Targeted delivery of siRNA to inhibit tumor growth

描述（由申请人提供）：系统的靶向载体系统对于基于核酸的治疗方法的成功和更广泛的应用至关重要，例如基因治疗、反义治疗和新兴的RNA干扰领域。系统靶向不仅是DNA等大分子药物的挑战，也是小分子药物的挑战。对于核酸递送，基于合成试剂的载体系统比病毒载体更适合，因为它们的免疫和安全问题风险较低。此外，合成载体可以重复施用，它们可以容纳多种形式的核酸，包括大质粒DNA和短寡核苷酸（DNA和RNA）。第一代基于阳离子脂质或聚合物的合成载体不适合用于全身靶向，因为它们的相互作用缺乏特异性。分子偶联物可以包含多个功能部分，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功能聚合物，它提供了有效基因传递载体所需的一些多种功能。这种聚合物偶联物可以将核酸凝聚成具有空间位阻保护层和靶向配体层的纳米颗粒。这种层状颗粒通过尾静脉静脉给药，提供肿瘤靶向的核酸递送。近年来，RNA干扰已被证明在基因下调中非常有效。短双链RNA （siRNA）具有特异性下调基因序列的作用。尽管该技术已被广泛接受用于靶标验证，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。我们已经获得了肿瘤生长抑制和血管生长抑制使用siRNA针对VEGFR2静脉注射使用三功能聚合物在一个神经2a肿瘤模型。我们建议将这项技术用于结肠癌的治疗。

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.