Thermally triggered drug release from temperature-sensitive liposomes (TSL) holds great promise for cancer therapy. Different types of TSL have been designed recently for heat triggered drug release inside tumor blood vessels or after accumulation into the tumor interstitium. However, justification of drug release profiles is for far mainly based on in vitro release data. While these methods could be good enough to give early indication about the thermal sensitivity of TSL, they are still far from being optimum. This is because these methods do not take into consideration the actual adsorption of proteins onto the surface of TSL after their in vivo administration, also known as “protein corona” and the influence this could have on drug release. Therefore, in this study we compared thermal triggered drug release profile of two different types of doxorubicin encapsulated TSL; namely the lysolipid-containing TSL (LTSL) and traditional TSL (TTSL) after their in vivo recovery from the blood circulation of CD-1 mice. Ex vivo release profile at 42 °C was then tested either in the presence of full plasma or after removal of unbound plasma proteins (i.e. protein corona coated TSL). Our data showed that the influence of the environment on drug release profile was very much dependent on the type of TSL. LTSL release profile was consistently characterized by ultrafast drug release independent on the conditions tested. On the contrary, TTSL release profile changed significantly. Doxorubicin release from in vivo recovered TTSL was slow and incomplete in the presence of unbound plasma proteins, whereas very rapid drug release was detected from in vivo recovered and purified protein corona-coated TTSL in the absence of unbound proteins. Using mass spectrometry and quantification of protein adsorption, we confirmed that this discrepancy is due to the changes in protein adsorption onto TTSL when heated in the presence of unbound proteins leading to reduction in drug release. In summary this study showed that the formation of the in vivo corona on TSL will have a dramatic impact on their release profile and is dependent on both their lipid composition and the protein content of the environment in which drug release is triggered.

温度敏感脂质体（TSL）的热触发药物释放对于癌症治疗具有广阔的前景。最近已经设计了不同类型的TSL，用于热触发药物在肿瘤血管内部释放或在肿瘤聚积到肿瘤间质后释放。然而，药物释放曲线的合理性目前主要是基于体外释放数据。尽管这些方法可能足以对TSL的热敏性提供早期指示，但它们仍远未达到最佳状态。这是因为这些方法没有考虑到体内蛋白质在TSL表面上的实际吸附给药，也称为“蛋白质电晕”及其对药物释放的影响。因此，在这项研究中，我们比较了两种不同类型的阿霉素封装的TSL的热触发药物释放曲线；从CD-1小鼠的血液循环体内恢复后，即含有溶血脂的TSL（LTSL）和传统的TSL（TTSL）。离体然后在完全血浆存在下或除去未结合的血浆蛋白（即蛋白电晕包被的TSL）后，在42°C下测试释放曲线。我们的数据表明，环境对药物释放曲线的影响在很大程度上取决于TSL的类型。LTSL的释放曲线始终具有超快的药物释放特征，而不受测试条件的影响。相反，TTSL的发行情况发生了重大变化。在存在未结合的血浆蛋白的情况下，从体内回收的TTSL中释放的阿霉素缓慢且不完全，而从体内检测到的药物释放非常快在没有未结合蛋白的情况下，回收并纯化了蛋白电晕包被的TTSL。使用质谱法和蛋白质吸附的定量分析，我们确认了这种差异是由于在未结合的蛋白质存在下加热时，蛋白质吸附到TTSL上的变化导致药物释放的减少。总而言之，这项研究表明，在TSL上体内电晕的形成将对其释放曲线产生巨大影响，并且取决于其脂质成分和触发药物释放的环境中的蛋白质含量。