TY - JOUR
T1 - Lytic peptides with improved stability and selectivity designed for cancer treatment
AU - Chen, Long
AU - Tu, Zhigang
AU - Voloshchuk, Natalya
AU - Liang, Jun F.
PY - 2012/4
Y1 - 2012/4
N2 - Lytic peptides are a group of membrane-acting peptides, which have excellent activity to drug-resistant cells. In this study, the stability and tumor selectivity of newly designed pH-activated lytic peptides were studied. We found that despite varied secondary structures, pH-induced structure changes could not be directly linked to the activity and pH sensitivity of peptides. On the contrary, formation of aggregates had great impacts on peptide binding and insertion into the lipid bilayer of cell membrane. It was found that the pH controlled peptide aggregation and dissolution was responsible for the pH-dependent membrane lysis activity of peptides. One peptide (PTP-7c) formed stable amyloid fibrils, which did not completely dissolve under acidic conditions. As a result, PTP-7c had the lowest membrane lysis and cell killing activities among tested lytic peptides. As solid tumors have consistently low extracellular pHs, peptides with acid-activation features showed improved selectivity to cancer cells. In addition, self-assembled lytic peptides were found to become more stable and showed dramatically increased half lives (up to 11 h) in human plasma. These new lytic peptides with good stability and acid-activated cell lysis activity will have wide biomedical applications especially for the treatment of cancers in which drug resistance has developed.
AB - Lytic peptides are a group of membrane-acting peptides, which have excellent activity to drug-resistant cells. In this study, the stability and tumor selectivity of newly designed pH-activated lytic peptides were studied. We found that despite varied secondary structures, pH-induced structure changes could not be directly linked to the activity and pH sensitivity of peptides. On the contrary, formation of aggregates had great impacts on peptide binding and insertion into the lipid bilayer of cell membrane. It was found that the pH controlled peptide aggregation and dissolution was responsible for the pH-dependent membrane lysis activity of peptides. One peptide (PTP-7c) formed stable amyloid fibrils, which did not completely dissolve under acidic conditions. As a result, PTP-7c had the lowest membrane lysis and cell killing activities among tested lytic peptides. As solid tumors have consistently low extracellular pHs, peptides with acid-activation features showed improved selectivity to cancer cells. In addition, self-assembled lytic peptides were found to become more stable and showed dramatically increased half lives (up to 11 h) in human plasma. These new lytic peptides with good stability and acid-activated cell lysis activity will have wide biomedical applications especially for the treatment of cancers in which drug resistance has developed.
KW - Acid-activation
KW - Cancer
KW - Formulation
KW - Histidine-rich peptides
KW - Macromolecular drug delivery
KW - Multi-drug resistance
KW - PH
KW - Peptide aggregates
KW - Solvation
KW - Stability
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U2 - 10.1002/jps.23043
DO - 10.1002/jps.23043
M3 - Article
AN - SCOPUS:84857504892
SN - 0022-3549
VL - 101
SP - 1508
EP - 1517
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 4
ER -