Hummler Henriette, Regenold Maximilian, Allen Christine, Heerklotz Heiko
Institute of Pharmaceutical Sciences, University of Freiburg, Freiburg D-97104, Germany.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
J Phys Chem B. 2025 Jul 24;129(29):7518-7527. doi: 10.1021/acs.jpcb.5c01564. Epub 2025 Jul 10.
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.
(i) 被包裹的药物通过膜孔泄漏；(ii) 由于用于远程载入的梯度消失（“卸载”），药物透过完整的膜渗透。我们评估了通过pH梯度载入含溶血脂质的热敏脂质体中的阿霉素的两种释放机制的作用。为此，将在生理pH值下释放到缓冲液中的情况与释放到酸性缓冲液中的情况进行比较，酸性缓冲液应能消除卸载，但对泄漏的影响不大。在约41°C的转变温度以上，卸载对30秒内发生的整体快速药物释放的贡献约为30%。在转变温度刚以下时，仍有部分释放和pH梯度的部分消失，但没有大量卸载。这可以用凝胶相脂质对（即使是去质子化的）阿霉素的低渗透性以及在这些pH值下去质子化不足来解释。
