Mechanistic study of enhanced drug release in mixed pH-responsive peptide-loaded liposomes

Liposomes serving as nanocarriers offer significant advantages in drug delivery for tumor treatment. There still exists challenges in controlling drug release by disintegrating the liposome membrane for the improvement of therapeutic efficiency. In this paper, a novel method involving the mixture of short peptides with pH-responsive characteristics into the cargo has been introduced. This approach facilitates the release of doxorubicin (DOX) in the acidic tumor tissue environment. The efficacy of this improvement was elucidated through molecular dynamics simulations and experiments. Liposomes incorporating a 1:1 ratio of peptides–DOX exhibited pronounced pH sensitivity and an enhanced drug release profile. The underlying mechanism is attributed to the peptides entering tumor tissues and undergoing protonation in acidic conditions, which increases the hydrophilicity of the peptide–DOX clusters and the internal surface tension of the liposomes. This alteration disrupts the balance between the inner and outer surface tensions of the nanocarrier, causing the liposomes to structurally disintegrate and thus enhancing drug release. The results from both thermodynamic analysis results and experimental data confirm the augmented drug release efficiency of this method, offering valuable theoretical insights for nanoparticle design and determining the optimal mixing ratio for therapeutic applications.