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The role of cell-penetrating peptides in potential anti-cancer therapy.

ABSTRACT: Due to the complex physiological structure, microenvironment and multiple physiological barriers, traditional anti-cancer drugs are severely restricted from reaching the tumour site. Cell-penetrating peptides (CPPs) are typically made up of 5-30 amino acids, and can be utilised as molecular transporters to facilitate the passage of therapeutic drugs across physiological barriers. Up to now, CPPs have widely been used in many anti-cancer treatment strategies, serving as an excellent potential choice for oncology treatment. However, their drawbacks, such as the lack of cell specificity, short duration of action, poor stability in vivo, compatibility problems (i.e. immunogenicity), poor therapeutic efficacy and formation of unwanted metabolites, have limited their further application in cancer treatment. The cellular uptake mechanisms of CPPs involve mainly endocytosis and direct penetration, but still remain highly controversial in academia. The CPPs-based drug delivery strategy could be improved by clever design or chemical modifications to develop the next-generation CPPs with enhanced cell penetration capability, stability and selectivity. In addition, some recent advances in targeted cell penetration that involve CPPs provide some new ideas to optimise CPPs.

SUBMITTER: Zhou M

PROVIDER: S-EPMC9121317 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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The role of cell-penetrating peptides in potential anti-cancer therapy.

Zhou Meiling M Zou Xi X Cheng Kexin K Zhong Suye S Su Yangzhou Y Wu Tao T Tao Yongguang Y Cong Li L Yan Bin B Jiang Yiqun Y

Clinical and translational medicine 20220501 5

Due to the complex physiological structure, microenvironment and multiple physiological barriers, traditional anti-cancer drugs are severely restricted from reaching the tumour site. Cell-penetrating peptides (CPPs) are typically made up of 5-30 amino acids, and can be utilised as molecular transporters to facilitate the passage of therapeutic drugs across physiological barriers. Up to now, CPPs have widely been used in many anti-cancer treatment strategies, serving as an excellent potential cho ...[more]

PMID: 35593206

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Project description:For the improved delivery of cancer therapeutics and imaging agents, the conjugation of cell-penetrating peptides (CPPs) increases the cellular uptake and water solubility of agents. Among the various CPPs, arginine-rich peptides have been the most widely used. Combining CPPs with enzyme-responsive peptides presents an innovative strategy to target specific intracellular enzymes in cancer cells and when combined with the appropriate click chemistry can enhance theranostic drug delivery through the formation of intracellular self-assembled nanostructures. However, one drawback of CPPs is their high positive charge which can cause nonspecific binding, leading to off-target accumulation and potential toxicity. Hence, balancing cell-specific penetration, toxicity, and biocompatibility is essential for future clinical efficacy. We synthesized six cancer-specific, legumain-responsive RnAANCK peptides containing one to six arginine residues, with legumain being an asparaginyl endopeptidase that is overexpressed in aggressive prostate tumors. When conjugated to Alexa Fluor 488, R1-R6AANCK peptides exhibited a concentration- and time-dependent cell penetration in prostate cancer cells, which was higher for peptides with higher R values, reaching a plateau after approximately 120 min. Highly aggressive DU145 prostate tumor cells, but not less aggressive LNCaP cells, self-assembled nanoparticles in the cytosol after the cleavage of the legumain-specific peptide. The in vivo biocompatibility was assessed in mice after the intravenous injection of R1-R6AANCK peptides, with concentrations ranging from 0.0125 to 0.4 mmol/kg. The higher arginine content in R4-6 peptides showed blood and urine indicators for the impairment of bone marrow, liver, and kidney function in a dose-dependent manner, with instant hemolysis and morbidity in extreme cases. These findings underscore the importance of designing peptides with the optimal arginine residue length for a proper balance of cell-specific penetration, toxicity, and in vivo biocompatibility.

Dataset Information

The role of cell-penetrating peptides in potential anti-cancer therapy.

Publications

The role of cell-penetrating peptides in potential anti-cancer therapy.

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