Cultrara Christopher N, Shah Sunil, Antuono Gina, Heller Claudia J, Ramos Jorge A, Samuni Uri, Zilberberg Jenny, Sabatino David
Department of Chemistry and Biochemistry, Seton Hall University, 400 South Orange Avenue, South Orange, NJ 07079, USA.
Department of Chemistry and Biochemistry, Queens College, City University of New York, Flushing, NY 11367, USA; PhD Programs in Biochemistry and Chemistry, The Graduate Center of the City University of New York, New York, NY 10016, USA.
Mol Ther Nucleic Acids. 2019 Dec 6;18:863-870. doi: 10.1016/j.omtn.2019.10.013. Epub 2019 Oct 23.
Oligoarginine sequences conjugated to a short cancer-targeting peptide (CTP) selective for the prostate-specific membrane antigen (PSMA) receptor was developed for selective small interfering RNA (siRNA) delivery to a human metastatic/castration-resistant prostate cancer (PCa) cell line, which expresses PSMA on the surface. The PSMA-R (n = 6 and 9) peptides were synthesized by solid-phase peptide synthesis, characterized by liquid chromatography-mass spectrometry (LC-MS) and condensed with glucose-regulated protein (GRP)-silencing siRNAs. Native gels showed formation of stable CTP:siRNA ionic complexes. Furthermore, siRNA release was effected by heparin competition, supporting the peptides' capabilities to act as condensing and releasing agents. However, dynamic light scattering (DLS) and transmission electron microscopy (TEM) studies revealed large anionic complexes that were prone to aggregation and limited cell uptake for RNAi activity. Taken together, these data support the notion that the development of efficient peptide-based siRNA delivery systems is in part contingent on the formulation of discrete nanoparticles that can effectively condense and release siRNA in cells.
开发了与对前列腺特异性膜抗原（PSMA）受体具有选择性的短癌症靶向肽（CTP）缀合的寡聚精氨酸序列，用于将选择性小干扰RNA（siRNA）递送至人转移性/去势抵抗性前列腺癌（PCa）细胞系，该细胞系在表面表达PSMA。通过固相肽合成法合成了PSMA-R（n = 6和9）肽，通过液相色谱-质谱（LC-MS）对其进行表征，并与葡萄糖调节蛋白（GRP）沉默siRNAs进行缩合。天然凝胶显示形成了稳定的CTP:siRNA离子复合物。此外，肝素竞争导致siRNA释放，这支持了这些肽作为缩合剂和释放剂的能力。然而，动态光散射（DLS）和透射电子显微镜（TEM）研究揭示了大的阴离子复合物，这些复合物易于聚集且细胞对RNAi活性的摄取有限。综上所述，这些数据支持这样一种观点，即基于肽的高效siRNA递送系统的开发部分取决于能够在细胞中有效缩合和释放siRNA的离散纳米颗粒的配方。
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