Comparative toxicological assessment of PAMAM and thiophosphoryl dendrimers using embryonic zebrafish

Abstract

Dendrimers are well-defined, polymeric nanomaterials currently being investigated for biomedical applications such as medical imaging, gene therapy, and tissue targeted therapy. Initially, higher generation (size) dendrimers were of interest because of their drug carrying capacity. However, increased generation was associated with increased toxicity. The majority of studies exploring dendrimer toxicity have focused on a small range of materials using cell culture methods, with few studies investigating the toxicity across a wide range of materials in vivo. The objective of the present study was to investigate the role of surface charge and generation in dendrimer toxicity using embryonic zebrafish ( Danio rerio ) as a model vertebrate. Due to the generational and charge effects observed at the cellular level, higher generation cationic dendrimers were hypothesized to be more toxic than lower generation anionic or neutral dendrimers with the same core composition. Polyamidoamine (PAMAM) dendrimers elicited significant morbidity and mortality as generation was decreased. No significant adverse effects were observed from the suite of thiophosphoryl dendrimers studied. Exposure to ≥50 ppm cationic PAMAM dendrimers G3-amine, G4-amine, G5-amine, and G6-amine caused 100% mortality by 24 hours post-fertilization. Cationic PAMAM G6-amine at 250 ppm was found to be statistically more toxic than both neutral PAMAM G6-amidoethanol and anionic PAMAM G6-succinamic acid at the same concentration. The toxicity observed within the suite of varying dendrimers provides evidence that surface charge may be the best indicator of dendrimer toxicity. Dendrimer class and generation are other potential contributors to the toxicity of dendrimers. Further studies are required to better understand the relative role each plays in driving the toxicity of dendrimers. To the best of our knowledge, this is the first in vivo study to address such a broad range of dendrimers.

Evaluation of cationic polyamidoamine dendrimers’ dermal toxicity in the rat skin model

“… 33 Generally, it was shown that the rank order of PAMAM toxicity is hydroxyl-terminated<carboxyl-terminated<amine-terminated dendrimers. 1 , 29 , 34 …”

Cationic nanoparticles directly bind angiotensin-converting enzyme 2 and induce acute lung injury in mice

“…Among these concerns, the potential toxicity of nanoparticles to humans is among the most distressing. Nanomaterials have been reported to be harmful at the cellular, subcellular, and protein levels, and they have been found to elicit injurious responses in various organisms [ 4 - 6 ]. Many of these studies have focused on lung diseases, including clinical studies of workers who developed pulmonary disease from nanoparticle exposure [ 7 - 11 ].…”

“…PAMAM dendrimers are commercially available as either whole (cationic) or half (anionic) generation polymers. The low polydispersity index and the ability to precisely control their surface chemistry make dendrimers useful for biomedicine applications such as drug or gene delivery and diagnostic imaging [ 6 , 14 ]. For example, PAMAM dendrimers can be used to inhibit inflammation [ 16 ], improve therapeutic responses against cancer [ 17 ], and suppress HIV-1 infection [ 18 ].…”

The engineered nanoparticles in food chain: potential toxicity and effects

“…Despite this exposure of embryos to ≥ 50 ppm cationic PAMAM dendrimers G3-amine, G4-amine, G5-amine, and G6-amine caused 100% mortality after 24 h fertilization. Neutral PAMAM G6-aminoethanol and anionic PAMAM G6-succinamic acid at 250 ppm showed less toxic effect than the same concentration of Cationic PAMAM G6-amine [224]. Heiden T.C.…”