Journal
ACS BIOMATERIALS SCIENCE & ENGINEERING
Volume 7, Issue 6, Pages 2530-2537Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acsbiomaterials.1c00213
Keywords
gene delivery; polymer; peptide; protein kinase
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The study explores a protein kinase C alpha (PKC alpha)-responsive gene carrier that selectively responds to malfunctioning intracellular signaling in cancer cells, showing potential for cancer-specific gene delivery and therapy.
The presence of intracellular signal transduction and its abnormal activities in many cancers has potential for medical and pharmaceutical applications. We recently developed a protein kinase C alpha (PKC alpha)-responsive gene carrier for cancerspecific gene delivery. Here, we demonstrate an in-depth analysis of cellular signal-responsive gene carrier and the impact of its selective transgene expression in response to malfunctioning intracellular signaling in cancer cells. We prepared a novel gene carrier consisting of a linear polyethylenimine (LPEI) main chain grafted to a cationic PKC alpha-specific substrate (FKKQGSFAKKK-NH2). The LPEI-peptide conjugate formed a nanosized polyplex with pDNA and mediated efficient cellular uptake and endosomal escape. This polyplex also led to successful transgene expression which responded to the target PKC alpha in various cancer cells and exhibited a 10-100-fold higher efficiency compared to the control group. In xenograft tumor models, the LPEI-peptide conjugate promoted transgene expression showing a clear-cut response to PKC alpha. Furthermore, when a plasmid containing a therapeutic gene, human caspase-8 (pcDNA-hcasp8), was used, the LPEIpeptide conjugate had significant cancer-suppressive effects and extended animal survival. Collectively, these results reveal that our method has great potential for cancer-specific gene delivery and therapy.
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