Abstract
We have previously developed efficient peptide-based nucleic acid delivery vectors PF14 and NF55, where we have shown that these vectors preferentially transfect lung tissue upon systemic administration with the nucleic acid. In the current work, we have explored the utilization and potential of these vectors for the lung-targeted gene therapy. Accordingly, we assessed the efficacy of these peptides in (i) two different lung disease models – acute lung inflammation and asthma in mice and (ii) using two different nucleic acid cargos – siRNA and pDNA encoding shRNA. Using RNAi against cytokine TNFα, we showed efficient anti-inflammatory effects in both disease models and observed decreased disease symptoms. Our results highlight the potential of our transfection vectors for lung gene therapy.
Highlights
We have previously developed efficient peptide-based nucleic acid delivery vectors PF14 and NF55, where we have shown that these vectors preferentially transfect lung tissue upon systemic administration with the nucleic acid
In the current work we took a different approach and instead of trying to adjust the drug delivery method to the disease requirements, we asked ourselves – which disease could benefit from our particular drug delivery system? As we show in this report, the drug carrier does not distribute evenly throughout the organism and some conditions could be predisposed to better treatment outcome than the others
When we look at the nucleic acid transfection after systemic administration of the peptides PF14 and NF55 (Table 1), there is strong transfection in the lung (Figs. 1a and S1) and a clear preference of the signal towards lungs (Fig. 1b), the physical accumulation of the cargo nucleic acid occurs mainly in liver (Supplementary Fig. S2)
Summary
We have previously developed efficient peptide-based nucleic acid delivery vectors PF14 and NF55, where we have shown that these vectors preferentially transfect lung tissue upon systemic administration with the nucleic acid. As an example of efficient transfection methods, we have previously developed two cell penetrating peptide (CPP) vectors that, in addition to cell cultures, demonstrate efficient in vivo activity[2,3]: i.e. they are able to deliver plasmid DNA (pDNA) or siRNA upon systemic injection[4]. These peptide-like entities are NF552 and PF143; they have an N-terminal fatty acid component that drives the formation of micelles in aqueous environment and they are extremely efficient in condensing the nucleic acid into nanoparticles[2] (Table 1). As detailed subsequently, we took advantage of the native liability of our peptide carriers to transfect lungs and focus on treatment potential of the pulmonary pathologies
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