Novel Histone-Based DNA Carrier Targeting Cancer-Associated Fibroblasts

Polymers

Victor Potapov¹  Irina Alekseenko¹  Olga Rakitina²  Alexey Kuzmich³  Marina Zinovyeva⁴  Eugene Sverdlov⁴  Dmitry Didych⁴ 

[1] 16/10, Miklukho-Maklaya, 117997 Moscow, Russia;2, Kurchatov Square, 123182 Moscow, Russia;Institute of Molecular Genetics, Russian Academy of Sciences;Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences;

关键词: histone H2A;    cancer-associated fibroblasts;    gene therapy;    targeted gene delivery;    internalization;    receptor-mediated endocytosis;   

DOI  :  10.3390/polym12081695

来源: DOAJ

【 摘 要 】

Nuclear proteins, like histone H2A, are promising non-viral carriers for gene delivery since they are biocompatible, biodegradable, bear intrinsic nuclear localization signal, and are easy to modify. The addition of surface-protein-binding ligand to histone H2A may increase its DNA delivery efficiency. Tumor microenvironment (TME) is a promising target for gene therapy since its surface protein repertoire is more stable than that of cancer cells. Cancer-associated fibroblasts (CAFs) are important components of TME, and one of their surface markers is beta-type platelet-derived growth factor receptor (PDGFRβ). In this study, we fused histone H2A with PDGFRβ-binding peptide, YG2, to create a novel non-viral fibroblast-targeting DNA carrier, H2A-YG2. The transfection efficiency of histone complexes with pDNA encoding a bicistronic reporter (enhanced green fluorescent protein, EGFP, and firefly luciferase) in PDGFRβ-positive and PDGFRβ-negative cells was estimated by luciferase assay and flow cytometry. The luciferase activity, percentage of transfected cells, and overall EGFP fluorescence were increased due to histone modification with YG2 only in PDGFRβ-positive cells. We also estimated the internalization efficiency of DNA-carrier complexes using tetramethyl-rhodamine-labeled pDNA. The ligand fusion increased DNA internalization only in the PDGFRβ-positive cells. In conclusion, we demonstrated that the H2A-YG2 carrier targeted gene delivery to PDGFRβ-positive tumor stromal cells.

【 授权许可】

Unknown