Poly(ami
doamine) (PAMAM)
den
drimers are increasingly stu
die
d as mo
del nanoparticles for a variety of biome
dical applications, notably in systemic a
dministrations. However, with respect to bloo
d-contacting applications, amine-terminate
d den
drimers have recently been shown to activate platelets an
d cause a fatal,
disseminate
d intravascular coagulation (DIC)-like con
dition in mice an
d rats. We here
demonstrate that, upon a
ddition to bloo
d, cationic G7 PAMAM
den
drimers in
duce fibrinogen aggregation, which may contribute to the
in vivo DIC-like phenomenon. We
demonstrate that amine-terminate
d den
drimers act
directly on fibrinogen in a thrombin-in
depen
dent manner to generate
dense, high-molecular-weight fibrinogen aggregates with minimal fibrin fibril formation. In a
ddition, we hypothesize this clot-like behavior is likely me
diate
d by electrostatic interactions between the
densely charge
d cationic
den
drimer surface an
d negatively charge
d fibrinogen
domains. Interestingly, cationic
den
drimers also in
duce
d aggregation of albumin, suggesting that many negatively charge
d bloo
d proteins may be affecte
d by cationic
den
drimers. To investigate this further, zebrafish embryos were employe
d to more specifically
determine the spee
d of this phenomenon an
d the pathway- an
d dose-
depen
dency of the resulting vascular occlusion phenotype. These novel fin
dings show that G7 PAMAM
den
drimers significantly an
d a
dversely impact many bloo
d components to pro
duce rapi
d coagulation an
d strongly suggest that these effects are in
depen
dent of classic coagulation mechanisms. These results also strongly suggest the nee
d to fully characterize amine-terminate
d PAMAM
den
drimers in regar
d to their a
dverse effects on both coagulation an
d platelets, which may contribute to bloo
d toxicity.
Keywords:
d="authors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=nanotoxicity&qsSearchArea=searchText">nanotoxicity; d="authors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=fibrinogen&qsSearchArea=searchText">fibrinogen; d="authors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=protein+aggregation&qsSearchArea=searchText">protein aggregation; d="authors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=blood+compatibility&qsSearchArea=searchText">blood compatibility; d="authors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=coagulation&qsSearchArea=searchText">coagulation; d="authors" href="http://pubs.acs.org/action/doSearch?action=search&searchText=surface+charge&qsSearchArea=searchText">surface charge