Targeted delivery of siRNA to inhibit tumor growth

描述(申请人提供)：系统的靶向载体系统对于基于核酸的疗法的成功和更广泛的应用是极其重要的，例如基因疗法、反义疗法和新兴的RNA干扰领域。系统性靶向不仅是对DNA等大分子药物的挑战，也是对小分子药物的挑战。对于核酸输送，基于合成试剂的载体系统比病毒载体更适合，因为它们出现免疫学和安全性问题的风险较低。此外，合成载体可以重复给药，它们可以容纳不同形式的核酸，包括大的质粒DNA和短的寡核苷酸(DNA和RNA)。基于阳离子脂类或聚合物的第一代合成载体由于缺乏相互作用的特异性而不适合用于系统靶向。能够结合多种功能基团的分子偶联物是设计和构建靶向载体系统的理想候选者。我们已经开发了一种原型三官能聚合物，它提供了有效的基因输送工具所需的多种功能中的一部分。这种聚合物偶联物可以将核酸凝聚成纳米粒子，在其表面具有空间保护层和靶向配位层。这种层状颗粒通过尾静脉给药提供了肿瘤靶向的核酸输送。最近，RNA干扰被证明在基因下调中非常有效。短双链RNA(SiRNA)是一种高效的特异性下调基因序列的方法。尽管这项技术已被广泛接受用于靶向验证，但其治疗潜力尚不清楚。我们首次证明了将这项技术用于癌症治疗的可行性。在Neuro2A肿瘤模型中，我们已经通过静脉注射针对VEGFR2的siRNA获得了肿瘤生长抑制和血管生长抑制。我们建议开发这项技术来治疗结肠癌。

DESCRIPTION (provided by applicant): A systemic targetable vector system is extremely important for the success and broader application of nucleic acids based therapeutics such as gene therapy, antisense therapy, and the emerging field of RNA interference. Systemic targeting has been a challenge not only for macromolecular drugs such as DNA, but also for small molecules. For nucleic acid delivery, vector systems based on synthetic reagents are better suited compared to viral vectors because of their lower risk for immunological and safety problems. In addition, synthetic vectors can be administered repeatedly and they can accommodate diverse forms of nucleic acids including large plasmid DNA and short oligonucleotides (DNA and RNA). First generation synthetic vectors based on cationic lipids or polymers are not suitable for systemic targeting due to the lack of specificity in their interactions. Molecular conjugates that can incorporate multiple functional moieties are ideal candidates for the design and construction of a targetable vector system. We have developed a prototype trifunctional polymer that provides some of the multiple functions needed for an effective gene delivery vehicle. This polymer conjugate can condense nucleic acid into nanoparticles with a steric protective layer and a targeting ligand layer on its surface. This layered particle provides tumor targeted delivery of nucleic acid from iv administration through tail vein. Recently, RNA interference has been demonstrated to be very effective in gene down regulation. Short double stranded RNA (siRNA) is very effective in down regulating genes sequence specifically. Though this technology has been widely accepted for target validation, its therapeutic potential is unknown. We have for the first time demonstrated the feasibility of using this technology for cancer therapy. We have obtained tumor growth inhibition and blood vessel growth inhibition using an siRNA against VEGFR2 delivered intravenously using the trifunctional polymer in a Neuro2A tumor model. We propose to develop this technology for the treatment of colon carcinoma.