Saccharide Functionalization of Bola-amphiphiles for siRNA Delivery

 描述（由申请人提供）：RNA干扰（RNAi）代表了基因治疗领域中具有巨大潜力的平台。对于治疗，将特定的小干扰RNA（siRNA）递送到细胞中用于选择性敲低编码蛋白质的表达。然而，为了充分实现siRNA治疗的潜力，必须开发安全有效的递送试剂。最近在Guan实验室，我们开发了一种树突状肽终止的bola两亲系统，可以成功地递送siRNA和敲低蛋白表达。然而，为了增加肽bola两亲物的临床应用，我们必须增加血清稳定性、生物相容性和全身递送。为了解决这些问题，我建议合成一个库的糖官能化bola两亲物。阿糖胞苷官能化将通过屏蔽siRNA-聚合物组装体的正表面电荷来增加血清稳定性，通过减少游离胺对膜的破坏来增加生物相容性，并且最终将通过凝集素-糖相互作用来增加全身递送。 我将利用本实验室开发的类似方法对相关的肽bola两亲物系统进行全面的研究，包括自组装、生物相容性、敲除和功效。由我自己完成的初步研究已经允许产生甘露糖官能化的bola两亲物，该两亲物已经显示出有希望的活性（在血清中88%的靶基因敲除）。拟议研究的成功完成将产生一种新的高效siRNA递送系统，使合作者能够进一步进行体内研究，这可能导致成功治疗多种疾病，包括癌症，神经退行性疾病和糖尿病。

 DESCRIPTION (provided by applicant): RNA interference (RNAi) represents a platform of tremendous potential in the field of gene therapy. For therapeutics, a specific small interfering RNA (siRNA) is delivered into cells for the selective knock down of the encoded protein's expression. However, to fully realize the potential of siRNA therapeutics, safe and efficient delivery reagents must be developed. Recently in the Guan lab we have developed a dendritic peptide terminated bolaamphiphile system that can successfully deliver siRNA and knockdown protein expression. However, to increase clinical applications of the peptide bolaamphiphile, we must increase serum stability, biocompatibility, and systemic delivery. To address these issues I propose to synthesize a library of saccharide-functionalized bolaamphiphiles. Saccharide functionalization will increase serum stability by shielding the positive surface charge of the siRNA-polymer assembly, increase biocompatibility through reducing the membrane disruption by free amines, and finally will increase systemic delivery through lectin-saccharide interactions. I will fully investigate the self-assembly, biocompatibility, knockdown, and efficacy of this syste using similar methods developed in our lab to test related peptide bolaamphiphile system. Initial studies completed by myself have allowed for the creation of a mannose-functionalized bola amphiphile that has shown promising activity (88% knockdown of the target gene in serum). Successful completion of the proposed study will result in a new highly efficient siRNA delivery system, enabling further in vivo studies with collaborators which could lead to the successful treatment of several diseases including cancers, neurodegenerative disorders, and diabetes.