Department of Biomedical Science and BK21 PLUS Center for Creative Biomedical Scientists at Chonnam National University, Chonnam National University Medical School, Gwangju 501-746, South Korea.
Medical Photonics Research Center, Korea Photonics Technology Institute, Gwangju 61007, South Korea.
J Control Release. 2018 Apr 28;276:72-83. doi: 10.1016/j.jconrel.2018.02.039. Epub 2018 Feb 28.
Stimuli-responsive polymeric nanoparticles are useful for overcoming challenges such as transfection efficiency and the specific and safe delivery of genes to cancer cells. Transfection outcomes can be improved through spatially and temporally controlled gene release. We formulated a nanoassembly comprising a disulfide-crosslinked polyethylenimine (ssPEI) conjugated with a tumor-specific cell-penetrating peptide (DS 4-3) (SPD) polyplex and bovine serum albumin (BSA)-loaded IR780 (BI) nanoparticle, thereby forming a dual-stimulus-triggered, tumor-penetrating and gene-carrying nanoassembly (BI-SPD) via electrostatic complexing. BI-SPD nanoassembly were composed of highly stable nanosized complexes with an average size of 457 ± 27.5 nm, exhibiting an up to two-fold enhanced transfection efficiency with no sign of potential cytotoxicity in breast cancer cells. Moreover, upon laser irradiation, a four-fold increase in transfection efficiency was achieved due to the rapid endosomal escape of polyplexes triggered by the local heat induced by the BI-SPD nanoassembly. Additionally, the high redox environment in tumor cells facilitated the disassembly of the SPD polyplex for efficient plasmid release in the cytosol. The BI-SPD nanoassembly also exhibited high penetration and enhanced photothermally triggered gene expression in the 4T1 spheroid model. This BI-SPD nanoassembly has the potential to enhance the expression of therapeutic genes in tumor models without causing significant toxicity to surrounding healthy tissues, since it has shown higher tumor targeting and accumulation in the 4T1 tumor in mice model.
刺激响应性聚合物纳米粒子在克服转染效率和将基因特异性和安全递送至癌细胞等挑战方面非常有用。通过时空控制基因释放可以改善转染结果。我们设计了一种纳米组装体，该组装体由二硫键交联的聚乙烯亚胺（ssPEI）与肿瘤特异性细胞穿透肽（DS4-3）（SPD）聚阳离子和牛血清白蛋白（BSA）负载的 IR780（BI）纳米颗粒组成，从而通过静电络合形成双刺激触发、肿瘤穿透和基因携带的纳米组装体（BI-SPD）。BI-SPD 纳米组装体由高度稳定的纳米尺寸复合物组成，平均粒径为 457±27.5nm，在乳腺癌细胞中表现出两倍的转染效率提高，且没有潜在细胞毒性的迹象。此外，在激光照射下，由于 BI-SPD 纳米组装体局部热引起的内体快速逃逸，转染效率提高了四倍。此外，肿瘤细胞中的高氧化还原环境促进了 SPD 聚阳离子的解组装，从而在细胞质中有效释放质粒。BI-SPD 纳米组装体在 4T1 球体模型中也表现出高穿透性和增强的光热触发基因表达。由于 BI-SPD 纳米组装体在小鼠模型中显示出对 4T1 肿瘤的更高肿瘤靶向性和积累，因此它有可能在不引起周围健康组织显著毒性的情况下增强肿瘤模型中的治疗基因表达。
