Kos Petra, Lächelt Ulrich, He Dongsheng, Nie Yu, Gu Zhongwei, Wagner Ernst
Pharmaceutical Biotechnology, Center for System-Based Drug Research, Ludwig-Maximilians-University Munich, Munich, D-81377, Germany.
J Pharm Sci. 2015 Feb;104(2):464-75. doi: 10.1002/jps.24194. Epub 2014 Sep 29.
For active cell targeting, viruses frequently capitalize on dual-receptor binding. With the intention to mimic this natural process, a dual peptide-based approach for targeting cancer cells was evaluated. For this purpose, sequence-defined pDNA binding oligo (ethane amino) amides containing a PEG chain with a peptidic targeting ligand at its distal end were applied. Integrin receptor-directed cyclic peptide cRGDfk, transferrin receptor-addressing peptide B6, and epidermal growth factor receptor-targeting peptide GE11 were used in the study in DU145 prostate cancer cells that express all three receptors. Dual-receptor targeted pDNA polyplexes were designed by combining two of the above ligands at various ratios, in order to find an optimal ligand combination. Two polycation/pDNA ratios of nitrogen/phosphate (N/P) 6 and 12 were tested. Dual targeting effects were most pronounced at the lower N/P ratio and found for all three combinations. Cell binding studies and pDNA transfections revealed GE11 plus B6 as the most potent combination. In general, a good correlation of cell binding with gene transfer was observed. Interestingly, GE11 peptide-based polyplexes-mediated bimodal cell association profiles. In contrast, B6 ligand, cRGD ligand, and dual-targeted polyplexes triggered more homogenous monomodal cell binding characteristics.
为了实现活性细胞靶向，病毒常常利用双受体结合。为了模拟这一自然过程，评估了一种基于双肽的癌细胞靶向方法。为此，应用了序列确定的与聚乙二醇链结合的寡（乙烷氨基）酰胺，该聚乙二醇链在其远端带有肽类靶向配体。整合素受体导向的环肽cRGDfk、转铁蛋白受体靶向肽B6和表皮生长因子受体靶向肽GE11用于对表达所有三种受体的DU145前列腺癌细胞的研究。通过以不同比例组合上述两种配体来设计双受体靶向的pDNA多聚体，以找到最佳的配体组合。测试了氮/磷（N/P）比为6和12的两种聚阳离子/pDNA比例。双靶向效应在较低的N/P比时最为明显，并且在所有三种组合中均观察到。细胞结合研究和pDNA转染表明，GE11加B6是最有效的组合。总体而言，观察到细胞结合与基因转移之间具有良好的相关性。有趣的是，基于GE11肽的多聚体介导了双峰细胞结合模式。相比之下，B6配体、cRGD配体和双靶向多聚体引发了更均匀的单峰细胞结合特征。
