Cell-penetrating peptides (CPPs) have been widely used for therapeutic delivery due to their unique ability to cross the cell membrane. However, the widespread application of CPPs was limited due to their low tumor specificity and limited retention in vivo. Peptide self-assembly offers an effective method to generate materials with dynamic control over both structures and bioactivity. We recently demonstrated a new family of Filamentous Cell-Penetrating Peptides (FCPPs) based on the self-assembly of de novo designed multidomain peptides (MDPs). While FCPPs have potent cell-penetrating activity, their tumor selectivity is poor. In this work, to construct tumor-selective FCPPs (TS-FCPPs), we append a cationic domain to the C-terminus of the optimal MDPs through a cleavable chemical linker. Under the physiological condition, the integrated peptide is unassembled due to electrostatic repulsion and has low cell-penetrating activity. Under the tumor microenvironment, the cleavage of the chemical linker releases the cationic domain and restores the ability of MDPs to form FCPPs with enhanced cell-penetrating activity. For proof of concept, we choose matrix metalloproteinase, MMP-2 as our initial target of the tumor microenvironment due to their overexpression by tumors. Biophysical characterization confirms the chemical and physical transformation from monomers to self-assembled nanofibers upon MMP-2 treatment. The in vitro cell uptake experiment showed enhanced cell-penetrating activity of TS-FCPPs in cancer cells with high levels of MMP-2 compared to cancer cells with low MMP-2. MDPs with a non-responsive MMP linker exhibited low cell-penetrating activity in all cell lines tested with different MMP-2 levels. Doxorubicin conjugated TS-FCPs demonstrated higher drug efficacy toward cancer cells with high levels of MMP-2 than cancer cells with low MMP-2 and healthy cells. The current results provide important insights into fundamental understanding of in situ triggered peptide self-assembly, which have great potential for the application of tumor-targeted therapeutic delivery with high selectivity.

In situ triggered filamentous cell-penetrating peptides (FCPPS) for tumor cell targeted therapeutic delivery

ACS Spring Meeting 2021

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