Glycopolymer–Cell-Penetrating Peptide (CPP) Conjugates for Efficient Epidermal Growth Factor Receptor (EGFR) Silencing,ACS Macro Letters

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Glycopolymer–Cell-Penetrating Peptide (CPP) Conjugates for Efficient Epidermal Growth Factor Receptor (EGFR) Silencing
ACS Macro Letters ( IF 5.1 ) Pub Date : 2022-04-07 , DOI: 10.1021/acsmacrolett.2c00046
Yi-Yang Peng ₁ , Haimei Hu _{2,

3} , Diana Diaz-Dussan ₁ , Jianyang Zhao _{2,

4} , Xiaojuan Hao ₂ , Ravin Narain ₁

Affiliation

Overexpression of epidermal growth factor receptor (EGFR) is observed in multiple cancers such as colorectal, lung, and cervical solid tumors. Regulating the EGFR expression is an efficient strategy to manage these malignancies, and it can be achieved by using short interfering RNA (siRNA). Cell-penetrating peptides (CPPs) demonstrated an excellent capability to enhance the cellular uptake of siRNA, but high knockdown efficiencies have not been achieved due to endosomal entrapment. In this work, Schiff’s base reaction was used to modify a block {P[LAEMA(2-lactobionamidoethyl methacrylamide)₃₇]-b-P[FPMA(4-formyl phenyl methacrylate)₂-st-DMA(N,N-dimethylacrylamide)₂], P2} and two statistical [P(LAEMA₂₃-st-FPMA₃) (P3) and P(LAEMA₂₅-st-FPMA₂-st-DMA₂) (P4)] aldehyde-based and galactose-based polymers, prepared via reversible addition–fragmentation chain-transfer (RAFT) polymerization. An arginine-rich peptide (ARP, KRRKRRRRRK) was used as a cell-penetrating peptide (CPP) and conjugated to the polymers via a Schiff base reaction. The resulting glycopolymer–peptide conjugates were utilized to condense the siRNA to prepare polyplexes with multivalent CPPs (MCPPs, a nanoparticle with multiple copies of the CPP) to enhance the endosomal escape. The polyplexes have different surface properties as determined by the architecture of polymers and the insertion of dimethyl amide moieties. The enhancement of cellular internalization of ARP was observed by labeling the polyplexes with fluorescein isothiocyanate (FITC)-siRNA showing a localization of polyplexes in the cytoplasm of a HeLa (cervical cancer) cell line. In the in vitro EFGR silencing study, the statistical glycopolymer–peptide (P3–P) polyplexes had superior EGFR silencing efficiency in comparison with the other polymers that were studied. Furthermore, P3–P polyplexes led to less off-targeting silencing than lipofectamine 3000. These encouraging results confirmed the potency of decorating galactose-based polymers with CPP, like ARP for their application in siRNA delivery and management of cervical carcinomas

中文翻译：

用于高效表皮生长因子受体 (EGFR) 沉默的糖聚合物-细胞穿透肽 (CPP) 偶联物

在结直肠癌、肺癌和宫颈实体瘤等多种癌症中观察到表皮生长因子受体 (EGFR) 的过度表达。调节 EGFR 表达是控制这些恶性肿瘤的有效策略，可以通过使用短干扰 RNA (siRNA) 来实现。细胞穿透肽 (CPP) 显示出增强 siRNA 细胞摄取的出色能力，但由于内体包埋，尚未实现高敲低效率。在这项工作中，席夫碱反应用于修饰嵌段 {P[LAEMA(2-lactobionamidoethyl methacrylamide) ₃₇ ]- b -P[FPMA(4-formyl phenyl methacrylate) ₂ - st -DMA(N,N-dimethylacrylamide) ₂ ], P2} 和两个统计 [P(LAEMA ₂₃ - st -FPMA ₃ ) ( P3 ) 和 P(LAEMA ₂₅ - st -FPMA ₂ - st -DMA ₂ ) ( P4)] 醛基和半乳糖基聚合物，通过可逆加成-断裂链转移 (RAFT) 聚合制备。富含精氨酸的肽（ARP，KRRKRRRRRRK）被用作细胞穿透肽（CPP），并通过席夫碱反应与聚合物结合。所得的糖聚合物-肽缀合物用于浓缩 siRNA，以制备具有多价 CPP（MCPP，具有多个 CPP 拷贝的纳米颗粒）的复合物，以增强内体逃逸。聚合物具有不同的表面特性，这取决于聚合物的结构和二甲基酰胺部分的插入。通过用异硫氰酸荧光素 (FITC)-siRNA 标记复合物来观察 ARP 细胞内化的增强，显示复合物在 HeLa（宫颈癌）细胞系的细胞质中的定位。在里面在体外EFGR 沉默研究中，统计糖聚合物-肽 ( P3 -P) 复合物与所研究的其他聚合物相比具有更高的 EGFR 沉默效率。此外，与 Lipofectamine 3000 相比， P3 –P 复合物导致更少的脱靶沉默。这些令人鼓舞的结果证实了用 CPP 装饰半乳糖基聚合物的效力，如 ARP 在 siRNA 递送和宫颈癌治疗中的应用

更新日期：2022-04-07

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