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

Abstract

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 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.

Function of mesenchymal stem cells following loading of gold nanotracers

“…However, MSC nanoparticle loading was not expected for cells incubated with PEGylated nanoparticles because of the well documented evidence for polyethylene glycol as a s tealthing agent. 23,24 Due to the fact that the nanoparticle formulations used in this study did not incorporate targeting agents (eg, targeting antibodies), nanoparticle uptake by cells was passive, and thus MSCs were unable to detect and passively uptake PEGylated nanoparticles.…”

The Effect of Generation 2 and 3 Poly(amidoamine) Dendrimers on Viability of Human Breast Cancer Cells

“…26) Yang et al have also showed that the cytotoxicity of PAMAM dendrimers was significantly reduced through PEGylation. 27) Both 3PEGs-G3.0 (PEGylation degree 9%) and 8PEGs-G3.0 (PEGylation degree 25%) gained significantly improved cytocompatibility as compared to unmodified dendrimers. 27) This can be explained by reduction of the overall positive charge when transforming the basic primary surface amino groups to noncharged amides as well as encapsulating the dendrimer cationic interior tertiary amines.…”

“…27) Both 3PEGs-G3.0 (PEGylation degree 9%) and 8PEGs-G3.0 (PEGylation degree 25%) gained significantly improved cytocompatibility as compared to unmodified dendrimers. 27) This can be explained by reduction of the overall positive charge when transforming the basic primary surface amino groups to noncharged amides as well as encapsulating the dendrimer cationic interior tertiary amines. 26) Our experiments made with annexin V-FITC and detection of apoptosis by a fluorescent microscopy assay revealed that G2 and G3 PAMAM-NH 2 dendrimers inhibited the proliferation of MCF-7 and MDA MB-231 malignant cells by increasing the number of apoptotic and necrotic cells.…”

Low generation polyamine dendrimers bearing flexible tetraethylene glycol as nanocarriers for plasmids and siRNA

“…22 Moreover, PEGylated biomacromolecules are approved by the FDA and attachment of PEG to dendrimers provides several other pharmacological advantages, such as increased blood circulation time, lower/nonimmunogenicity, and improved bio-distribution. [23][24][25][26] Furthermore, the inclusion of PEG chains in the backbone of dendrimers also enhances water solubility, which in turn improves bioavailability and pharmacokinetic profiles. During the past decade, significant progress has been made in the field of dendrimer syntheses, indicating that many of the drawbacks, such as high cost, multi-step synthesis, low reproducibility and complex purification procedures, can be partly resolved.…”