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）：清楚地需要对晚期卵巢癌进行更有效的治疗。为了满足这一需求，我们的长期目标是为高级转移性卵巢癌开发一种有效管理癌症的纳米疗法，从而带来更长，健康的寿命。该提出的实验的目的是将修改引入有希望的新型阳离子，可生物降解的可生物降解的聚（2-氨基酯）聚合物，从而导致DNA对DNA的有效，有针对性的纳米颗粒 - 递送到卵巢肿瘤细胞。提出的实验检验了以下假设：腹膜内施用聚合物纳米颗粒，旨在针对编码所谓的自杀基因到卵巢癌细胞的DNA递送有效地杀死细胞，从而导致卵巢肿瘤回归。我们将以三种方式修饰聚合物，旨在增强其靶向DNA向卵巢癌细胞递送的能力，并提高其通过血清灭活的耐药性。一种方法是将聚合物聚合物并将它们结合到两个单链可变抗体片段（SCFV）之一，对卵巢肿瘤细胞表面或叶酸表面上的蛋白质有反应性。第二种方法是与SCFV或叶酸偶联的聚（丙烯酸）的复杂DNA聚（2-氨基酯） - 纳米颗粒。第三种方法是将组合末端修饰与聚（2-氨基酯）s的结构进行。我们将使用高通量细胞的转染测定法来识别赋予最高程度的血清抗性和DNA递送的改良聚合物。然后，我们将在三种体内小鼠模型中测试选定的聚合物制剂的有效性：卵巢癌的转基因模型，一种Sygeneic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递送到卵巢癌细胞外，我们还旨在使用卵巢特异性启动子序列靶向基因表达。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 - 脱剂DT-A治疗的反应。此外，我们将确定这种疗法对寿命的影响，并确定该治疗是否导致非特异性毒性。目前尚无针对晚期卵巢癌患者的有效疗法。我们的期望是，纳米颗粒将自杀基因靶向卵巢癌细胞的递送，再加上将基因表达靶向这些细胞的策略，将导致对这种致命疾病的有效治疗。尽管我们在这里着重于开发卵巢癌的新疗法，但这项研究将有助于建立纳米颗粒用于基因疗法的实用性，并为其在治疗其他类型的癌症和其他疾病的更广泛应用铺平道路上。 项目叙述：聚（2-氨基酯）S是阳离子，可生物降解的聚合物，它们是将治疗性DNA传递到癌细胞的非病毒载体的巨大希望。目前尚无对晚期卵巢癌患者的有效疗法，可以对初始疗法反应或复发性疾病。这项研究的目的是对poly（2-氨基酯）进行修改，从而导致腹膜内治疗后，导致编码自杀基因的DNA的有效的，有针对性的纳米颗粒 - 递送到卵巢肿瘤细胞。靶向纳米疗法单独使用或作为辅助治疗，应为转移性卵巢癌患者提供更有效的治疗方法。