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.


BACKGROUND
This 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.
Institute of Clinical Pharmacology, Center of Pharmacology and Toxicology, University of Rostock, Rostock, Germany.
Sandra
S
Moeller
Ricarda
R
Kegler
Katrin
K
Sternberg
Ralf G
RG
Mundkowski
D056704:Adaptive Immunity; D016503:Drug Delivery Systems / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects; D053758:Nanoparticles / Q000008:administration & dosage / Q000737:chemistry; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects*; D010316:Particle Size; D011091:Polyesters / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects; D012995:Solubility
D007166:Immunosuppressive Agents; D011091:Polyesters; D011092:Polyethylene Glycols; C033616:poly(lactide); D020123:Sirolimus