Aparicio-Lopez Cesar B, Timmerman Sarah, Lorino Gabriella, Rogers Tatiana, Pyle Marla, Shrestha Tej B, Basel Matthew T
Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA.
Department of Electrical and Computer Engineering, Kansas State University, Manhattan, KS 66506, USA.
Cancers (Basel). 2024 Sep 1;16(17):3048. doi: 10.3390/cancers16173048.
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.
纤维组织增生增加、血管化不良以及血浆半衰期短。聚乙二醇修饰的热敏脂质体（PEG化脂质体）可提高血浆稳定性、降低清除率并减少副作用。然而，热敏脂质体向临床转化受到吉西他滨低载药效率以及体内诱导热疗困难的阻碍。本研究旨在探讨磷脂含量对脂质体在37℃时稳定性及其在热疗条件下释放的影响；这是通过采用两阶段加热方法实现的。首先将脂质体快速加热，然后转移至保温浴中。用DPPC:DSPC:PEG2k（80:15:5，摩尔%）配制的热敏脂质体在37℃下30分钟内羧基荧光素释放极少，表明在生理条件下具有稳定性。然而，在热疗条件下（43℃和45℃），这些脂质体显示其包封内容物快速且显著释放。吉西他滨的包封效率经计算为16.9%。此外，在去除未包封的吉西他滨过程中的荧光分析显示pH值升高。用BxPC3和KPC细胞模型进行的体外试验表明，这些热敏脂质体在高于41℃的温度下诱导出与游离吉西他滨相当的热依赖性细胞毒性作用。本研究突出了加热机制和细胞模型在理解开发载吉西他滨热敏脂质体当前挑战方面的有效性。
