Saccharide Functionalization of Bola-amphiphiles for siRNA Delivery

 描述(申请人提供)：RNA干扰(RNAi)在基因治疗领域是一个具有巨大潜力的平台。在治疗方面，一种特定的小干扰RNA(SiRNA)被送入细胞，选择性地下调编码蛋白的表达。然而，为了充分发挥siRNA治疗的潜力，必须开发安全高效的递送试剂。最近，在关氏实验室，我们开发了一种树状多肽终止的Bola两亲性系统，该系统可以成功地传递siRNA和击倒蛋白表达。然而，为了增加多肽Bola两亲性的临床应用，我们必须增加血清的稳定性、生物相容性和全身给药。为了解决这些问题，我提议合成一个糖基功能化的双亲分子文库。糖的功能化将通过屏蔽siRNA-聚合物组装件的表面正电荷来增加血清的稳定性，通过减少游离胺对膜的破坏来增加生物相容性，最终将通过凝集素-糖的相互作用增加系统的递送。 我将使用我们实验室开发的类似方法来测试相关的多肽Bola两亲性系统，以全面研究该系统的自组装、生物相容性、击倒和有效性。我自己完成的初步研究已经创造了一种甘露糖功能化的波拉两亲物，它显示出了有希望的活性(88%的目标基因在血清中被敲除)。这项拟议研究的成功完成将带来一种新的高效siRNA传递系统，使与合作者进行进一步的体内研究成为可能，从而成功治疗包括癌症、神经退行性疾病和糖尿病在内的几种疾病。

 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.