Targeted Nanoparticle DNA Therapy for Ovarian Cancer

卵巢癌的靶向纳米颗粒 DNA 治疗

• 批准号: 7760543
• 负责人: JANET A SAWICKI
• 金额: $ 27.52万
• 依托单位: LANKENAU INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7760543
• 关键词: Address; Adjuvant Therapy; Affinity; Attention; Biodistribution; Biological Assay; Biological Availability; Bioluminescence; Blood; Cancer Patient; Cell model; Cells; Chemicals; Communities; Complex; DNA; DNA delivery; Development; Diagnosis; Disease; Drug Formulations; Effectiveness; Esters; Folic Acid; Gene Expression; Goals; Human; Image; Imaging technology; Immunoglobulin Fragments; Lead; Life; Light; Longevity; Luciferases; Malignant Neoplasms; Malignant neoplasm of ovary; Modality; Modification; Mus; Names; Nature; Neoplasm Metastasis; Non-Viral Vector; Operative Surgical Procedures; Organ; Ovarian; Ovarian Carcinoma; Ovary; Pathology; Patients; Platinum; Polymers; Principal Investigator; Proteins; Recurrent disease; Regimen; Reporter Genes; Research; Resistance; Screening procedure; Serum; Specificity; Staging; Structure; Surface; Survival Rate; Testing; Therapeutic; Time; Toxic effect; Transfection; Transgenic Model; Treatment Efficacy; Tumor Debulking; United States; Variant; Vertebral column; Viral Vector; Woman; Xenograft Model; acrylic acid; base; biodegradable polymer; cancer cell; cancer type; cell killing; chemotherapy; combinatorial; design; effective therapy; expectation; gene therapy; immunogenicity; improved; in vivo; innovation; intraperitoneal; mesothelin; mouse model; mullerian-inhibiting hormone; nanoparticle; nanotherapy; neoplastic cell; ovarian neoplasm; programs; promoter; receptor; research study; response; standard care; suicide gene; targeted delivery; therapeutic gene; tumor

DESCRIPTION (provided by applicant): There is a clear and immediate need for a more effective therapy for advanced ovarian cancer. To address this need, our long-term goal is to develop a nanotherapy for advanced-stage metastatic ovarian cancer that effectively manages the cancer, resulting in a longer, healthy life. The objective of the proposed experiments is to introduce modifications to a promising new class of cationic, biodegradable poly(2-amino ester) polymers that result in efficient, targeted nanoparticle-delivery of DNA to ovarian tumor cells. The proposed experiments test the hypothesis that intraperitoneal administration of polymeric nanoparticles designed to target the delivery of DNA encoding so-called suicide genes to ovarian cancer cells will effectively kill the cells, resulting in ovarian tumor regression. We will modify polymers in three ways, aiming to enhance their ability to target DNA delivery to ovarian cancer cells and to improve their resistance to inactivation by serum. One approach will be to pegylate polymers and conjugate them to one of two single chain variable antibody fragments (scFvs) having reactivity to proteins found on the surface of ovarian tumor cells, or to folic acid. The second approach will be to complex DNA poly(2-amino ester)-nanoparticles with scFv- or folic acid-conjugated poly(acrylic acid). The third approach will be to make combinatorial end-modifications to the structure of poly(2-amino ester)s. We will use a high-throughput cell-based transfection assay to identify the modified polymers imparting the highest degree of serum resistance and DNA delivery. We will then test the effectiveness of selected polymer formulations in three in vivo mouse models: a transgenic model for ovarian cancer, a sygeneic mouse/tumor cell model, and a human tumor cell xenograft model. In addition to targeting DNA delivery to ovarian cancer cells, we aim to target gene expression using ovarian-specific promoter sequences. We will use non-invasive imaging technologies (bioluminescence and microCT) to assess longitudinally the response of tumors to the nanoparticle-delivers DT-A therapy. In addition, we will determine the effect of this therapy on life span and determine whether the therapy results in non-specific toxicity. There are currently no effective therapies for advanced-stage ovarian cancer patients. Our expectation is that the innovative use of nanoparticles to target delivery of suicide genes to ovarian cancer cells, combined with a strategy for targeting gene expression to these cells, will lead to an effective treatment for this deadly disease. While we focus here on the development of a new therapy for ovarian cancer, this study will help establish the utility of nanoparticles for gene therapy and pave the way for their broader application for treating additional types of cancer and other diseases. Project Narrative: Poly(2-amino ester)s is cationic, biodegradable polymers that show great promise as non-viral vectors for the delivery of therapeutic DNA to cancer cells. There are currently no effective therapies for advanced-stage ovarian cancer patients that either do not respond to initial therapy or those with recurrent disease. The purpose of this study is to introduce modifications to poly(2-amino ester)s that result in efficient, targeted nanoparticle-delivery of DNA encoding suicide genes to ovarian tumor cells following intraperitoneal administration. Targeted nanotherapy, used alone or as an adjuvant therapy, should lead to a more effective treatment for patients with metastatic ovarian cancer.

描述（由申请人提供）：对于晚期卵巢癌，迫切需要一种更有效的治疗方法。为了满足这一需求，我们的长期目标是开发一种针对晚期转移性卵巢癌的纳米疗法，有效控制癌症，从而延长患者的健康寿命。拟议实验的目的是对一类有前途的新型阳离子、可生物降解的聚（2-氨基酯）聚合物进行修饰，从而将 DNA 高效、靶向地纳米颗粒递送至卵巢肿瘤细胞。拟议的实验测试了这样的假设：腹腔内施用聚合物纳米粒子，旨在将编码所谓自杀基因的DNA靶向递送至卵巢癌细胞，将有效杀死细胞，从而导致卵巢肿瘤消退。我们将以三种方式对聚合物进行修饰，旨在增强其将 DNA 递送至卵巢癌细胞的能力，并提高其对血清灭活的抵抗力。一种方法是将聚乙二醇化聚合物并将其与两个单链可变抗体片段（scFv）之一缀合，该片段对卵巢肿瘤细胞表面的蛋白质或叶酸具有反应性。第二种方法是将 DNA 聚（2-氨基酯）纳米颗粒与 scFv 或叶酸缀合的聚（丙烯酸）复合。第三种方法是对聚（2-氨基酯）的结构进行组合末端修饰。我们将使用基于细胞的高通量转染测定来鉴定具有最高程度的血清抗性和 DNA 递送的修饰聚合物。然后，我们将在三种体内小鼠模型中测试所选聚合物配方的有效性：卵巢癌转基因模型、同基因小鼠/肿瘤细胞模型和人类肿瘤细胞异种移植模型。除了将 DNA 递送至卵巢癌细胞外，我们还旨在使用卵巢特异性启动子序列来靶向基因表达。我们将使用非侵入性成像技术（生物发光和 microCT）来纵向评估肿瘤对纳米颗粒 DT-A 疗法的反应。此外，我们将确定该疗法对寿命的影响，并确定该疗法是否会导致非特异性毒性。目前尚无针对晚期卵巢癌患者的有效治疗方法。我们的期望是，创新性地使用纳米颗粒将自杀基因靶向递送至卵巢癌细胞，结合靶向这些细胞的基因表达的策略，将为这种致命疾病提供有效的治疗。虽然我们重点关注卵巢癌新疗法的开发，但这项研究将有助于确立纳米颗粒在基因治疗中的实用性，并为其更广泛地应用于治疗其他类型的癌症和其他疾病铺平道路。 项目叙述：聚（2-氨基酯）是一种阳离子、可生物降解的聚合物，作为非病毒载体向癌细胞输送治疗性 DNA，显示出巨大的前景。对于对初始治疗无反应或疾病复发的晚期卵巢癌患者，目前尚无有效的治疗方法。本研究的目的是对聚（2-氨基酯）进行修饰，从而在腹膜内给药后，将编码自杀基因的 DNA 高效、靶向地纳米颗粒递送至卵巢肿瘤细胞。靶向纳米疗法，单独使用或作为辅助疗法，应该可以为转移性卵巢癌患者提供更有效的治疗。