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

Luis F. Barraza, Verõnica A. Jiménez, Joel B. Alderete

Research output: Contribution to journalArticlepeer-review

23 Citations (Scopus)

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-fluorouracil (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 affinity 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. MD simulations reveal that partial PEGylation of PAMAM-G4 at 25% retains the complexation capability of PAMAM-G4, while providing additional assistance for drug complexation and drug retention through the interaction between drug molecules and PEG chains.

Original languageEnglish
Pages (from-to)1689-1701
Number of pages13
JournalMacromolecular Chemistry and Physics
Volume216
Issue number16
DOIs
Publication statusPublished - 1 Aug 2015

Keywords

  • 5-fluorouracil
  • dendrimers
  • molecular dynamics
  • PAMAM
  • PEGylation

ASJC Scopus subject areas

  • Condensed Matter Physics
  • Physical and Theoretical Chemistry
  • Polymers and Plastics
  • Organic Chemistry
  • Materials Chemistry

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