Fluorinated Cell-Penetrating Peptide for Co-Delivering siHIF-1α and Sorafenib to Enhance In Vitro Anti-Tumor Efficacy

Antiangiogenic therapy with sorafenib (SF) alone is ineffective in eradicating tumors, and its long-term application can exacerbate tumor hypoxia, which in turn restricts SF's therapeutic efficacy. Here, a redox-responsive fluorinated peptide (DEN-TAT-PFC) consisting of dendritic poly-lysine, c...

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Bibliographic Details
Published in:Pharmaceutics 2023-12, Vol.15 (12), p.2789
Main Authors: Wan, Yu, Yang, Yuhan, Lai, Qiuyue, Wang, Wangxia, Wu, Mingyu, Feng, Shun
Format: Article
Language:English
Subjects:
Angiogenesis
Antibodies
Chemical bonds
Chemotherapy
Cytotoxicity
Efficiency
Ethylenediaminetetraacetic acid
fluorination
Fluorine
Gene therapy
Health aspects
Hypoxia
Kinases
Liver cancer
peptide
Peptides
Perfluorocarbons
RNA
siRNA delivery
Tumors
Vascular endothelial growth factor
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Summary:Antiangiogenic therapy with sorafenib (SF) alone is ineffective in eradicating tumors, and its long-term application can exacerbate tumor hypoxia, which in turn restricts SF's therapeutic efficacy. Here, a redox-responsive fluorinated peptide (DEN-TAT-PFC) consisting of dendritic poly-lysine, cell-penetrating peptide TAT, and perfluorocarbon was designed and synthesized to co-load siRNA-targeting hypoxia-inducible factors (siHIF-1α) and SF. The unique architecture of the peptide and fluorinated modifications enhanced the siRNA delivery efficiency, including increased siRNA binding, GSH-responsive release, cellular uptake, endosomal escape, and serum resistance. Simultaneously, the DEN-TAT-PFC/SF/siHIF-1α co-delivery system achieved efficient knockdown of HIF-1α at mRNA and protein levels, thus alleviating hypoxia and further substantially reducing VEGF expression. Additionally, the excellent oxygen-carrying ability of DEN-TAT-PFC may facilitate relief of the hypoxic microenvironment. As a result of these synergistic effects, DEN-TAT-PFC/SF/siHIF-1α exhibited considerable anti-tumor cell proliferation and anti-angiogenesis effects. Therefore, DEN-TAT-PFC can be a versatile platform for fabricating fluorine-containing drugs/siRNA complex nano-systems.
ISSN:1999-4923
1999-4923
DOI:10.3390/pharmaceutics15122789