Mechanism of cell death induced by cationic dendrimers in RAW 264.7 murine macrophage-like cells

Cationic dendrimers possess attractive nano‐sized architectures that make them suitable as targeted drug/gene delivery systems. However, very little is known about their mechanisms of cell death in cellular systems. In the current study, the apoptotic and necrotic effects of starburst polyamidoamine...

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Veröffentlicht in:Journal of pharmacy and pharmacology 2005-04, Vol.57 (4), p.489-495
Hauptverfasser: Kuo, Jung-hua Steven, Jan, Ming-shiou, Chiu, Hsuan Wen
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Jan, Ming-shiou
Chiu, Hsuan Wen
description Cationic dendrimers possess attractive nano‐sized architectures that make them suitable as targeted drug/gene delivery systems. However, very little is known about their mechanisms of cell death in cellular systems. In the current study, the apoptotic and necrotic effects of starburst polyamidoamine (PAMAM) and polypropylenimine (DAB) dendrimers in cultured RAW 264.7 murine macrophage‐like cells were investigated. Cationic dendrimer treatment produced a typically dose‐dependent cytotoxic effect on macrophage cells. RAW 264.7 cells exposed to cationic dendrimers exhibited morphological features of apoptosis. Apoptotic ladders were observed in DNA extracted from RAW 264.7 cells treated with cationic dendrimers. Analysis from flow cytometry demonstrated an increase in hypodiploid DNA population (sub‐G1) and a simultaneous decrease in diploid DNA content, indicating that DNA cleavage occurred after exposure of the cells to cationic dendrimers. Also, cells treated with DAB dendrimer induced a higher percentage of sub‐G1 population than those treated with PAMAM dendrimer at the same dose. In addition, it was shown that pre‐treatment of RAW 264.7 cells with the general caspase inhibitor zVAD‐fmk prevented some degree of apoptosis induced by cationic dendrimers, suggesting that apoptosis in macrophage cells involves a caspasedependent pathway. Macrophage cells were also found to be sensitive to induction of apoptosis by dendrimers, whereas NIH/3T3 cells (mouse fibroblast) and BNL CL.2 (mouse liver) cells did not undergo apoptosis. These results could be helpful for optimizing the biocompatibility of dendrimers used for targeted drug/gene delivery.
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However, very little is known about their mechanisms of cell death in cellular systems. In the current study, the apoptotic and necrotic effects of starburst polyamidoamine (PAMAM) and polypropylenimine (DAB) dendrimers in cultured RAW 264.7 murine macrophage‐like cells were investigated. Cationic dendrimer treatment produced a typically dose‐dependent cytotoxic effect on macrophage cells. RAW 264.7 cells exposed to cationic dendrimers exhibited morphological features of apoptosis. Apoptotic ladders were observed in DNA extracted from RAW 264.7 cells treated with cationic dendrimers. Analysis from flow cytometry demonstrated an increase in hypodiploid DNA population (sub‐G1) and a simultaneous decrease in diploid DNA content, indicating that DNA cleavage occurred after exposure of the cells to cationic dendrimers. Also, cells treated with DAB dendrimer induced a higher percentage of sub‐G1 population than those treated with PAMAM dendrimer at the same dose. In addition, it was shown that pre‐treatment of RAW 264.7 cells with the general caspase inhibitor zVAD‐fmk prevented some degree of apoptosis induced by cationic dendrimers, suggesting that apoptosis in macrophage cells involves a caspasedependent pathway. Macrophage cells were also found to be sensitive to induction of apoptosis by dendrimers, whereas NIH/3T3 cells (mouse fibroblast) and BNL CL.2 (mouse liver) cells did not undergo apoptosis. 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However, very little is known about their mechanisms of cell death in cellular systems. In the current study, the apoptotic and necrotic effects of starburst polyamidoamine (PAMAM) and polypropylenimine (DAB) dendrimers in cultured RAW 264.7 murine macrophage‐like cells were investigated. Cationic dendrimer treatment produced a typically dose‐dependent cytotoxic effect on macrophage cells. RAW 264.7 cells exposed to cationic dendrimers exhibited morphological features of apoptosis. Apoptotic ladders were observed in DNA extracted from RAW 264.7 cells treated with cationic dendrimers. Analysis from flow cytometry demonstrated an increase in hypodiploid DNA population (sub‐G1) and a simultaneous decrease in diploid DNA content, indicating that DNA cleavage occurred after exposure of the cells to cationic dendrimers. Also, cells treated with DAB dendrimer induced a higher percentage of sub‐G1 population than those treated with PAMAM dendrimer at the same dose. In addition, it was shown that pre‐treatment of RAW 264.7 cells with the general caspase inhibitor zVAD‐fmk prevented some degree of apoptosis induced by cationic dendrimers, suggesting that apoptosis in macrophage cells involves a caspasedependent pathway. Macrophage cells were also found to be sensitive to induction of apoptosis by dendrimers, whereas NIH/3T3 cells (mouse fibroblast) and BNL CL.2 (mouse liver) cells did not undergo apoptosis. 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source MEDLINE; Access via Wiley Online Library; Oxford University Press Journals All Titles (1996-Current)
subjects Amino Acid Chloromethyl Ketones - pharmacology
Animals
Apoptosis
Caspase Inhibitors
Cations
Cell Line
Cell Survival - drug effects
Dendrimers
DNA - analysis
DNA Fragmentation
Drug Delivery Systems
L-Lactate Dehydrogenase - biosynthesis
Macrophages - drug effects
Macrophages - pathology
Mice
Nanostructures
Necrosis
Polyamines - pharmacology
Polypropylenes - pharmacology
title Mechanism of cell death induced by cationic dendrimers in RAW 264.7 murine macrophage-like cells
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