Developmental toxicity of low generation PAMAM dendrimers in zebrafish.
Biological molecules and intracellular structures operate at the nanoscale; therefore, development of nanomedicines shows great promise for the treatment of disease by using targeted drug delivery and gene therapies. PAMAM dendrimers, which are highly branched polymers with low polydispersity and high functionality, provide an ideal architecture for construction of effective drug carriers, gene transfer devices and imaging of biological systems. For example, dendrimers bioconjugated with selective ligands such as Arg-Gly-Asp (RGD) would theoretically target cells that contain integrin receptors and show potential for use as drug delivery devices. While RGD-conjugated dendrimers are generally considered not to be cytotoxic, there currently exists little information on the risks that such materials pose to human health. In an effort to compliment and extend the knowledge gleaned from cell culture assays, we have used the zebrafish embryo as a rapid, medium throughput, cost-effective whole-animal model to provide a more comprehensive and predictive developmental toxicity screen for nanomaterials such as PAMAM dendrimers. Using the zebrafish embryo, we have assessed the developmental toxicity of low generation (G3.5 and G4) PAMAM dendrimers, as well as RGD-conjugated forms for comparison. Our results demonstrate that G4 dendrimers, which have amino functional groups, are toxic and attenuate growth and development of zebrafish embryos at sublethal concentrations; however, G3.5 dendrimers, with carboxylic acid terminal functional groups, are not toxic to zebrafish embryos. Furthermore, RGD-conjugated G4 dendrimers are less potent in causing embryo toxicity than G4 dendrimers. RGD-conjugated G3.5 dendrimers do not elicit toxicity at the highest concentrations tested and warrant further study for use as a drug delivery device.
Heiden
Tisha C King
TC
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin, Madison, WI 53705-2222, USA.
Dengler
Emelyne
E
Kao
Weiyuan John
WJ
Heideman
Warren
W
Peterson
Richard E
RE
D000818:Animals; D050091:Dendrimers; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D016503:Drug Delivery Systems; D047108:Embryonic Development / Q000187:drug effects*; D016023:Integrins / Q000378:metabolism; D008024:Ligands; D023421:Models, Animal; D009842:Oligopeptides / Q000008:administration & dosage / Q000633:toxicity; D011073:Polyamines / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D013329:Structure-Activity Relationship; D013997:Time Factors; D018675:Toxicity Tests; D015027:Zebrafish
D050091:Dendrimers; D004337:Drug Carriers; D016023:Integrins; D008024:Ligands; D009842:Oligopeptides; C104700:PAMAM Starburst; D011073:Polyamines; C047981:arginyl-glycyl-aspartic acid