Phosphane Functionalized Diblock Copolymers for Targeted siRNA Delivery

描述（由申请人提供）：该SBIR项目旨在开发一种新的非病毒载体，用于靶向特异性递送小干扰RNA（siRNA）。将siRNA从实验室试剂转化为治疗剂的主要挑战之一是开发靶特异性递送系统以将siRNA引入靶细胞。从而可以实现最大的治疗益处，减少所需的药物剂量，避免非靶细胞中的非特异性沉默和毒性。该提案描述了一种新的二嵌段共聚物，其具有带正电荷的嵌段以与siRNA复合，具有用于防止非特异性吸附的聚（环氧乙烷）嵌段，以及在PEG末端上的膦基团，用于通过Staudinger连接进行靶向配体缀合。II期工作预计将在动物模型中研究这种新型siRNA递送系统的安全性和有效性。该I期提案的具体目标包括：1）优化特殊二嵌段共聚物的合成; 2）将靶向配体缀合至二嵌段共聚物; 3）开发用于制备siRNA/聚合物纳米颗粒的方法; 4）评估新siRNA递送系统的细胞毒性; 5）证明基因表达的抑制;以及6）研究细胞内运输。

DESCRIPTION (provided by applicant): This SBIR project is designed to develop a new non-viral carrier for target-specific delivery of small interfering RNA (siRNA). One of the major challenges in transforming siRNA from laboratory reagents to therapeutics is developing a target-specific delivery system to introduce siRNAs into target cells. Maximal therapeutic benefit with decrease in the required drug dose and avoidance of nonspecific silencing and toxicity in nontarget cells could thereby be achieved. This proposal describes a new diblock copolymer with a positively charged block to complex with siRNA, a poly(ethyleneoxide) block for protection against non-specific adsorption, and a phosphane group on the PEG end for targeting ligand conjugation through Staudinger ligation. The Phase II work is expected to investigate the safety and efficacy of this novel siRNA delivery system in an animal model for therapeutic application. Specific aims of this Phase I proposal include: 1) optimize the synthesis of special diblock copolymers; 2) conjugate targeting ligands to diblock copolymers; 3) develop the methodology for preparing siRNA/polymer nanoparticles; 4) evaluate cytotoxicity of the new siRNA delivery system; 5) demonstrate inhibition of gene expression; and 6) investigate intracellular trafficking.