Well-defined block copolymers for gene delivery to dendritic cells: probing the effect of polycation chain-length.
Well-defined block copolymers for gene delivery to dendritic cells: probing the effect of polycation chain-length.
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DOI：
10.1016/j.jconrel.2009.10.021
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发表时间：
2010-03-03
影响因子：
10.8
通讯作者：
Wang, Chun
中科院分区：
文献类型：
--
作者：
Tang, Rupei;Palumbo, R. Noelle;Nagarajan, Lakshmi;Krogstad, Emily;Wang, Chun
开发安全高效的DNA疫苗载体需要对聚合物载体的结构-功能关系及其与抗原提呈细胞的相互作用进行机制理解。本文采用原子转移自由基聚合技术合成了一系列链长明确的二嵌段共聚物，并表征了多阳离子链长对聚合物/DNA复合物的理化性质以及与树突状细胞的相互作用的影响。共聚物由亲水性聚乙二醇嵌段和阳离子聚甲基丙烯酸氨基乙酯（PAEM）嵌段组成。PAEM嵌段的平均聚合度（DP）在19、39和75之间变化，几乎均匀分布。随着PAEM链长度的增加，二嵌段共聚物与质粒DNA形成的多聚物平均粒径变小，抗盐和肝素静电破坏的稳定性更高。该聚合物对小鼠树突状细胞（dc）没有毒性，仅在高浓度（1mg /mL）时表现出链长依赖性毒性。体外基因转染效率和多聚体摄取在DCs中也被发现与PAEM块的链长度相关，更长的聚合物链有利于转染和细胞摄取。多聚体诱导DC成熟的表面标记物适度上调，不显著依赖于PAEM链长度。最后，在皮下注射小鼠24小时后，从最长PAEM块（DP为75）制备的复合物在引流淋巴结中的dc摄取方面比非凝聚阴离子葡聚糖平均提高了20%。从研究这种结构明确的聚合物载体及其与树突状细胞的相互作用中获得的见解可能有助于改进实际有用的DNA疫苗递送系统的设计。
The development of safe and efficient polymer carriers for DNA vaccine delivery requires mechanistic understanding of structure-function relationship of the polymer carriers and their interaction with antigen-presenting cells. Here we have synthesized a series of diblock copolymers with well-defined chain-length using atom transfer radical polymerization and characterized the influence of polycation chain-length on the physico-chemical properties of the polymer/DNA complexes as well as the interaction with dendritic cells. The copolymers consist of a hydrophilic poly(ethylene glycol) block and a cationic poly(aminoethyl methacrylate) (PAEM) block. The average degree of polymerization (DP) of the PAEM block was varied among 19, 39, and 75, with nearly uniform distribution. With increasing PAEM chain-length, polyplexes formed by the diblock copolymers and plasmid DNA had smaller average particle size and showed higher stability against electrostatic destabilization by salt and heparin. The polymers were not toxic to mouse dendritic cells (DCs) and only displayed chain-length-dependent toxicity at a high concentration (1 mg/mL). In vitro gene transfection efficiency and polyplex uptake in DCs were also found to correlate with chain-length of the PAEM block with the longer polymer chain favoring transfection and cellular uptake. The polyplexes induced a modest up-regulation of surface markers for DC maturation that was not significantly dependent on PAEM chain-length. Finally, the polyplex prepared from the longest PAEM block (DP of 75) achieved an average of 20% enhancement over non-condensed anionic dextran in terms of uptake by DCs in the draining lymph nodes 24 hours after subcutaneous injection into mice. Insights gained from studying such structurally well-defined polymer carriers and their interaction with dendritic cells may contribute to improved design of practically useful DNA vaccine delivery systems.
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