Abstract
An important hurdle for the intracellular delivery of large cargo is the cellular membrane, which protects the cell from exogenous substances. Cell-penetrating peptides (CPPs) can cross this barrier but their use as drug delivery vehicles is hampered by their lack of cell type specificity. Over the past years, several approaches have been explored to control the activity of CPPs that can be primed for cellular uptake. Since the first report on such activatable CPPs (ACPPs) in 2004, various methods of activation have been developed. Here, we provide an overview of the different ACPPs strategies known to date and summarize the benefits, drawbacks, and future directions.
Highlights
Cells have a complex and mostly impermeable cell membrane to ensure stable intracellular conditions and to protect the cell from harmful exogenous substances
We provide an overview of the strategies in the design of activatable CPPs (ACPPs) since their discovery more than 15 years ago
This strategy was expanded to the noninternalizing, lysine rich, apoptotic peptide KLAK. When this peptide was conjugated to the polymer (DP = 5, 10, 15), again, cellular uptake was observed through flow cytometry while the apoptotic properties of KLAK remained intact in a dosedependent manner
Summary
Cells have a complex and mostly impermeable cell membrane to ensure stable intracellular conditions and to protect the cell from harmful exogenous substances. The Murdoch group reported on the control of CPP activity by using acid sensitive side chain modifications They conjugated succinyl moieties to the glutamine and both lysine residues of Tat and used these to coat PEG-based micelles loaded with Nile Red dye or DOX (Table 3, entry 3).[58] These ACPP-coated micelles were not taken up at physiological pH, while an 8 hour incubation at pH 5.0 resulted in cellular uptake comparable to that of micelles coated with unmodified CPPs. The ACPP-coated micelles displayed reduced blood clearance and increased localization to tumour cells in vivo, compared to unmodified CPP-coated controls. The group of Matile reported on-site ring-opening disulphide-exchange polymerization to obtain cell-penetrating poly(disulphides) (CPDs) (Table 5, entry 4).[76,77]
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