Poly(alkylene oxide) copolymers for nucleic acid delivery.
Poly(alkylene oxide) copolymers for nucleic acid delivery.
复制标题
DOI：
10.1021/ar200232n
复制
发表时间：
2012-07-17
影响因子：
18.3
通讯作者：
Roth, Charles M.
中科院分区：
文献类型：
--
作者：
Mishra, Swati;Peddada, Lavanya Y.;Devore, David I.;Roth, Charles M.
以基因为基础的疗法在临床上的进展受到能否安全有效地将生理相关剂量的核酸输送到靶组织的能力的限制。在过去的几十年里，基于聚合物和脂质的纳米组装已经成功地用于运送核酸来治疗各种疾病状态。评估这些基因传递载体的有效性和生物安全性的I/II期临床研究结果令人鼓舞，从而促进了更有效和生物兼容系统的设计。研究的重点是设计载体以实现生物相容性、循环系统的稳定性、靶向疾病部位的生物分布和细胞内递送，所有这些都增强了由此产生的治疗效果。聚环氧乙烷(PAO)包括无规聚合物、嵌段聚合物和支化聚合物，其中ABA型环氧乙烷(EO)和环氧丙烷(PO)三嵌段共聚物(商业上称为Pluronic®)得到了最大的考虑。在本文中，我们重点介绍聚阳离子-PAO结合物、脂质体-PAO制剂以及用于核酸输送的PAO胶束的例子。在各种聚合物设计考虑因素中，包括聚合物的相对分子质量、嵌段的相对分子质量和嵌段的长度，人们发现总体疏水-亲脂平衡(HLB)是定义用于基因传递的聚合物偶联物行为的关键参数。改变这一参数的影响将在改善基因传递过程的背景下进行讨论，如血清稳定性和与细胞膜的结合。这一类别中讨论的其他创新性大分子修饰包括我们团队使用PAO接枝共聚物提高脂合物的血清稳定性和效率的工作，用于持续和刺激响应性递送的PAO凝胶载体的开发，以及可生物降解的PAO基两亲性嵌段共聚物。
The advancement of gene-based therapeutics to the clinic is limited by the ability to deliver physiologically relevant doses of nucleic acids to target tissues safely and effectively. Polymer and lipid based nano-assemblies have been successfully employed over the last couple of decades for the delivery of nucleic acids to treat a variety of disease states. Results of phase I/II clinical studies to evaluate the efficacy and biosafety of these gene delivery vehicles have been encouraging, thus promoting the design of more efficient and biocompatible systems. Research has focused on designing carriers to achieve biocompatibility, stability in the circulatory system, biodistribution to target the disease site, and intracellular delivery, all of which enhance the resulting therapeutic effect. The family of poly(alkylene oxide) (PAO) includes random, block and branched polymers, among which the ABA type triblocks copolymers of ethylene oxide (EO) and propylene oxide (PO) (commercially known as Pluronic®) have received the greatest consideration. In this Account, we highlight examples of polycation-PAO conjugates, liposome-PAO formulations, and PAO micelles for nucleic acid delivery. Among the various polymer design consideration, which include molecular weight of polymer, molecular weight of blocks, and length of blocks, it has been found that the overall hydrophobic-lipophilic balance (HLB) is a critical parameter in defining the behavior of the polymer conjugates for gene delivery. The effects of varying this parameter are discussed in the context of improving gene delivery processes, such as serum-stability and association with cell membranes. Other innovative macromolecular modifications discussed in this category include the work done by our group to enhance the serum stability and efficiency of lipoplexes using PAO graft copolymers, development of a PAO gel-based carrier for sustained and stimuli responsive delivery, and biodegradable PAO-based amphiphilic block copolymers.
登录
查看更多内容
影响因子：
4.2
作者：
Chang, SF;Chang, HY;Liaw, JH
通讯作者：
Liaw, JH
影响因子：
10.8
作者：
Agarwal, Ankit;Vilensky, Rita;Mallapragada, Surya K.
通讯作者：
Mallapragada, Surya K.
影响因子：
2.8
作者：
Kuo, JHS
通讯作者：
Kuo, JHS
影响因子：
5.5
作者：
ALEXANDRIDIS, P;HOLZWARTH, JF;HATTON, TA
通讯作者：
HATTON, TA
影响因子：
4.8
作者：
Grossman, Paul Michael;Mendelsohn, Farrell;Rocha-Singh, Krishna
通讯作者：
Rocha-Singh, Krishna