Poly(amidoamine) (PAMAM) Dendrimers
Poly(amidoamine) (PAMAM) dendrimers are nano-sized hyperbranched cationic polymers reported for a variety of biomedical applications and increasingly studied as model nanomaterials for use in imaging, drug delivery and antimicrobials.  The dense cationic 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 in vivo nanotoxicity studies showed that intravenous administration of amine-terminated high-generation PAMAM dendrimers to mice was rapidly lethal, causing a disseminated intravascular coagulation-like condition.  In vitro assessments of platelet functions in contact with PAMAM dendrimers were undertaken to elucidate the mechanisms underlying this coagulopathy.  We demonstrate that cationic high-generation G7 PAMAM dendrimers dramatically activate platelets and alter their morphology, substantially changing platelet function, including increased aggregation and surface adherence.  Surprisingly, dendrimer exposure also attenuates platelet-dependent thrombin generation, indicating that not all platelet functions remained intact.  Dendrimer effects on the platelet prothrombinase complex indicate that thrombin activation and fibrinogen cleavage are abnormally perturbed by cationic dendrimers.  These findings provide new insights into PAMAM dendrimer adverse effects on blood coagulation and underscore the necessity for further research on the effects and mechanisms of PAMAM-specific and general nanoparticle toxicity in blood.  In vitro toxicity assays for nanoparticles using new kidney organoid cultures can provide some information on their cellular and tissue interactions, but come with particle-specific limitations.

Bio
David Grainger is a University Distinguished Professor, and George S. and Dolores Doré Eccles Presidential Endowed Chair in Pharmaceutics and Pharmaceutical Chemistry, and Professor of Bioengineering at the University of Utah.  The Grainger Group at the University of Utah currently pursues research in areas of surface analytical chemistry, polymer chemistry, drug delivery, diagnostics, and biomaterials. An interdisciplinary approach comprising elements of materials chemistry, surface and bio-analysis, molecular and cell biology, protein physical chemistry and pharmaceutics is typical. The research experience is rich and diverse with exposure to numerous aspects of chemistry in biology and medicine.