Activatable cell penetrating peptides are unlocking new opportunities for targeted entry to cancer cells. 

Cell penetrating peptides (CPPs) can be used to deliver molecular cargo, such as imaging agents or drugs, into cells. However, the uptake of these peptides is not limited to tumour cells and they are not suitable for widespread distribution in the body as they are naturally toxic. 

Now Roger Tsien and colleagues at the University of California at San Diego, US, have made CPPs that are activated by diseased cells. This reduces the toxicity to healthy cells and allows different types of tumours to be targeted. 'The mechanism of binding and uptake of CPPs is rather non-specific, based upon electrostatic charge of amino acid residues,' comments Todd Aguilera, a member of the research team. Activatable CPPs (ACPPs) consist of a polycationic CPP connected via a linker to a matching polyanion. This reduces the overall charge to nearly zero and inhibits electrostatic uptake to cells. The linker can be cleaved by enzymes produced in cancerous cells (matrix metalloproteinases or MMPs). This turns on the cell penetrating properties of the peptide, allowing entry into the cancer cells.

Enzymes present in tumors act as a scissor to cut the linker and allow CPPs to enter diseased cells

Enzymes present in tumors act as a scissor to cut the linker and allow CPPs to enter diseased cells

When investigating the system further, the team found that while polyarginine CPPs were toxic, ACPPs with linkers designed to be uncleavable - so they were not activated by the enzymes - were not toxic. This implies that designing disease specific cleavage systems could eliminate background toxicity to healthy cells, says Aguilera. The team also found that by linking the ACPPs to high molecular weight carriers they could improve the bio-distribution of the peptides. 

Robin Polt, an expert in biological chemistry at the University of Arizona, Tuscon, US, welcomes the research saying, 'Tsien's use of MMPs to cleave a covalently attached polyanionic 'damper' which blocks the polycationic cell-penetrating moiety of the peptide is quite novel.  In this way, the properties of the target cells 'turn on' the cell penetrating properties of the peptide when it becomes useful, but the polyanionic moiety keeps the CPP activity 'turned off' until acted upon by the cancer cell's MMPs.  This work represents an important advance in the design of biologically active peptides that have the potential for systemic distribution.'
 
Russell Johnson

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