Design of acid-activated cell penetrating peptide for delivery of active molecules into cancer cells

Bioconjug Chem. 2011 Jul 20;22(7):1410-5. doi: 10.1021/bc200138d. Epub 2011 Jun 21.


TP10-5 (TK) was screened as the most promising candidate among the designed analogues of transportan 10 (TP10), a cell penetrating peptide (CPP) with remarkable capacity for membrane translocation. However, low levels of specificity and high toxicity limit its successful use for drug delivery applications. Here, we developed a new type of acid-activated CPP (TH) by replacement of all lysines of TK with histidines. As expected, histidine-containing TH can be activated and subsequently enter cells at pH 6.0, whereas it is less active at pH 7.4. In contrast, the uptake of TK has no significant difference for both pH values. Importantly, the toxicity of TH is significantly lower than that of TK under physiological conditions. After attachment of camptothecin (CPT) to TH, this conjugate exhibited remarkable cytotoxicity to cancer cells in a pH-dependent manner compared with free CPT and TK-CPT. This study opens a new avenue to design CPPs that preferentially enter cells in acidic solid tumors, with minimal cellular uptake in normal tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Antineoplastic Agents, Phytogenic / administration & dosage*
  • Antineoplastic Agents, Phytogenic / chemistry
  • Antineoplastic Agents, Phytogenic / pharmacokinetics
  • Antineoplastic Agents, Phytogenic / pharmacology
  • Camptothecin / administration & dosage*
  • Camptothecin / chemistry
  • Camptothecin / pharmacokinetics
  • Camptothecin / pharmacology
  • Cell Line, Tumor
  • Cell-Penetrating Peptides / chemistry*
  • Drug Delivery Systems*
  • HeLa Cells
  • Histidine / chemistry
  • Humans
  • Hydrogen-Ion Concentration
  • Molecular Sequence Data
  • Neoplasms / drug therapy*


  • Antineoplastic Agents, Phytogenic
  • Cell-Penetrating Peptides
  • Histidine
  • Camptothecin