کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
877400 | 911024 | 2015 | 10 صفحه PDF | دانلود رایگان |
The anticancer nanodrug Doxil®, a pegylated liposomal doxorubicin (PLD), accumulates at the tumor site due to the enhanced permeability and retention effect. However, the mechanism of doxorubicin release from the liposome within the tumor is unknown. We propose that ammonia produced at the tumor site by glutaminolysis enhances release. Using tumor cells in culture, we show that PLD, when ammonia is present, kills tumor cells with an efficacy similar to that of free doxorubicin, while PLD without ammonia and ammonia without PLD have very poor cytotoxicity. We confirm in tumor mouse models that ammonium/ammonia levels measured at the tumors are in the millimolar range, much higher than in the plasma of these mice. This is a new concept of stimulus–response, therapeutically efficacious drug release in tumors, with ammonia derived from tumor cell glutaminolysis acting as the stimulus. There may also be additional microenvironment-related variables that influence therapeutic efficacy.From the Clinical EditorThe use of liposomal platform as a drug carrier has brought success to Doxil. Nonetheless, the underlying mechanism of drug release at tumor site and subsequent tumor killing was largely unknown. In this article, the authors demonstrated in their experiments that higher ammonia level in the tumor environment was the main mechanism for drug release.
Graphical AbstractPegylated liposomal doxorubicin has been proven to effectively treat tumors in patients, but the mechanism by which it does this is not entirely clear. To be effective, the doxorubicin must be released from the liposomes once at the tumor site, but not before. This study aims to clarify the release step, and states that ammonia endogenous to tumors is a key factor in inducing release.Figure optionsDownload high-quality image (72 K)Download as PowerPoint slide
Journal: Nanomedicine: Nanotechnology, Biology and Medicine - Volume 11, Issue 7, October 2015, Pages 1841–1850