Rapid Release of Doxorubicin from Thermosensitive Liposomes─Contributions of Leakage Versus Unloading

Drug release from liposomes loaded by remote loading can proceed via two principal routes: (i) the leakage of the entrapped drug through membrane pores; (ii) the permeation of the drug through the intact membrane as the gradient used for remote loading is collapsed ("unloading"). We assess the contributions of the two release mechanisms for doxorubicin loaded via a pH-gradient into lysolipid-containing thermosensitive liposomes. To this end, release into buffer at physiological pH is compared with release into acidic buffer which should eliminate unloading but leave leakage largely unaffected. Above the transition point at ≈41 °C, unloading contributes ∼30% to the overall fast drug release occurring within 30 s. Immediately below the transition, there is still partial release and partial collapse of the pH-gradient but no substantial unloading. This can be explained by a low permeability of gel-phase lipid for (even deprotonated) doxorubicin and insufficient deprotonation at these pH values.