A family of mPEG-b-polycarbonate (mPEG-PC) diblock pendant polymers were synthesized from trimethylene carbonate and other cyclic carbonate monomers bearing hydrophobic guest ligands via organocatalytic ring-opening polymerization using 1,4,5-triazabicyclo[4.4.0]dec-5-ene catalyst or 1,8-diazabicyclo[5.4.0]undec-7-ene/thiourea cocatalyst. Diblock copolymers composed of a methoxypoly(ethylene oxide) (mPEG) block and a polycarbonate block containing either homopolymer or mixed polycarbonates (PC) were prepared by homopolymerization or copolymerization of the cyclic carbonate monomers in the presence of mPEG2000 or mPEG5000 initiator to give materials having a tunable pendant group density along the polycarbonate backbone. Polycarbonate blocks targeting the 2.4–10 kDa range were prepared with good molecular weight control and modest polydispersities (averaging ∼1.3). Complexation of plasmid DNA with β-cyclodextrin–polyethylenimine2.5 kDa produced nanoparticle cores that were then coated with the mPEG–PC diblock copolymers to produce transfection complexes in the 100–250 nm size range. Stable transfection complexes prepared at N/P ratios >10 had slightly positive ζ potentials and showed comparable or modestly better transfection efficiencies in HeLa cells than the commercial transfection agent, Lipofectamine2000. Transfection efficiencies were not dependent on polycarbonate block molecular weights. The mPEG-PC constructs displayed similar efficacy for adamantyl and cholesteryl pendants that strongly bind to β-cyclodextrin; however, slightly better performance was observed for the weakly bound pendant, benzyl. These findings suggest that pDNA release is largely mediated by hydrolysis of the ester-bound pendant ligand within the endolysosomal compartment of the cell, with desorption of the mPEG–PC layer also contributing to plasmid release and activation in the case of weak binding pendant groups. We infer from these results that mPEG-PC may be an effective degradable transfection agent for in vivo applications.

中文翻译：

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聚碳酸酯侧链聚合物的有机催化合成和评价：基于β-环糊精的核酸递送载体

mPEG- b家族-碳酸酯（mPEG-PC）二嵌段侧链聚合物是由碳酸亚丙酯和其他带有疏水性客体配体的环状碳酸酯单体通过有机催化开环聚合反应使用1,4,5-三氮杂双环[4.4.0] dec-5-ene催化剂或1,8-二氮杂双环[5.4.0]十一碳-7-烯/硫脲助催化剂。在mPEG2000或mPEG5000引发剂的存在下，通过环状碳酸酯单体的均聚或共聚反应，制得由甲氧基聚环氧乙烷（mPEG）嵌段和含有均聚物或混合聚碳酸酯（PC）的聚碳酸酯嵌段组成的二嵌段共聚物，得到具有沿聚碳酸酯主链的可调侧基密度。制备的目标分子量为2.4-10 kDa的聚碳酸酯嵌段具有良好的分子量控制和适度的多分散性（平均约1.3）。质粒DNA与β-环糊精-聚乙烯亚胺2.5 kDa的复合产生了纳米颗粒核，然后用mPEG–PC二嵌段共聚物包被以产生100–250 nm大小范围的转染复合体。以N / P比率> 10制备的稳定的转染复合物具有稍微正的ζ电位，并且在HeLa细胞中显示出比市售转染剂Lipofectamine2000更好的或适度的转染效率。转染效率不取决于聚碳酸酯嵌段的分子量。mPEG-PC构建体对与β-环糊精牢固结合的金刚烷基和胆固醇基侧基显示出相似的功效。但是，对于弱结合的侧基苄基，观察到性能稍好。这些发现表明，pDNA的释放主要是通过细胞内溶酶体区隔中酯结合的侧基配体的水解来介导的，在弱结合侧基的情况下，mPEG–PC层的解吸也有助于质粒的释放和活化。我们从这些结果推断，mPEG-PC可能是一种有效的可降解转染剂，可用于体内应用。