Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands; Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging, University Clinic and Helmholtz Institute for Biomedical Engineering, RWTH Aachen University, Aachen, Germany.
Imaging Division, University Medical Center Utrecht, Utrecht, The Netherlands.
Int J Pharm. 2018 Sep 15;548(2):778-782. doi: 10.1016/j.ijpharm.2017.11.002. Epub 2017 Nov 7.
Fast hyperthermia (i.e. 39-42 °C) triggered doxorubicin release from lysolipid-containing thermosensitive liposomes (LTSL) in the tumor vasculature has been demonstrated to result in considerable enhancement of bioavailable drug levels in heated tumor tissue in preclinical tumor models. However, there is also significant leakage of doxorubicin already at 37 °C in the bloodstream, making these LTSL less efficient and increasing the risk for systemic toxicity. In conventional liposomes, cholesterol is incorporated in the bilayer to increase the stability of the liposomes. Here, we investigate the effect of cholesterol inclusion on the doxorubicin release characteristics of LTSL at 37 °C and hyperthermic temperatures. For this purpose, three LTSL formulations with 0, 5 and 10 mol% cholesterol were prepared. Inclusion of cholesterol reduced the undesired doxorubicin leakage at 37 °C in Hepes-buffered saline (HBS) as well as in fetal bovine serum (FBS). The incorporation of cholesterol in the LTSL bilayers did not influence the hyperthermia-triggered release property of the LTSL. These results were supported by DSC measurements. Therefore, in conclusion, our data indicate that cholesterol inclusion in LTSL offers a simple solution to the problem of significant leakage of doxorubicin from LTSL already at 37 °C in the bloodstream.
快速热疗（即 39-42°C）可触发含有溶酶体的热敏脂质体（LTSL）在肿瘤血管中释放阿霉素，已被证明可显著提高临床前肿瘤模型中加热肿瘤组织中生物可用药物水平。然而，在血液中，即使在 37°C 时，阿霉素也会有明显的渗漏，这使得这些 LTSL 的效率降低，并增加了全身毒性的风险。在传统的脂质体中，胆固醇被包含在双层中以增加脂质体的稳定性。在这里，我们研究了胆固醇的包含对 LTSL 在 37°C 和热疗温度下阿霉素释放特性的影响。为此，我们制备了三种含有 0、5 和 10mol%胆固醇的 LTSL 制剂。胆固醇的包含降低了 Hepes 缓冲盐水（HBS）和胎牛血清（FBS）中不希望的阿霉素在 37°C 时的渗漏。胆固醇在 LTSL 双层中的掺入并不影响 LTSL 的热疗触发释放特性。这些结果得到了 DSC 测量的支持。因此，总之，我们的数据表明，胆固醇包含在 LTSL 中为解决在血液中 37°C 时已经存在的 LTSL 中阿霉素大量渗漏的问题提供了一种简单的解决方案。
