Pharmaceutical Biotechnology, Department of Pharmacy, Ludwig-Maximilians-Universität München, Munich, Germany.
J Gene Med. 2018 Jul;20(7-8):e3041. doi: 10.1002/jgm.3041. Epub 2018 Jul 17.
Developing new drug delivery carriers addressing chemoresistance is still full of challenges and opportunities. As the rapid development of small interfering RNA (siRNA) provides promising therapeutic perspectives, nanocarriers for drug and siRNA co-delivery present new alternatives for cancer therapy.
A co-delivery nanosystem for methotrexate (MTX) or gamma-glutamylated derivatives (gE -MTX and gE -MTX) and antitumoral EG5 siRNA has been developed utilizing the sequence defined cationic lipo-oligomers 454, 1021 and 1027. Based on a lipo-oligomer-MTX-siRNA core, an epidermal growth factor receptor (EGFR) targeted delivery system was established via post modification with the GE11 targeting peptide.
Almost 100% MTX derivative incorporation was achieved in gE -MTX or gE -MTX siRNA/454 polyplexes, whereas the particle sizes (100-150 nm) and siRNA binding abilities were well maintained. Our co-delivery system greatly increased the MTX sensitivity of MTX resistant KB cells. Enhanced cellular internalization of GE11 siRNA/454 polyplexes incorporating either gE -MTX or gE -MTX was observed and attributed to GE11-mediated targeting of EGFR overexpressing KB cells. GE11 modified gE -MTX or gE -MTX EG5 siRNA polyplexes illustrated the highest anti-tumoral activities compared to free MTX or nontargeted polyplexes. The His-containing gE -MTX or gE -MTX siRNA/1027 polyplexes showed increased tumor cell killing compared to the His-free analogous 1021 polyplexes.
A new strategy for co-delivering negatively charged MTX and cytotoxic siRNA has been developed by utilizing sequence defined cationic lipo-oligomers. Mediated by the combined effect of antifolate MTX, antimitotic EG5 siRNA and EGFR targeting by GE11, superior tumor cell killing was obtained with GE11 gE -MTX or gE -MTX EG5 siRNA/454 polyplexes.
开发针对化疗耐药性的新型药物递送载体仍然充满了挑战和机遇。随着小干扰 RNA（siRNA）的快速发展提供了有前途的治疗前景，药物和 siRNA 共递送的纳米载体为癌症治疗提供了新的选择。
利用序列定义的阳离子脂质寡聚物 454、1021 和 1027，开发了甲氨蝶呤（MTX）或 γ-谷氨酰化衍生物（gE-MTX 和 gE-MTX）和抗肿瘤 EG5 siRNA 的共递纳米系统。基于脂质寡聚物-MTX-siRNA 核心，通过用 GE11 靶向肽进行后修饰，建立了表皮生长因子受体（EGFR）靶向递送系统。
gE-MTX 或 gE-MTX siRNA/454 超分子复合物中几乎实现了 100%的 MTX 衍生物掺入，而粒径（100-150nm）和 siRNA 结合能力得到了很好的保持。我们的共递系统大大增加了 MTX 耐药性 KB 细胞对 MTX 的敏感性。观察到并归因于 GE11 介导的过表达 EGFR 的 KB 细胞靶向，GE11 修饰的 gE-MTX 或 gE-MTX EG5 siRNA/454 超分子复合物的细胞内摄取增强。与游离 MTX 或非靶向超分子复合物相比，GE11 修饰的 gE-MTX 或 gE-MTX EG5 siRNA 超分子复合物表现出最高的抗肿瘤活性。与无 His 的类似物 1021 超分子复合物相比，含有 His 的 gE-MTX 或 gE-MTX siRNA/1027 超分子复合物显示出更高的肿瘤细胞杀伤能力。
通过利用序列定义的阳离子脂质寡聚物，开发了一种共递负电荷 MTX 和细胞毒性 siRNA 的新策略。通过叶酸拮抗剂 MTX、抗有丝分裂 EG5 siRNA 和 GE11 对 EGFR 的靶向作用的共同作用，GE11 gE-MTX 或 gE-MTX EG5 siRNA/454 超分子复合物获得了优异的肿瘤细胞杀伤效果。
