Synthesis of Electroneutralized Amphiphilic Copolymers with Peptide Dendrons for Intramuscular Gene Delivery
Synthesis of Electroneutralized Amphiphilic Copolymers with Peptide Dendrons for Intramuscular Gene Delivery
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用于肌内基因递送的具有肽树突的电中和两亲性共聚物的合成
DOI：
10.1021/acsami.6b02592
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发表时间：
2016
影响因子：
9.5
通讯作者：
Gu Zhongwei
中科院分区：
文献类型：
--
作者：
Pu Linyu;Wang Jiali;Li Na;Chai Quxia;Irache Juan M.;Wang Gang;Tang James Zhenggui;Gu Zhongwei
肌内注射基因载体在质粒基因治疗系统中具有重要的作用，但其设计和合成方法尚不成熟。先前的研究表明，肽树枝基三嵌段共聚物及其组分以反向生物膜结构排列，可以显著增加肌内基因递送和表达。在此，我们想知道具有生物膜模拟排列的共聚物是否在肌内基因递送中具有类似的功能。同时，揭示电荷和分子结构对共聚物功能的影响具有重要意义。为了解决这些问题，两亲性的三嵌段共聚物排列在疏水-疏水-亲水结构的构建，尽管矛盾的特性和困难，在合成这样的亲水性，但电中性分子。制备的两种共聚物dendronG 2（l-赖氨酸-OH）-聚丙二醇2k（PPG 2k）-树枝状G2（l-赖氨酸-OH）（rL 2 PL 2）和dendronG 3（l-赖氨酸-OH）-PPG 2k-dendronG 3（l-赖氨酸-OH）（rL 3 PL 3）具有相似的结构，但具有不同的亲水组分和表面电荷，因此导致在骨骼肌中基因递送和表达的不同能力。当介导荧光素酶时，rL 2 PL 2比PluronicL 64和rL 3 PL 3更有效，β-半乳糖苷酶和荧光蛋白表达。此外，rL 2 PL 2介导的生长激素释放激素表达可在注射后的前21天显著诱导小鼠体重增加。此外，rL 2 PL 2和rL 3 PL 3在局部和全身给药时均表现出良好的体内生物安全性。总之，rL 2 PL 2介导的基因表达在骨骼肌中表现出可应用的基因治疗的潜力。研究表明，分子结构和电荷是决定共聚物肌内基因传递功能的关键因素。可以得出结论，结合之前的研究，与生物膜相反或相似的两种结构排列都可以有效地设计此类共聚物。这也为设计和合成新的电中和三嵌段共聚物提供了一种创新的方法，可以安全有效地用于肌内基因递送。
Intramuscular gene delivery materials are of great importance in plasmid-based gene therapy system, but there is limited information so far on how to design and synthesize them. A previous study showed that the peptide dendron-based triblock copolymer with its components arranged in a reversed biomembrane architecture could significantly increase intramuscular gene delivery and expression. Herein, we wonder whether copolymers with biomembrane-mimicking arrangement may have similar function on intramuscular gene delivery. Meanwhile, it is of great significance to uncover the influence of electric charge and molecular structure on the function of the copolymers. To address the issues, amphiphilic triblock copolymers arranged in hydrophilic–hydrophobic–hydrophilic structure were constructed despite the paradoxical characteristics and difficulties in synthesizing such hydrophilic but electroneutral molecules. The as-prepared two copolymers, dendronG2(l-lysine-OH)-poly propylene glycol2k(PPG2k)-dendronG2(l-lysine-OH) (rL2PL2) and dendronG3(l-lysine-OH)-PPG2k-dendronG3(l-lysine-OH) (rL3PL3), were in similar structure but had different hydrophilic components and surface charges, thus leading to different capabilities in gene delivery and expression in skeletal muscle.rL2PL2was more efficient than Pluronic L64 andrL3PL3when mediating luciferase, β-galactosidase, and fluorescent protein expressions. Furthermore,rL2PL2-mediated growth-hormone-releasing hormone expression could significantly induce mouse body weight increase in the first 21 days after injection. In addition, bothrL2PL2andrL3PL3showed good in vivo biosafety in local and systemic administration. Altogether,rL2PL2-mediated gene expression in skeletal muscle exhibited applicable potential for gene therapy. The study revealed that the molecular structure and electric charge were critical factors governing the function of the copolymers for intramuscular gene delivery. It can be concluded that, combined with the previous study, both structural arrangements either reverse or similar to the biomembrane are effective in designing such copolymers. It also provides an innovative way in designing and synthesizing new electroneutralized triblock copolymers, which could be used safely and efficiently for intramuscular gene delivery.