Biomedical Engineering Reference
In-Depth Information
proteins of
80% was observed, indicating that this could
also be a path to protein delivery [142].
Improved understanding of CPPs and the uptake mecha-
nisms involved in CPP-mediated delivery will greatly facil-
itate advances in both drug delivery and future therapeutic
design. To date, the internalization mechanism of CPP
remains a topic of much debate, though it appears that
different CPPs use distinct cellular translocation pathways
that in turn can be influenced by parameters such as cell type,
cargo, and concentration [143,144]. The exact mechanisms
of CPP-mediated transduction across the cell membrane
remain largely unknown though several studies [145,146]
suggest arginine content distribution can play a significant
role in transduction efficiency. Furthermore, cell surface
heparan sulfate appears to mediate peptide uptake in certain
cases [147], suggesting a possibility to exploit cell surface
molecules to increase protein transduction efficiency.
Because CPPs, and especially CPP-cargo conjugates,
have been shown to internalize largely via endocytotic
mechanisms, endosomal escape is now discussed as a pos-
sible route for efficient CPP-cargo delivery [11,148].
Tools such as CPP sequence prediction models [149] for
improving rational design of CPP may aid in the production
of next generation of CPPs that have improved uptake,
specificity, and reduced toxicity. Another means to improve
CPP-fusion protein therapeutics is to modify the protein
fused to the CPP enhancing desired biological properties.
Protein transduction has progressed significantly and the
number of preclinical and clinical trials has increased mark-
edly. Studies show encouraging results where the drugs
appear to be safe and specific. Owings to a short plasma
half-life and rapid distribution in tissue, the risk of generating
immune responses is considered to be slim [115]. However,
potential issues with specificity, toxicity [91], stability, and
immunogenicity [103] impede the use of CPPs as pharma-
ceutical components. Nevertheless, the growing numbers of
reports of successful in vivo transduction and promising
clinical trials are both exciting and encouraging.
>
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ACKNOWLEDGMENTS
This work was supported by grants from the Swedish
Research Council (VR-NT), the Knut and Alice Wallenberg
Foundation, the Swedish Governmental Agency for Innova-
tion Systems (VINNOVA-SAMBIO 2006), and the Swedish
Center for Biomembrane Research, Stockholm.
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third helix of the Antennapedia homeodomain translocates
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