提供）： 传统的癌症化疗主要是基于非特异性靶向任何分裂细胞的高细胞毒性药物，从而诱导全身毒性，仅适度改善患者存活率。事实上，癌症仍然是美国第二大死亡原因，2007年有1，444，920例新发病例和559，650例死亡。显然，迫切需要一种新的癌症管理模式。该项目的目标是设计下一代纳米颗粒，其可以部署异常致癌途径的信号转导抑制剂沿着细胞毒性化疗剂的组合，以发挥上级抗肿瘤结果，同时减少不良反应。 具体来说，我们将设计一种多功能纳米颗粒，它可以抑制促分裂原活化蛋白激酶（MAPK）途径，这是一种关键的致癌途径，并在归巢到肿瘤后额外提供阿霉素。具体目标是：目标1：从确定比例的聚丙交酯聚乙交酯（PLGA）-阿霉素和PLGA-PD 98059（MAPK（MEK）抑制剂）设计肿瘤“靶向”多功能纳米颗粒。此外，我们将整合一个靶向肽的纳米粒子，它已经被优化为靶向纳米粒子的肿瘤，以测试的假设，“靶向”纳米粒子导致上级抗肿瘤的结果相比，归巢增强渗透性和保留（EPR）的效果。目的2：检测多功能纳米粒的体内外药效。我们已经鉴定了表现出活化的MAPK状态并且对阿霉素敏感或耐药的癌细胞系，这将作为测试和优化多功能纳米颗粒的有力工具。此外，我们还建立了表达RAS的卵巢转基因小鼠模型、4 T1乳腺癌模型和具有活化的MAPK信号传导的B16/F10黑色素瘤同基因模型，这些模型将用于本研究。目标3。阐明多功能纳米颗粒的活性机制。在组织水平上，我们将测试纳米颗粒的组织分布，预期增强对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，以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，实现这些目标将能够开发一种机械激发的多功能纳米颗粒，用于治疗由MAPK信号通路驱动的癌症。 此外，它将揭示纳米颗粒中两种活性剂的合理组合，从而开辟了工程化下一代纳米颗粒的可能性。 公共卫生相关性： 癌症仍然是美国第二大死亡原因，2007年有1，444，920例新发病例和559，650例死亡。显然，迫切需要一种新的癌症管理模式。 该项目的目标是设计下一代纳米颗粒，其可以部署异常致癌途径的信号转导抑制剂沿着细胞毒性化疗剂的组合，以发挥上级抗肿瘤结果，同时减少不良反应。我们预计，实现这些目标将能够开发一种机械激发的多功能纳米颗粒，用于治疗由MAPK信号通路驱动的癌症。 此外，它将揭示纳米颗粒中两种活性剂的合理组合，从而开辟了工程化下一代纳米颗粒的可能性。

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.