Multifunctional nanoparticles for targeting aberrant tumorigenic pathways

描述(申请人提供)：传统的癌症化疗主要是基于高度细胞毒性的药物，这些药物非特异性地针对任何分裂细胞，从而在仅适度改善患者生存的情况下诱导全球全身毒性。事实上，癌症仍然是美国第二大死亡原因，2007年新增病例1,444,920例，死亡559,650例。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一种下一代纳米颗粒，它可以部署异常致癌途径的信号转导抑制剂和细胞毒性化疗药物的组合，以发挥更好的抗肿瘤效果，同时减少不良反应。具体地说，我们将设计一种多功能纳米颗粒，它可以抑制关键的致癌途径-丝裂原活化蛋白激酶(MAPK)途径，并在进入肿瘤后额外输送阿霉素。具体目标是：目标1：从聚乳酸聚乙交酯(PLGA)-阿霉素和丝裂原活化蛋白激酶(MAPK)抑制剂PLGA-PD98059的特定比例中设计出一种肿瘤靶向的多功能纳米颗粒。此外，我们将在纳米颗粒中集成靶向多肽，该纳米颗粒已经针对纳米颗粒的肿瘤靶向进行了优化，以测试与通过增强渗透性和保留力(EPR)效应而归巢相比，靶向纳米颗粒产生更好的抗肿瘤效果的假设。目的：检测多功能纳米粒的体内外药效。我们已经确定了表现出激活的MAPK状态的癌细胞株，并且对阿霉素敏感或耐药，这将成为测试和优化多功能纳米粒的有力工具。此外，我们还建立了表达荧光素酶的RAS激活的卵巢癌小鼠模型、4T1乳腺癌模型和具有激活MAPK信号的B16/F10黑色素瘤同基因模型，这将用于本研究。目的3.阐明多功能纳米粒子的活性机制。在组织水平上，我们将测试纳米颗粒的组织分布，预期增强对肿瘤的输送可能是改善治疗指数的机制。我们将从分子水平剖析治疗对ERK磷酸化状态的影响，及其与细胞增殖指数、细胞凋亡和肿瘤血管生成的关系。我们预计，实现这些目标将使一种机械激发的多功能纳米粒子的开发成为可能，用于由MAPK信号通路驱动的癌症治疗。此外，它还将深入了解两种活性物质在纳米颗粒中的合理组合，从而为设计下一代纳米颗粒打开了可能性。

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.