Targeting Nanoparticle DNA Delivery to Prostate Tumors

将纳米颗粒 DNA 递送至前列腺肿瘤

基本信息

批准号：
7433143
负责人：
JANET A SAWICKI
金额：
$ 31.08万
依托单位：
LANKENAU INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-06-01 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7433143
关键词：
Abate Ablation Address Adverse effects Affinity Aftercare Androgens Antibodies Attention Binding Biodistribution Biological Assay Biological Availability Bioluminescence Blood Cancer Etiology Cells Cessation of life Chemicals Class Coagulation Process Communities Complex Cytosine deaminase DNA DNA delivery Development Diagnosis Diphtheria Toxin Disease Disease Progression Disease regression Disseminated Malignant Neoplasm Drug Delivery Systems Drug Formulations Effectiveness Esters Flucytosine Ganciclovir Gene Delivery Gene Expression Gene Expression Regulation Generations Genes Glutamate Carboxypeptidase II Goals Histopathology Hormones Human Image Immunoglobulin Fragments Incidence Integrins Lead Libraries Life Light Longevity Luciferases Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Metastatic Prostate Cancer Modification Mus Neoplasm Metastasis Non-Viral Vector Numbers Operative Surgical Procedures Organ Pathology Patients Peptides Plasma Polymerase Chain Reaction Polymers Positioning Attribute Primary Neoplasm Procedures Prodrugs Prostate Prostate Cancer therapy Prostatic Neoplasms Proteins Radiation Recurrence Reporter Genes Research Resistance Screening procedure Serum Simplexvirus Specificity Staging Suicide Gene Therapy Surface Surface of the Prostate System Testing Thymidine Kinase Time Tissue Microarray Toxic effect Transfection Tumor-Associated Vasculature Variant Vertebral column Viral Vector Work Yeasts acrylic acid base cancer cell cancer type chemotherapy combinatorial experience fusion gene gene therapy immunogenicity improved killings men mouse model nanoparticle neoplastic cell research study response size suicide gene targeted delivery therapeutic gene tumor

Abate Ablation Address Adverse effects Affinity Aftercare Androgens Antibodies Attention Binding Biodistribution Biological Assay Biological Availability Bioluminescence Blood Cancer Etiology Cells Cessation of life Chemicals Class Coagulation Process Communities Complex Cytosine deaminase DNA DNA delivery Development Diagnosis Diphtheria Toxin Disease Disease Progression Disease regression Disseminated Malignant Neoplasm Drug Delivery Systems Drug Formulations Effectiveness Esters Flucytosine Ganciclovir Gene Delivery Gene Expression Gene Expression Regulation Generations Genes Glutamate Carboxypeptidase II Goals Histopathology Hormones Human Image Immunoglobulin Fragments Incidence Integrins Lead Libraries Life Light Longevity Luciferases Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Metastatic Prostate Cancer Modification Mus Neoplasm Metastasis Non-Viral Vector Numbers Operative Surgical Procedures Organ Pathology Patients Peptides Plasma Polymerase Chain Reaction Polymers Positioning Attribute Primary Neoplasm Procedures Prodrugs Prostate Prostate Cancer therapy Prostatic Neoplasms Proteins Radiation Recurrence Reporter Genes Research Resistance Screening procedure Serum Simplexvirus Specificity Staging Suicide Gene Therapy Surface Surface of the Prostate System Testing Thymidine Kinase Time Tissue Microarray Toxic effect Transfection Tumor-Associated Vasculature Variant Vertebral column Viral Vector Work Yeasts acrylic acid base cancer cell cancer type chemotherapy combinatorial experience fusion gene gene therapy immunogenicity improved killings men mouse model nanoparticle neoplastic cell research study response size suicide gene targeted delivery therapeutic gene tumor

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项目摘要

DESCRIPTION (provided by applicant): The high incidence of prostate cancer deaths in the USA is attributable to metastatic tumors present at initial diagnosis. In contrast to primary tumors that are often treated successfully by surgery and/or radiation, albeit with significant unwanted side effects, current therapies to treat metastatic prostate cancer, such as hormone ablation and chemotherapy, are ineffective. There is a clear need for a more effective therapy for these patients. Our long-term goal is to address this need by developing a gene therapy for metastatic prostate cancer that effectively manages the cancer, resulting in a longer, healthy life. Systemic delivery of targeted gene therapy holds great promise for improving the treatment of metastatic prostate cancer. Our objective is to introduce modifications to a promising new class of cationic, biodegradable, poly(¿-amino ester) polymers that result in efficient, targeted nanoparticle-delivery of DNA to prostate tumor cells and associated neovasculature. Following synthesis and identification of modified polymers that deliver DNA payloads efficiently to cells in culture, we will use mouse models for prostate cancer to perform the ultimate test of their ability to deliver two suicide genes, a gene encoding diphtheria toxin and a fusion gene encoding cytosine deaminase + herpes simplex virus thymidine kinase to primary and metastatic prostate tumors. Our specific aims are to: 1. Generate single chain variable antibody fragments (scFvs) to two proteins on the surface of prostate tumor cells, a?¿3 integrin and prostate specific membrane antigen (PSMA). 2. Synthesize and screen modified poly(¿-amino ester) polymers to identify nanoparticle formulations that deliver DNA efficiently to target cells in culture and are resistant to inactivation by serum. 3. Determine how effectively selected modifications poly(¿-amino esters) (scFvs, tumor-targeting peptides, pegylation) or complexation of DNA/poly(¿-amino ester)-nanoparticles with scFvs-poly(acrylic acid) target delivery of DNA to prostate tumor cells and reduce serum inhibition of DNA delivery following systemic administration to mice. 4. Determine how effectively targeted nanoparticle-delivery of suicide genes, administered systemically to mice, promotes regression of primary and metastatic prostate tumors, resulting in an increase in life span. While we focus here on the development of a new therapy for prostate cancer, accomplishing these specific aims 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.

描述（由适用提供）：美国前列腺癌死亡的高气归因于初始诊断时存在的转移性肿瘤。与通常通过手术和/或放射线成功治疗的原发性肿瘤，尽管具有明显的不良副作用，但治疗转移性前列腺癌的当前疗法（例如Horsene消融和化学疗法）却无效。对于这些患者来说，显然需要更有效的治疗。我们的长期目标是通过开发一种有效管理癌症的转移性前列腺癌基因疗法来满足这种需求，从而带来更长，健康的寿命。靶向基因疗法的全身分娩具有改善转移性前列腺癌治疗的巨大希望。我们的目的是将修改引入有望的新型阳离子，可生物降解的，可生物降解的聚（ - 氨基酯）聚合物，从而导致DNA的有效，有针对性的纳米颗粒递送到前列腺肿瘤细胞及其相关的新生血管系统。 Following synthesis and identification of modified polymers that deliver DNA payloads efficiently to cells in culture, we will use mouse models for prostate cancer to perform the ultimate test of their ability to deliver two suicide genes, a gene encoding diphtheria toxin and a fusion gene encoding cytosine deathinase + herpes simplex virus thymidine kinase to primary and metastatic prostate tumors.我们的具体目的是：1。对前列腺肿瘤细胞表面上的两个蛋白质产生单链可变抗体片段（SCFV），A？€3整联蛋白和前列腺特异性膜抗原（PSMA）。 2。合成和筛选改性的聚（-Amino酯）聚合物，以鉴定有效地传递DNA的纳米颗粒公式，可有效地传递DNA培养物中的靶细胞，并且可以通过血清抗活化。 3。确定如何有效选择的修饰poly（-Amino酯）（SCFV，靶向肿瘤的肽，Pegylation）或DNA/Poly（-Amino酯） - 纳米粒子与SCFVS-POLY（丙烯酸）（丙烯酸酸）靶标（丙烯酸）靶标（丙烯酸）靶向DNA的3。 4。确定自杀基因的纳米颗粒降低的有效靶向，系统地给小鼠施用，促进原发性和转移性前列腺肿瘤的消退，从而增加寿命。尽管我们在这里着重于开发针对前列腺癌的新疗法，但实现这些特定目标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广泛应用中铺平道路。