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用于治疗性核酸递送的生物响应性聚合物。

Bioresponsive polymers for the delivery of therapeutic nucleic acids.

机构信息

Pharmaceutical Biotechnology, LMU University, Butenandtstrasse 5-13, Munich, Germany.

出版信息

Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2011 Jan-Feb;3(1):33-46. doi: 10.1002/wnan.97.

Abstract

Polymers present an interesting option for the delivery of genes and other therapeutic nucleic acids. In the delivery process, the polymeric carriers face many different delivery tasks and different physiological microenvironments. Polymers can be designed to respond to microenvironmental differences with changes in their physio-chemical properties, enabling them to perform individual delivery tasks. Cleavage of covalent bonds, disassembly of noncovalent interactions, changes of protonation, conformation, or hydrophilicity/lipophilicity, can trigger such dynamic physicochemical adjustments. The polymeric carrier has to stably bind the therapeutic nucleic acid during the extracellular delivery phase and protect it against degradation in the bloodstream. At the intracellular site of action, the polyplex has to disassemble to an extent that the nucleic acid is functionally accessible. Polyplexes need to be shielded in the circulation and be inert against numerous possible biological interactions, but should actively interact with the target cell surface by electrostatic or ligand receptor interactions. Lipid-membrane destabilization at the cell membrane or nontarget sites is usually associated with undesired cytotoxicity, the analogous biophysical event, however, is required within an endocytic vesicle for polyplex transfer into the cytosol. Strategies will be presented how bioresponsive polymers can be designed and incorporated into polyplexes. Examples include dynamic stabilization of the polymer/nucleic acid core and transient activation of properties required for crossing lipid-membrane barriers. Bioresponsive delivery domains at the polyplex surface required for shielding, deshielding, and cell targeting also contribute to better performance.

摘要

聚合物在基因和其他治疗性核酸的递送上提供了一个很有前景的选择。在递药过程中,聚合物载体面临着许多不同的递药任务和不同的生理微环境。聚合物可以通过改变其物理化学性质来响应微环境差异,从而实现单一的递药任务。共价键的断裂、非共价相互作用的解体、质子化、构象或亲水性/疏水性的变化,可以触发这种动态物理化学调整。聚合物载体必须在细胞外递药阶段稳定地结合治疗性核酸,并保护其免受血液中降解的影响。在细胞内作用部位,必须使多聚物解体到一定程度,使核酸具有功能上的可及性。多聚物需要在循环中被屏蔽,以防止与许多可能的生物相互作用发生反应,但应该通过静电或配体受体相互作用与靶细胞表面积极相互作用。细胞膜或非靶部位的脂质膜不稳定通常与不期望的细胞毒性有关,但在内涵体中,类似的生物物理事件对于多聚物转移到细胞质中是必需的。本文将介绍如何设计和将生物响应性聚合物纳入多聚物中。例如,聚合物/核酸核心的动态稳定和穿过脂质膜屏障所需的特性的瞬时激活。多聚物表面上用于屏蔽、去屏蔽和细胞靶向的生物响应性递药结构域也有助于提高性能。

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