1 research outputs found
Increasing Cancer-Specific Gene Expression by Targeting Overexpressed α<sub>5</sub>β<sub>1</sub> Integrin and Upregulated Transcriptional Activity of NF-κB
We developed a modular multifunctional
nonviral gene delivery system
by targeting the overexpressed cancer surface receptor α<sub>5</sub>β<sub>1</sub> integrin and the upregulated transcriptional
activity of the cancer resistance mediating transcription factor NF-κB,
thereby introducing a new form of transcriptional targeting. NF-κB
regulated therapy can improve specificity of gene expression in cancer
tissue and also may offset NF-κB mediated cancer resistance.
We delivered a luciferase gene under the control of an NF-κB
responsive element (pNF-κB-Luc) encapsulated in a PR_b peptide
functionalized stealth liposome that specifically targets the α<sub>5</sub>β<sub>1</sub> integrin and achieved increased gene expression
in DLD-1 colorectal cancer cells compared to BJ-fibroblast healthy
cells <i>in vitro</i>. The multitargeted system was also
able to differentiate between cancer cells and healthy cells better
than either of the individually targeted systems. In addition, we
constructed a novel cancer therapeutic plasmid by cloning a highly
potent diphtheria toxin fragment A (DTA) expressing gene under the
control of an NF-κB responsive element (pNF-κB-DTA). A
dose-dependent reduction of cellular protein expression and increased
cytotoxicity in cancer cells was seen when transfected with PR_b functionalized
stealth liposomes encapsulating the condensed pNF-κB-DTA plasmid.
Our therapeutic delivery system specifically eradicated close to 70%
of a variety of cancer cells while minimally affecting healthy cells <i>in vitro</i>. Furthermore, the modular nature of the nonviral
design allows targeting novel pairs of extracellular receptors and
upregulated transcription factors for applications beyond cancer gene
therapy