Effect of PEGylation on the Structure and Drug Loading Capacity of PAMAM-G4 Dendrimers: A Molecular Modeling Approach on the Complexation of 5-Fluorouracil with Native and PEGylated PAMAM-G4

Abstract

Fully atomistic molecular dynamics (MD) simulations have been performed to examine the effect of PEGylation on the structure and drug loading properties of 25%-100% PEGylated poly(amidoamine) (PAMAM)-G4 dendrimers in complex with 5-fl uorouracil (5-FU) as a model anticancer compound. Theoretical estimates predict a complex stoichiometry of 23:1 for the 5-FU:PAMAM-G4 system in high agreement with isothermal titration calorimetry and nuclear magnetic resonance (NMR) experiments, thus supporting the validity of our computational approach. MD simulations reveal a progressive increase in the total drug loading capacity as the PEGylation degree becomes higher. In systems with PEGylation degrees ≥50%, drug complexation occurs almost exclusively within outermost polyethylene glycol (PEG) chains, due to their higher affi nity toward complexation with 5-FU compared to PAMAM-G4 branches. On the other hand, the 25% PEG-PAMAM-G4 system retains the internal complexation capability of PAMAM-G4 and provides additional assistance for drug retention through the cooperative interaction with back folded PEG chains, appearing as the most suitable option for drug delivery applications.

Methotrexate Complexation with Native and PEGylated PAMAM‐G4: Effect of the PEGylation Degree on the Drug Loading Capacity and Release Kinetics

“…These results suggest that partial PEGylation is the most adequate strategy to maximize the drug loading capacity of PEGylated PAMAM dendrimers as drug carriers of MTX. Similar results have been recently predicted from molecular dynamics simulations for the complexation of other drugs with PEGylated PAMAM‐G4 systems …”

“…Finally, in the 100% PEGylated system a more intense interaction between MTX and PEG chains is observed, together with less intense cross‐peaks corresponding to the interaction between MTX and PAMAM‐G4 branches, which is indicative of a lessened internal complexation capability compared to native PAMAM‐G4. This result can be a consequence of PEG crowding on the dendrimer surface, which might be detrimental for drug diffusion toward the innermost PAMAM‐G4 cavities in the fully PEGylated system, as previously described in the literature from molecular dynamics simulations on PEGylated PAMAM systems …”

“…In regards to this, more quantitative information is required aimed at identifying the optimum PEGylation degree that provides the best drug loading capacity for different drug–dendrimer systems. In a recent report, we addressed this issue by means of molecular dynamics simulations on partially PEGylated PAMAM dendrimers, in which PEGylation degrees <50% were predicted as the best choice to optimize the complexation capability of PEGylated systems . These theoretical predictions are still to be validated by experimental data regarding the association of drug molecules with PEGylated PAMAM dendrimers, together with kinetic data to support the effect of PEGylation on the rate of drug release, which is a critical factor to assess the efficiency of a drug carrier system.…”

Analyzing PEGylation through Molecular Dynamics Simulations

“…Albertazzi and co‐workers, synthesized and performed MD simulations of hybrid dendrimers with PEG 2 and 4‐arm cores and came to the conclusion that dendrimers with more PEG cores have increased delivery capabilities. Barraza and co‐workers, performed fully atomistic MD simulations to have an even better understanding of the complexation phenomena in PEGylated drug‐PAMAM systems using 5‐fluorouracil, following Karatasos work . They came to the conclusion that PEGylation does have an impact in the conformation and complexation of this type of dendrimers and accordingly to experimental observations, the drug loading capacity progressively increases.…”

Dendrimers as Modulators of Brain Cells

“…These terminal groups are then utilized for PEGylation, acetylation, conjugation to carbohydrates, peptides, and other bioactive molecules [ 86 , 87 ]. For instance, PEGylated PAMAM dendrimers have been shown to possess higher drug-loading capacity, enhanced hydrophilicity and biocompatibility, prolonged plasma circulation, improved stability of drug cargos, lowered cytotoxicity and decreased susceptibility to immunogenicity [ 88 , 89 ]. Surface decoration with functional groups allows dendrimers to incorporate drug molecules via covalent interactions, achieving multi-drug delivery and targetability to specific receptors or molecules [ 90 ].…”