In vivo toxicity of poly(propyleneimine) dendrimers

Abstract

Dendrimers are highly branched macromolecules with the potential to be used for biomedical applications. Several dendrimers are toxic owing to their positively charged surfaces. However, this toxicity can be reduced by coating these peripheral cationic groups with carbohydrate residues. In this study, the toxicity of three types of 4th generation poly (propyleneimine) dendrimers were investigated in vivo; uncoated (PPI-g4) dendrimers, and dendrimers in which 25% or 100% of surface amino groups were coated with maltotriose (PPI-g4-25%m or PPI-g4-100%m), were administered to Wistar rats. Body weight, food and water consumption, and urine excretion were monitored daily. Blood was collected to investigate biochemical and hematological parameters, and the general condition and behavior of the animals were analyzed. Unmodified PPI dendrimers caused changes in the behavior of rats, a decrease in food and water consumption, and lower body weight gain. In the case of PPI-g4 and PPI-g4-25%m dendrimers, disturbances in urine and hematological and biochemical profiles returned to normal during the recovery period. PPI-g4-100%m was harmless to rats. The PPI dendrimers demonstrated dose- and sugar-modification-degree dependent toxicity. A higher dose of uncoated PPI dendrimers caused toxicity, but surface modification almost completely abolished this toxic effect.

Interaction study between maltose-modified PPI dendrimers and lipidic model membranes

“…However, many reports are available describing the relationship between the number of positive groups and toxic properties of these molecules. Apparently, increasing the number of positively charged groups on dendrimers increases their toxicity [8,9,18,19].…”

“…Positively charged dendrimers are highly toxic to the cells as a result of increasing permeability and destroy the integrity of the cell membrane [8,9,18]. The destabilization of the lipidic part of biological membranes has been investigated in several models of liposomes.…”

“…The results also indicate that the PPI dendrimers' toxicity is associated with the interaction with components of biological membranes such as proteins or negatively charged lipids. It is therefore not surprising that surface group modifications, especially the sugar decoration of PPI dendrimers, have been made to decrease the toxicity of cationic PPI dendrimers [8][9][10]18,19].…”

“…As mentioned before, an ideal dendritic candidate for a DDS is preferentially non-toxic. Thus, much effort has been invested to achieve new properties of cationic polyamine dendrimers through various surface modifications [5,[7][8][9].…”

Fungal diseases: could nanostructured drug delivery systems be a novel paradigm for therapy?

“…Their properties are often not satisfactory because of the high cytotoxicity of the nanomolecules and their low solubility and biocompatibility. Thus, dendrimers are often subjected to various modifications in order to improve their features: dendrimer conjugate with PEG, 200 carbohydrates, 201 or acetyl groups 202 to reduce the cytotoxicity. The compounds bound to dendrimers can improve the surface activity as well as their biological and physical properties.…”