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：
7789537
负责人：
JANET A SAWICKI
金额：
$ 33.34万
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 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7789537
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 Coagulation Process Communities Complex Cytosine deaminase DNA DNA delivery Development Diagnosis Diphtheria Toxin Disease Disease Progression 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 Operative Surgical Procedures Organ Pathology Patients Peptides Plasma 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 Variant Vertebral column Viral Vector Work Yeasts acrylic acid base cancer cell cancer type chemotherapy combinatorial effective therapy experience fusion gene gene therapy immunogenicity improved killings men mouse model nanoparticle neoplastic cell neovasculature research study response suicide gene targeted delivery therapeutic gene tumor

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（由申请人提供）：美国前列腺癌死亡的高发生率可归因于初次诊断时存在的转移性肿瘤，而原发性肿瘤通常可以通过手术和/或放射成功治疗，但会产生显着的不良副作用。目前治疗转移性前列腺癌的疗法（例如激素消融和化疗）无效，这些患者显然需要更有效的治疗方法，我们的长期目标是通过开发转移性基因疗法来满足这一需求。前列腺癌有效靶向基因治疗的全身性治疗对于改善转移性前列腺癌的治疗具有巨大的希望，我们的目标是对一种有前途的新型阳离子、可生物降解的聚（¿-）进行修饰。氨基酯）聚合物，可将 DNA 靶向纳米颗粒递送至前列腺肿瘤细胞和相关的新血管系统。在合成和鉴定可将 DNA 有效负载有效递送至培养中的高效细胞的修饰聚合物后，我们将使用前列腺小鼠模型。癌症对它们向原发性和转移性前列腺肿瘤传递两种自杀基因（一种编码白喉毒素的基因和一种编码胞嘧啶脱氨酶+单纯疱疹病毒胸苷激酶的融合基因）的能力进行最终测试： 1. 产生单一的前列腺肿瘤。链可变抗体片段（scFv）与前列腺肿瘤细胞表面的两种蛋白质，a？¿ 3 整合素和前列腺特异性膜抗原 (PSMA) 2. 合成并筛选修饰的聚（氨基酯）聚合物，以鉴定能够将 DNA 有效递送至培养物中的靶细胞并抵抗血清灭活的纳米颗粒制剂。选择有效修饰聚（¿-氨基酯）（scFv、肿瘤靶向肽、聚乙二醇化）或络合具有 scFvs-聚（丙烯酸）的 DNA/聚（氨基酯）-纳米颗粒将 DNA 靶向递送至前列腺肿瘤细胞，并减少对小鼠全身给药后 DNA 递送的血清抑制。 4. 确定纳米颗粒靶向递送的有效性。对小鼠全身施用自杀基因，可促进原发性和转移性前列腺肿瘤的消退，从而延长寿命，而我们在此专注于开发前列腺癌新疗法，以实现这些特定目标。将有助于建立纳米粒子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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

FRET-labeled siRNA probes for tracking assembly and disassembly of siRNA nanocomplexes.

DOI：
10.1021/nn3013838
发表时间：
2012-07-24
期刊：
ACS NANO
影响因子：
17.1
作者：
Alabi, Christopher A.;Love, Kevin T.;Sahay, Gaurav;Stutzman, Tina;Young, Whitney T.;Langer, Robert;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.

Degradable lipid nanoparticles with predictable in vivo siRNA delivery activity.

DOI：
10.1038/ncomms5277
发表时间：
2014-06-27
期刊：
NATURE COMMUNICATIONS
影响因子：
16.6
作者：
Whitehead, Kathryn A.;Dorkin, J. Robert;Vegas, Arturo J.;Chang, Philip H.;Veiseh, Omid;Matthews, Jonathan;Fenton, Owen S.;Zhang, Yunlong;Olejnik, Karsten T.;Yesilyurt, Volkan;Chen, Delai;Barros, Scott;Klebanov, Boris;Novobrantseva, Tatiana;Langer, Robert;Anderson, Daniel G.
通讯作者：
Anderson, Daniel G.