Cationic PAMAM dendrimers aggressively initiate blood clot formation.
Poly(amidoamine) (PAMAM) dendrimers are increasingly studied as model nanoparticles for a variety of biomedical applications, notably in systemic administrations. However, with respect to blood-contacting applications, amine-terminated dendrimers have recently been shown to activate platelets and cause a fatal, disseminated intravascular coagulation (DIC)-like condition in mice and rats. We here demonstrate that, upon addition to blood, cationic G7 PAMAM dendrimers induce fibrinogen aggregation, which may contribute to the in vivo DIC-like phenomenon. We demonstrate that amine-terminated dendrimers act directly on fibrinogen in a thrombin-independent manner to generate dense, high-molecular-weight fibrinogen aggregates with minimal fibrin fibril formation. In addition, we hypothesize this clot-like behavior is likely mediated by electrostatic interactions between the densely charged cationic dendrimer surface and negatively charged fibrinogen domains. Interestingly, cationic dendrimers also induced aggregation of albumin, suggesting that many negatively charged blood proteins may be affected by cationic dendrimers. To investigate this further, zebrafish embryos were employed to more specifically determine the speed of this phenomenon and the pathway- and dose-dependency of the resulting vascular occlusion phenotype. These novel findings show that G7 PAMAM dendrimers significantly and adversely impact many blood components to produce rapid coagulation and strongly suggest that these effects are independent of classic coagulation mechanisms. These results also strongly suggest the need to fully characterize amine-terminated PAMAM dendrimers in regard to their adverse effects on both coagulation and platelets, which may contribute to blood toxicity.
Department of Pharmaceutics and Pharmaceutical Chemistry, Health Sciences, University of Utah, Salt Lake City, Utah 84112, United States.
Clinton F
CF
Jones
Robert A
RA
Campbell
Amanda E
AE
Brooks
Shoeleh
S
Assemi
Soheyl
S
Tadjiki
Giridhar
G
Thiagarajan
Cheyanne
C
Mulcock
Andrew S
AS
Weyrich
Benjamin D
BD
Brooks
Hamidreza
H
Ghandehari
David W
DW
Grainger
D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology*; D002412:Cations; D050091:Dendrimers / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology*
D002412:Cations; D050091:Dendrimers; C104700:PAMAM Starburst