Differences in toxicity of anionic and cationic PAMAM and PPI dendrimers in zebrafish embryos and cancer cell lines.
Dendrimers are an emerging class of polymeric nanoparticles with beneficial biomedical applications like early diagnostics, in vitro gene transfection or controlled drug delivery. However, the potential toxic impact of exposure on human health or the environment is often inadequately defined. Thus, polyamidoamine (PAMAM) dendrimers of generations G3.0, 3.5, 4.0, 4.5 and 5.0 and polypropylenimine (PPI) dendrimers G3.0, 4.0 and 5.0 were tested in zebrafish embryos for 96h and human cancer cell lines for 24h, to assess and compare developmental in vivo toxicity with cytotoxicity. The zebrafish embryo toxicity of cationic PAMAM and PPI dendrimers increased over time, with EC50 values ranging from 0.16 to just below 1.7μM at 24 and 48hpf. The predominant effects were mortality, plus reduced heartbeat and blood circulation for PPI dendrimers. Apoptosis in the embryos increased in line with the general toxicity concentration-dependently. Hatch and dechorionation of the embryos increased the toxicity, suggesting a protective role of the chorion. Lower generation dendrimers were more toxic in the embryos whereas the toxicity in the HepG2 and DU145 cell lines increased with increasing generation of cationic PAMAMs and PPI dendrimers. HepG2 were less sensitive than DU145 cells, with IC50 values≥402μM (PAMAMs) and ≤240μM (PPIs) for HepG2 and ≤13.24μM (PAMAMs) and ≤12.84μM (PPIs) for DU145. Neither in fish embryos nor cells toxicity thresholds were determinable for anionic PAMAM G3.5 and G4.5. The study demonstrated that the cytotoxicity underestimated the in-vivo toxicity of the dendrimers in the fish embryos.
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt & Aachen, Germany; Institute of Environmental Research (Biology V), RWTH Aachen University, Germany.
Lambert
L
Bodewein
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Molecular Biology Division, Aachen, Germany.
Frank
F
Schmelter
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Molecular Biology Division, Aachen, Germany.
Stefano
S
Di Fiore
Institute of Environmental Research (Biology V), RWTH Aachen University, Germany.
Henner
H
Hollert
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt & Aachen, Germany; Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Molecular Biology Division, Aachen, Germany.
Rainer
R
Fischer
Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine and Pharmacology, Frankfurt & Aachen, Germany. Electronic address: martina.fenske@ime.fraunhofer.de.
Martina
M
Fenske
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D050091:Dendrimers / Q000737:chemistry / Q000633:toxicity*; D004625:Embryo, Nonmammalian / Q000187:drug effects; D006801:Humans; D011126:Polypropylenes / Q000737:chemistry / Q000633:toxicity*; D015027:Zebrafish
D050091:Dendrimers; C104700:PAMAM Starburst; D011126:Polypropylenes; C443641:poly(propyleneimine)
Dendrimers; Human cell lines; Polyamidoamine (PAMAM); Polypropylenimine (PPI); Toxicity; Zebrafish embryo