title: Cationic PAMAM dendrimers disrupt key platelet functions.
abstract: Poly(amidoamine) (PAMAM) dendrimers have been proposed for a variety of biomedical applications and are increasingly studied as model nanomaterials for such use. The dendritic structure features both modular synthetic control of molecular size and shape and presentation of multiple equivalent terminal groups. These properties make PAMAM dendrimers highly functionalizable, versatile single-molecule nanoparticles with a high degree of consistency and low polydispersity. Recent nanotoxicological studies showed that intravenous administration of amine-terminated PAMAM dendrimers to mice was lethal, causing a disseminated intravascular coagulation-like condition. To elucidate the mechanisms underlying this coagulopathy, in vitro assessments of platelet functions in contact with PAMAM dendrimers were undertaken. This study demonstrates that cationic G7 PAMAM dendrimers activate platelets and dramatically alter their morphology. These changes to platelet morphology and activation state substantially altered platelet function, including increased aggregation and adherence to surfaces. Surprisingly, dendrimer exposure also attenuated platelet-dependent thrombin generation, indicating that not all platelet functions remained intact. These findings provide additional insight into PAMAM dendrimer effects on blood components and underscore the necessity for further research on the effects and mechanisms of PAMAM-specific and general nanoparticle toxicity in blood.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry, Health Sciences, University of Utah , Salt Lake City, Utah 84112-5820, United States.
authors.forename: Clinton F
authors.initials: CF
authors.lastname: Jones
authors.forename: Robert A
authors.initials: RA
authors.lastname: Campbell
authors.forename: Zechariah
authors.initials: Z
authors.lastname: Franks
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Gibson
authors.forename: Giridhar
authors.initials: G
authors.lastname: Thiagarajan
authors.forename: Adriana
authors.initials: A
authors.lastname: Vieira-de-Abreu
authors.forename: Sivaprasad
authors.initials: S
authors.lastname: Sukavaneshvar
authors.forename: S Fazal
authors.initials: SF
authors.lastname: Mohammad
authors.forename: Dean Y
authors.initials: DY
authors.lastname: Li
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Ghandehari
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Weyrich
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Brooks
authors.forename: David W
authors.initials: DW
authors.lastname: Grainger
mesh_terms: D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D050091:Dendrimers / Q000009:adverse effects*; D005434:Flow Cytometry; D006801:Humans; D018613:Microscopy, Confocal; D053758:Nanoparticles / Q000009:adverse effects; D036103:Nanotechnology; D015539:Platelet Activation / Q000187:drug effects; D010979:Platelet Function Tests; D013917:Thrombin / Q000378:metabolism
chemical_list: D050091:Dendrimers; C104700:PAMAM Starburst; D013917:Thrombin