Systemic delivery of chitosan/miRNA nanoparticles to prostate tumors

描述（由申请人提供）：微小RNA（miRNA）已成为一类有前途的新型癌症治疗剂。miRNA是小的非编码RNA，其通过转录后调节广泛但特异的基因组的表达来决定细胞命运。miRNA可以作为常规的致癌基因和肿瘤抑制因子发挥作用，并且当通过例如异常表达而被错误调节时，miRNA可以促进癌症的发展。我们假设，通过用miRNA模拟物替代miRNA或用miRNA拮抗剂抑制miRNA来对抗这种错误调节，将干扰癌表型并诱导治疗反应。 迄今为止，最知名的肿瘤抑制miRNA是miR-34，它是Mirna Therapeutics治疗开发的主要候选者。Mirna Therapeutics已经生成了大量数据，描述了miR-34在人类原发性和转移性前列腺癌小鼠模型中的抗肿瘤活性。然而，需要临床相关的递送技术将miR-34治疗剂带到临床。我们的提案探索了化学修饰的壳聚糖纳米颗粒作为递送载体，其将促进miRNA对原位生长的前列腺肿瘤的全身给药。与德克萨斯大学奥斯汀分校的Roy博士合作，我们将开发功能化的壳聚糖纳米颗粒，这些纳米颗粒显示出增强的miRNA递送特性和低毒性。我们将确定这些纳米颗粒在血浆和各种组织中的生物分布和半衰期，测试其递送至原位前列腺肿瘤，最重要的是，抑制原发性和转移性肿瘤生长。我们相信这些研究将有助于开发一种递送技术，使治疗性miRNA能够全身性地施用到前列腺肿瘤和潜在的其他实体肿瘤，并将推动治疗性miRNA的开发更接近临床。 公共卫生相关性：晚期前列腺癌仍然是男性癌症死亡的第二大原因，并且通常对常规疗法具有抗性。我们的工作可能会导致基于microRNA的疗法的发展，这些疗法可以全身施用，并且对前列腺癌细胞具有高度和特异性的活性。这将导致 降低前列腺癌的死亡率。

DESCRIPTION (provided by applicant): MicroRNAs (miRNAs) have emerged as a promising new class of therapeutics for cancer. miRNAs are small, non-coding RNAs that determine cell fate by post-transcriptionally regulating the expression of a broad but nevertheless specific set of genes. miRNAs can function as conventional oncogenes and tumor suppressors and, when misregulated by e.g. aberrant expression, miRNAs can contribute to the development of cancer. We hypothesize that countering this misregulation - either by miRNA replacement with miRNA mimics or by miRNA inhibition with miRNA antagonists - will interfere with the cancerous phenotype and induce a therapeutic response. Among the most well-known tumor suppressor miRNAs to date is miR-34, the lead candidate for therapeutic development of Mirna Therapeutics. Mirna Therapeutics has generated extensive data describing the anti-tumor activity of miR-34 in mouse models of human primary and metastatic prostate cancer. However, a clinically-relevant delivery technology is required to bring a miR-34 therapeutic to the clinic. Our proposal explores chemically modified chitosan nanoparticles as a delivery vehicle that would facilitate the systemic administration of miRNAs to orthotopically grown prostate tumors. In collaboration with Dr. Roy at the University of Texas in Austin, we will develop functionalized chitosan nanoparticles that show enhanced properties for miRNA delivery and low toxicity. We will determine biodistribution and half-life of these nanoparticles in plasma and various tissues test for delivery to orthotopic prostate tumors and most importantly, inhibition of primary and metastatic tumor growth. We believe these studies will help developing a delivery technology that enables the systemic administration of therapeutic miRNAs to prostate tumors and potentially other solid tumors and will advance the development of therapeutic miRNAs closer to the clinic. PUBLIC HEALTH RELEVANCE: Advanced prostate cancer continues to be the second leading cause of cancer deaths in males, and is often resistant to conventional therapeutics. Our work may lead to the development of microRNA-based therapies that can be systemically administered and are highly and specifically active towards prostate cancer cells. This will result in a reduced incidence of death from prostate cancer.