Toxicity of dendrimers

Dendrimers such as poly(amidoamine) (PAMAM) and poly(propylenimine) (PPI) have also been studied for gene delivery in vitro and in vivo due to their high transfection efficiency. However, the toxicity of the dendrimers is of major concern for their medical use. Generally, in vivo toxicity of dendrimers is related to various factors, including their chemical structure, surface charge, generation and the dose of dendrimer used. Surface modification with PEG or replacement with low generation dendrimers have been reported to be able to improve the biocompatibility of these biomaterials. ... 

Toxicity analysis of nanosized constructs is critical for any of them to be useful clinically and have the potential to be greatly informed by pharmacokinetic studies. Toxicity of dendrimers have been reviewed recently and it was found that one mechanism of dendrimer toxicity is surface charge amine terminated dendrimers were detrimental to cells, while neutral and negative surface charges were much less toxic, or had no toxicity at all. 

Follow-on functionalisation with molecular moieties of biological importance, such as anti-tumour agents (e.g. 5-fluorouracil) currently appears particularly attractive. In this context, acetylation is particularly suitable as functionalisation reaction for oligo/polyamine dendrimers. It renders the dendrimers more water soluble, which is essential for biomedical applications [25]. The toxicity of den-... 

An important question in cell uptake of DNA is the potential toxicity of the dendrimer nucleotide complexes. In general, the toxicity has been found to be lower for dendrimer-nucleotides than for other transfection systems including polylysine [154-156]. 

Heiden TCK, Dengler E, Kao WJ, et al. Developmental toxicity of low generation PAMAM dendrimers in zebrafish. Toxicol Appl Pharmacol. 2007 225(l) 70-79. 

First investigations with cell cultures showed that certain dendrimers support the transfection of mammalian cells by plasmids. The controlled synthesis, low toxicity, and pH buffering eflect of dendrimers are the main criteria for dendrimers suitable for gene-transfer experiments. [44]... 

In biology, phosphorus-containing dendrimers - a non-toxic class of dendrimers - offer a broad range of possible appHcations from DNA transfection agents to DNA chips or as anti-prions, or anti-HIV species. 

Dendrimer-based drug delivery systems have been successful in both improving bioavailability as well as targeting drugs. The main advantages for the use of dendrimers as drug carriers reside in their multivalent design and their well-defined structure that results from the stepwise, iterative approach used in their preparation. The anionic and neutral dendrimers have been shown to be less toxic than the cationic dendrimers but at the same time they suffer from lower permeability compared to cationic dendrimers. Typically the smaller size of dendrimers... 

S. Sadekar, H. Ghandehari, Transepithelial transport and toxicity of PAMAM dendrimers implications for oral drag delivery, Adv. Drag Deliv. Rev. 64 (6) (2012) 571-588. 

Application of dendrimers as gene therapy vectors requires the presence of positive charges on the dendrimers for a proper interaction with the nucleic acids. As this measurement is important in dendriplex for-mation, previous knowledge of the charge on the dendrimer is of interest, as it can give information on the possible strength of the dendriplex or inform about toxicity, as it increases with positive charge. ... 

The toxicological profiles of dendrimers and dendritic nanoparticles can be also controlled by their size and surface modifications. Importantly, the charge-based non-specific interaction between positively charged dendrimers and cell membranes are typically associated with toxicity.[84,85] As discussed earlier (Section 2.A non-specific cell interaction), the electrostatic interactions of cationic dendrimers with cell membrane induced membrane disruption, which could be a reason for the apparent toxicity observed in animal studies.[86] Surface modification of terminal amine groups to different groups (charge neutral or... 

---