Targeting Nanoparticle DNA Delivery to Prostate Tumors

描述（由申请人提供）：在美国，前列腺癌死亡率的高发生率可归因于初始诊断时存在的转移性肿瘤。原发肿瘤通常通过手术和/或放疗成功治疗，尽管有明显的副作用，但目前治疗转移性前列腺癌的方法，如激素消融和化疗，是无效的。对于这些患者，显然需要一种更有效的治疗方法。我们的长期目标是通过开发一种有效治疗转移性前列腺癌的基因疗法来满足这一需求，从而使癌症得到更长久、更健康的生活。靶向基因治疗的系统传递对于改善转移性前列腺癌的治疗具有很大的希望。我们的目标是对一种有前途的新型阳离子、可生物降解的聚氨基酯聚合物进行修饰，从而有效地、有针对性地将纳米颗粒DNA递送到前列腺肿瘤细胞和相关的新生血管中。在合成和鉴定了能够将DNA有效载荷有效地传递到培养细胞中的修饰聚合物之后，我们将使用前列腺癌小鼠模型对它们将两个自杀基因（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进行最终测试。我们的具体目标是：1。对前列腺肿瘤细胞表面的两种蛋白产生单链可变抗体片段（scFvs）。整合素与前列腺特异性膜抗原（PSMA）。2. 合成和筛选修饰的聚氨基酯聚合物，以鉴定纳米颗粒配方，有效地将DNA传递到培养中的靶细胞，并耐血清灭活。3. 确定选择的修饰聚氨基酯（scFvs，肿瘤靶向肽，聚乙二醇化）或DNA/聚氨基酯纳米颗粒与scFvs聚丙烯酸的络合如何有效地靶向DNA递送到前列腺肿瘤细胞，并降低小鼠全身给药后血清对DNA递送的抑制。4. 确定如何有效地靶向纳米颗粒递送自杀基因，系统给药小鼠，促进原发和转移性前列腺肿瘤的消退，从而增加寿命。当我们专注于开发前列腺癌的新疗法时，完成这些特定的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。

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.