Interactions between U-937 human macrophages and poly(propyleneimine) dendrimers.
Interest in using poly(propyleneimine) (PPI) dendrimers for biomedical applications is increasing. Before using PPI dendrimers in vivo, their interactions with macrophages must be fully understood because they are primarily removed from circulation by the macrophages of the mononuclear phagocyte system. However, few investigators have studied in detail the intracellular responses that cationic dendrimers induce in macrophages. Here we examined the intracellular responses-reactive oxygen species (ROS) content, mitochondria membrane potential, cell size and complexity, and cell cycle profiles-in U-937 human macrophages treated with poly(propyleneimine) dendrimers generation 2 (DAB 2.0) and 3 (DAB 3.0). Our study focused on the concentration ranges within which cell viability was greater than 90% after PPI dendrimers had been incubated for 16 h. For spontaneous ROS generation, DAB 2.0 did not consistently generate hydrogen peroxide production with increasing dosages over the entire culture period while it was capable of generating superoxide content except during the 12 h of incubation. In contrast, DAB 3.0 did not induce any hydrogen peroxide and superoxide production except for an abrupt increase of superoxide content at 60 microg/mL after 6 h of incubation. Our results showed that ROS responses in macrophages were strongly influenced by the nature of the dendrimer surface. Except at 3 h, DAB 2.0 increased mitochondrial membrane potential for every dose and culture period. In contrast, DAB 3.0 caused a significant fluctuation in mitochondrial membrane potential only at 6 h, compared with other incubation times. Exposing macrophages to PPI dendrimers caused dramatic and significant changes in macrophage cell size and complexity, and DAB 3.0 caused greater changes than DAB 2.0 did. For incubation times longer than 1 h, propidium iodide staining showed that cells treated with DAB 2.0 and 3.0 had a higher subG1 phase (indicative of apoptosis) than did untreated cells. PPI dendrimers induced different activated patterns in ROS generation and changes of mitochondrial membrane potential than did other carriers such as cationic liposomes and polyalkylcyanoacrylate. The nature of interactions between macrophages and PPI dendrimers is crucial for the design of safer and more effective delivery systems for macrophages. Our findings provide a novel insight into the cytotoxic effects at the molecular level that dendrimers cause in macrophages.
Kuo
Jung-hua Steven
JH
Graduate Institute of Pharmaceutical Science, Chia Nan University of Pharmacy and Science, Sec. 1, Jen-Te, Tainan, Taiwan. kuojunghua@yahoo.com.tw <kuojunghua@yahoo.com.tw>
Jan
Ming-shiou
MS
Lin
Yi-lin
YL
D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000378:metabolism / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D005434:Flow Cytometry; D006801:Humans; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011126:Polypropylenes / Q000378:metabolism / Q000633:toxicity*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013997:Time Factors; D020298:U937 Cells
D050091:Dendrimers; D004337:Drug Carriers; D011126:Polypropylenes; D017382:Reactive Oxygen Species; C443641:poly(propyleneimine)