Targeting Nanoparticle DNA Delivery to Prostate Tumors

将纳米颗粒 DNA 递送至前列腺肿瘤

• 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
• 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

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。与通常通过手术和/或放射成功治疗的原发性肿瘤相反，尽管具有显著的不希望的副作用，但目前治疗转移性前列腺癌的疗法，如激素消融和化疗，是无效的。对于这些患者，显然需要更有效的治疗。我们的长期目标是通过开发转移性前列腺癌的基因疗法来解决这一需求，该疗法可以有效地控制癌症，从而延长健康的生命。靶向基因治疗的全身递送为改善转移性前列腺癌的治疗带来了巨大的希望。我们的目标是对一类有前途的新型阳离子、可生物降解的聚（戊-氨基酯）聚合物进行修饰，从而将DNA高效、靶向地递送至前列腺肿瘤细胞和相关的新生血管。在合成和鉴定了能够有效地将DNA有效载荷传递到培养细胞的修饰聚合物之后，我们将使用前列腺癌小鼠模型来进行它们将两种自杀基因（编码白喉毒素的基因和编码胞嘧啶脱氨酶+单纯疱疹病毒胸苷激酶的融合基因）传递到原发性和转移性前列腺肿瘤的能力的最终测试。我们的具体目标是：1.产生单链可变抗体片段（scFv）的前列腺肿瘤细胞表面的两个蛋白质，一个？3整合素和前列腺特异性膜抗原（PSMA）。2.合成和筛选改性的聚（戊-氨基酯）聚合物，以确定纳米颗粒制剂，有效地将DNA输送到培养中的靶细胞，并抵抗血清灭活。3.确定选择的修饰聚（<$-氨基酯）（scFv，肿瘤靶向肽，聚乙二醇化）或DNA/聚（<$-氨基酯）-纳米颗粒与scFv-聚（丙烯酸）的复合物如何有效地将DNA靶向递送至前列腺肿瘤细胞，并在全身施用至小鼠后降低DNA递送的血清抑制。4.确定如何有效地有针对性的纳米粒子递送自杀基因，全身给药小鼠，促进原发性和转移性前列腺肿瘤的消退，从而延长寿命。虽然我们在这里专注于前列腺癌新疗法的开发，但实现这些特定目标将有助于建立纳米颗粒在基因治疗中的效用，并为其在治疗其他类型的癌症和其他疾病方面的更广泛应用铺平道路。

项目成果

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.