School of Chemical Engineering and Technology, Xi'an Jiaotong University, Xi'an 710049, China.
Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.
J Control Release. 2024 Apr;368:131-139. doi: 10.1016/j.jconrel.2024.02.002. Epub 2024 Feb 21.
Poly(β-amino ester)s (PAEs) have emerged as a type of highly safe and efficient non-viral DNA delivery vectors. However, the influence of amphiphilicity and chain sequence on DNA transfection efficiency and safety profile remain largely unexplored. In this study, four PAEs with distinct amphiphilicity and chain sequences were synthesized. Results show that both amphiphilicity and chain sequence significantly affect the DNA binding and condensation ability of PAEs, as well as size, zeta potential and cellular uptake of PAE/DNA polyplexes. PAEs with different amphiphilicity and chain sequence exhibit cell type-dependent transfection capabilities: in human bladder transitional cell carcinoma (UM-UC-3), hydrophilic PAE (P-Philic) and amphiphilic PAE random copolymer (R-Amphilic) exhibit relatively higher gene transfection efficiency, while in human bladder epithelial immortalized cells (SV-HUC-1), hydrophobic PAE (P-Phobic), R-Amphilic, and amphiphilic PAE block copolymer (B-Amphilic) demonstrate higher transfection capability. Regardless of cell types, amphiphilic PAE block copolymer (B-Amphilic) always exhibits much lower gene transfection efficiency. In addition, in human colon cancer cells (HCT-116), P-Philic and R-Amphilic achieved superior gene transfection efficiency at high and low polymer/DNA weight ratios, respectively. Importantly, R-Amphilic can effectively deliver the gene encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to human chondrosarcoma cells SW1353 to induce their apoptosis, highlighting its potential application in cancer gene therapy. This study not only establishes a new paradigm for enhancing the gene transfection efficiency of PAEs by modulating their amphiphilicity and chain sequence but also identifies R-Amphilic as a potential candidate for the effective delivery of TRAIL gene in cancer gene therapy.
聚（β-氨基酯）（PAEs）已成为一类非常安全有效的非病毒 DNA 递送载体。然而，亲疏水性和链序列对 DNA 转染效率和安全性的影响在很大程度上仍未得到探索。在这项研究中，合成了四种具有不同亲疏水性和链序列的 PAEs。结果表明，亲疏水性和链序列都显著影响 PAE 的 DNA 结合和凝聚能力，以及 PAE/DNA 复合物的粒径、ζ 电位和细胞摄取。具有不同亲疏水性和链序列的 PAEs 表现出依赖细胞类型的转染能力：在人膀胱移行细胞癌（UM-UC-3）中，亲水性 PAE（P-Philic）和两亲性 PAE 无规共聚物（R-Amphilic）表现出相对较高的基因转染效率，而在人膀胱上皮永生化细胞（SV-HUC-1）中，疏水性 PAE（P-Phobic）、R-Amphilic 和两亲性 PAE 嵌段共聚物（B-Amphilic）则表现出更高的转染能力。无论细胞类型如何，两亲性 PAE 嵌段共聚物（B-Amphilic）的基因转染效率总是较低。此外，在人结肠癌细胞（HCT-116）中，P-Philic 和 R-Amphilic 在高和低聚合物/DNA 重量比下分别实现了优异的基因转染效率。重要的是，R-Amphilic 可以有效地将编码肿瘤坏死因子相关凋亡诱导配体（TRAIL）的基因递送到人软骨肉瘤细胞 SW1353 中，诱导其凋亡，突出了其在癌症基因治疗中的应用潜力。这项研究不仅建立了通过调节亲疏水性和链序列来提高 PAE 基因转染效率的新范例，还确定了 R-Amphilic 作为 TRAIL 基因在癌症基因治疗中有效传递的潜在候选者。
