11вЂ“ 14 Although the mechanism explaining generational effects is still unclear, higher generation dendrimers have been observed to cause nanoscale holes in the lipid bilayer, resulting in more toxicity while other authors have found that increasing generation attenuates toxicity 13вЂ“ 15 especially for very high generation dendrimers, perhaps due to conformational changes. Note: Dendrimers consist of core, interior branching, and terminal functional groups.Дespite the myriad of potential biomedical applications of dendrimers, previous research exploring the toxicity and biocompatibility of dendritic therapeutics suggests some dendrimers may display inherent toxicity attributed to a combination of generation and charge. 8вЂ“ 10 The stability, precise size, and defined chemistry of dendrimers also make them ideal for the development of structure-property relationships.ДЇigure 1 Generation (G) 3 dendrimer architecture. 4вЂ“ 7 The low polydispersity index and the ability to precisely control their surface chemistry make dendrimers useful for medical imaging, enhancing the solubility and/or bioavailability of drugs, brain-target drug therapy, and specific targeting mechanism for anti-cancer therapeutics and gene therapy. 2, 3 Subsequent generations increase in diameter, the number of terminal functional groups, and the number of vacancies available to carry therapeutics. 1 Dendrimers have a well-defined branching architecture consisting of an initiator core, a radiating interior structural layer composed of repeating generations (G0-G10), and terminal functional groups attached to the outermost generation ( Figure 1). The use of polymeric nanomaterials such as dendrimers in the development and delivery of therapeutic compounds has emerged as a promising field of biomedical engineering. Keywords: nanomaterials, in vivo, toxicity, generation, surface chemistry, zebrafish To the best of our knowledge, this is the first in vivo study to address such a broad range of dendrimers. Further studies are required to better understand the relative role each plays in driving the toxicity of dendrimers. Dendrimer class and generation are other potential contributors to the toxicity of dendrimers. The toxicity observed within the suite of varying dendrimers provides evidence that surface charge may be the best indicator of dendrimer toxicity. 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. Exposure to в‰Ґ50 ppm cationic PAMAM dendrimers G3-amine, G4-amine, G5-amine, and G6-amine caused 100% mortality by 24 hours post-fertilization. No significant adverse effects were observed from the suite of thiophosphoryl dendrimers studied. Polyamidoamine (PAMAM) dendrimers elicited significant morbidity and mortality as generation was decreased. 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. 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. 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. However, increased generation was associated with increased toxicity. Initially, higher generation (size) dendrimers were of interest because of their drug carrying capacity.

Joseph B Pryor, 1 Bryan J Harper, 1 Stacey L Harper 1,2ДЎDepartment of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR, USA 2School of Chemical, Biological, and Environmental Engineering, Oregon State University, Corvallis, OR, USAДЄbstract: Dendrimers are well-defined, polymeric nanomaterials currently being investigated for biomedical applications such as medical imaging, gene therapy, and tissue targeted therapy.

Sigmaplot 11 add new axis