Cationic therapeutic peptides have received widespread attention due to their excellent antibacterial and antitumor properties. However, most of these peptides have undesirable delivery efficiency and high hemolytic toxicity due to the positively charged α-helix structure containing many lysine and arginine, which may restrict its in vivo applications. Herein, a conformationally transformed therapeutic peptide Pep-HCO3 modified with bicarbonates on guanidine groups is designed. Such a design allows Pep-HCO3 ((nap-RAGLQFPVGRLLRRLLRRLLR) nHCO3 ) to self-assemble into nanoparticles (NP-Pep) due to disrupting helix folding and the formation of intermolecular hydrogen bonding between bicarbonates and guanidine groups. When pH is from 7.4 to 6.5 at the tumor sites, guanidine bicarbonate can be hydrolyzed to form CO2 and guanidine groups, resulting in the disassembling of the NP-Pep into monomers α-Pep with a positively charged α-helix structure. In vivo, NP-Pep not only inhibits the tumor growth of xenografted mice with a twofold enhanced inhibition rate compared with α-Pep treatment group, but also significantly reduces the hemolytic toxicity by responding to the pH of tumor microenvironment. Therefore, the strategy of conformational transition-triggered disassembly of nanoparticles allows efficient delivery of cationic therapeutic peptides and lowering the hemolytic toxicity, which may provide an avenue for developing high-performance cationic peptide in vivo applications.
Keywords: conformational transition; peptides; self-assembly; therapy; tumor microenvironment responsiveness.
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