Multifunctional nanoparticles for targeting aberrant tumorigenic pathways

针对异常致瘤途径的多功能纳米颗粒

• 批准号: 8607832
• 负责人: Shiladitya Sengupta
• 金额: $ 34.85万
• 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/8607832
• 关键词: Address; Adverse effects; Apoptosis; Avastin; Biomedical Engineering; Breast Cancer Model; Cancer Model; Cancer cell line; Cell Proliferation; Cell Survival; 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; ERBB2 gene; 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; Vascular Endothelial Growth Factor Receptor; 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.

描述（由申请人提供）：传统的癌症化疗主要基于非特异性靶向任何分裂细胞的高细胞毒性药物，从而诱导全身性毒性，而对患者存活率仅略有改善。事实上，癌症仍然是美国第二大死亡原因，2007 年有 1,444,920 例新病例和 559,650 例死亡。显然迫切需要一种新的癌症治疗模式。该项目的目标是设计下一代纳米颗粒，它可以将异常致癌途径的信号转导抑制剂与细胞毒性化疗剂结合使用，以发挥优异的抗肿瘤效果，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，它可以抑制丝裂原激活蛋白激酶（MAPK）途径（一种关键的致癌途径），并在归巢到肿瘤后另外输送阿霉素。具体目标是： 目标 1：以规定比例的聚丙交酯聚乙交酯 (PLGA)-阿霉素和 PLGA-PD98059（一种 MAPK (MEK) 抑制剂）设计出一种“靶向”肿瘤的多功能纳米颗粒。此外，我们将把靶向肽整合到纳米颗粒中，该纳米颗粒已经针对纳米颗粒靶向肿瘤进行了优化，以测试“靶向”纳米颗粒与通过增强渗透性和保留（EPR）效应归巢相比可产生更好的抗肿瘤效果的假设。目标2：测试多功能纳米粒子的体外和体内功效。我们已经鉴定出表现出激活的 MAPK 状态并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粒子的强大工具。此外，我们还建立了表达荧光素酶的RAS激活的卵巢小鼠转基因癌症模型、4T1乳腺癌模型和激活MAPK信号的B16/F10黑色素瘤同系模型，将用于本研究。目标 3. 阐明多功能纳米颗粒活性的机制。在组织水平上，我们将测试纳米粒子的组织分布，并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，及其与细胞增殖指数、细胞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出一种受机械启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，它将深入了解纳米粒子中两种活性剂的合理组合，从而开启设计下一代纳米粒子的可能性。

项目成果

Rationally designed oxaliplatin-nanoparticle for enhanced antitumor efficacy.

• DOI: 10.1088/0957-4484/23/7/075103
• 发表时间: 2012-02-24
• 期刊: Nanotechnology
• 影响因子: 3.5
• 作者: Paraskar A;Soni S;Roy B;Papa AL;Sengupta S
• 通讯作者: Sengupta S

Design principles for clinical efficacy of cancer nanomedicine: a look into the basics.

• DOI: 10.1021/nn4015399
• 发表时间: 2013-04-23
• 期刊: ACS NANO
• 影响因子: 17.1
• 作者: Sengupta, Shiladitya;Kulkarni, Ashish
• 通讯作者: Kulkarni, Ashish

Preclinical Cancer Models and Biomarkers for Drug Development: New Technologies and Emerging Tools.

• DOI: 10.4172/2155-9929.1000356
• 发表时间: 2017-09-01
• 期刊: Journal of molecular biomarkers & diagnosis
• 作者: Dhandapani, Muthu;Goldman, Aaron
• 通讯作者: Goldman, Aaron

Supramolecular nanoparticles that target phosphoinositide-3-kinase overcome insulin resistance and exert pronounced antitumor efficacy.

靶向磷酸肌醇-3-激酶的超分子纳米颗粒克服了胰岛素抵抗并发挥显着的抗肿瘤功效。

• DOI: 10.1158/0008-5472.can-12-4477
• 发表时间: 2013
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Kulkarni,AshishA;Roy,Bhaskar;Rao,PoornimaS;Wyant,GregoryA;Mahmoud,Ayaat;Ramachandran,Madhumitha;Sengupta,Poulomi;Goldman,Aaron;Kotamraju,VenkataRamana;Basu,Sudipta;Mashelkar,RaghunathA;Ruoslahti,Erkki;Dinulescu,DanielaM;Sen
• 通讯作者: Sen

Rationally engineered polymeric cisplatin nanoparticles for improved antitumor efficacy.

• DOI: 10.1088/0957-4484/22/26/265101
• 发表时间: 2011-07-01
• 期刊: Nanotechnology
• 影响因子: 3.5
• 作者: Paraskar A;Soni S;Basu S;Amarasiriwardena CJ;Lupoli N;Srivats S;Roy RS;Sengupta S
• 通讯作者: Sengupta S