Treatment of pancreatic ductal adenocarcinoma with gemcitabine is limited by an increased desmoplasia, poor vascularization, and short plasma half-life. Heat-sensitive liposomes modified by polyethylene glycol (PEG; PEGylated liposomes) can increase plasma stability, reduce clearance, and decrease side effects. Nevertheless, translation of heat-sensitive liposomes to the clinic has been hindered by the low loading efficiency of gemcitabine and by the difficulty of inducing hyperthermia in vivo. This study was designed to investigate the effect of phospholipid content on the stability of liposomes at 37 °C and their release under hyperthermia conditions; this was accomplished by employing a two-stage heating approach. First the liposomes were heated at a fast rate, then they were transferred to a holding bath. Thermosensitive liposomes formulated with DPPC: DSPC: PEG2k (80:15:5, mole%) exhibited minimal release of carboxyfluorescein at 37 °C over 30 min, indicating stability under physiological conditions. However, upon exposure to hyperthermic conditions (43 °C and 45 °C), these liposomes demonstrated a rapid and significant release of their encapsulated content. The encapsulation efficiency for gemcitabine was calculated at 16.9%. Additionally, fluorescent analysis during the removal of unencapsulated gemcitabine revealed an increase in pH. In vitro tests with BxPC3 and KPC cell models showed that these thermosensitive liposomes induced a heat-dependent cytotoxic effect comparable to free gemcitabine at temperatures above 41 °C. This study highlights the effectiveness of the heating mechanism and cell models in understanding the current challenges in developing gemcitabine-loaded heat-sensitive liposomes.
吉西他滨治疗胰腺导管腺癌的疗效受限于间质纤维化加剧、血管化不良及血浆半衰期短等问题。经聚乙二醇修饰的热敏脂质体（PEG化脂质体）可提升血浆稳定性、降低清除率并减少副作用。然而，热敏脂质体的临床转化仍面临吉西他滨载药效率低及体内难以诱导高温两大障碍。本研究通过设计两阶段加热方案（快速升温后转入恒温槽），系统探究磷脂组成对脂质体在37℃稳定性及高温释放特性的影响。采用DPPC:DSPC:PEG2k（摩尔比80:15:5）构建的热敏脂质体在37℃条件下30分钟内羧基荧光素释放量极低，表明其在生理环境中具有良好稳定性。但在高温环境（43℃和45℃）中，该脂质体可实现包载物的快速高效释放。吉西他滨的包封率测定为16.9%，去除未包封药物过程中的荧光分析显示pH值有所升高。通过BxPC3与KPC细胞模型的体外实验证实，当温度超过41℃时，该热敏脂质体可产生与游离吉西他滨相当的、具有温度依赖性的细胞毒性效应。本研究通过加热机制与细胞模型的联合验证，为解析吉西他滨热敏脂质体研发中的现存挑战提供了有效策略。
Thermosensitive Liposomes for Gemcitabine Delivery to Pancreatic Ductal Adenocarcinoma
肿瘤(癌症)患者之家