Influence of sirolimus-loaded nanoparticles on physiological functions of native human polymorphonuclear neutrophils

Sirolimus (SRL) is an immunosuppressive agent of high clinical relevance that has been associated with serious side effects. Biodegradable, SRL-loaded poly(d,l-lactide) nanoparticles (SRL-PLA-NPs) are being investigated as a drug delivery system to improve drug targeting. Polymorphonuclear neutrophils (PMNs) are phagocytes for particulate xenobiotics and also important trigger cells of the primary immune response. Therefore, the effects of SRL, SRL-PLA-NPs, and plain PLA-NPs on the viability of human PMNs, their essential functions, and the secretion of relevant cytokines were determined and evaluated with respect to the intracellular concentrations assessed by liquid chromatography–mass spectrometry ultra-trace analysis. For the first time to our knowledge, incorporation of NPs into PMNs was monitored by flow cytometry using fluorescence-labeled NPs. SRL accumulated intracellularly, exceeding therapeutic blood levels by a factor of two to four. Phagocytic activity was promptly reduced but recovered within 3 hours. No other parameters of the PMNs were affected. Hence, PLA-NPs appear suitable as drug carriers for SRL, allowing for better control of drug release.From the Clinical EditorThis team of authors describe the incorporation of sirolimus loaded florescent NPs into polymorphonuclear neutrophils, a process that has been monitored by flow cytometry utilizing the fluorescent properties of the polymeric NPs. SRL accumulated intracellularly, exceeding therapeutic blood levels by a factor of two to four, resulting in reduced phagocytic activity that recovered within 3 hours.

Graphical AbstractPoly(d,l-lactide) nanoparticles are here shown to be suitable as drug carriers for the immunosuppressant sirolimus, offering the potential of better control over drug release. Deeper insight into the phagocytosis of these nanoparticles by polymorphonuclear neutrophils reveals interesting new details about the ingestion and elimination processes, as well as the pharmacodynamic or toxicodynamic implications for the functionality of these important trigger cells.Figure optionsDownload high-quality image (243 K)Download as PowerPoint slide