Stealth dendrimers for drug delivery: correlation between PEGylation, cytocompatibility, and drug payload

It is advantageous to utilize low generation polyamidoamine (PAMAM) dendrimers for drug delivery because low generations (generation 4.0 or below) have more biologically favorable properties as compared to high generations. Nevertheless, modification of low generation dendrimers with PEG to create stealth dendrimers is still necessary to avoid potential side effects by long term accumulation. However, low generation dendrimers have much fewer surface sites for drug loading as compared to higher generations. To efficiently utilize low generation dendrimer-based stealth dendrimers for drug loading, PEGylation needs to be optimized. In this study, we synthesized a series of stealth dendrimers based on low generation Starburst (TM) PAMAM dendrimers (i.e., G2.5, G3.0, G3.5, and G4.0) and quantitatively assessed PEGylation efficacy in modulating cytocompatibility of low generation PAMAM dendrimers. Cytocompatibility of stealth dendrimers was examined using endothelial cells. The results showed that PEGylation degree on low generation dendrimers could be dramatically reduced to leave as many unoccupied surface groups as possible for drug loading, while maintaining the drug carrier cytocompatibility. 3PEGs-G3.0 and 10PEGs-G4.0 were considered initially optimized stealth dendrimers that would be further modified to deliver drugs of interest. Correlation of PEGylation, cytocompatibility, and drug payload allowed us to optimize low generation dendrimer-based stealth dendrimers for drug delivery and advance the understanding of structure-property relationship of stealth dendrimers.