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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
Author(s) -
Barraza Luis F.,
Jiménez Verónica A.,
Alderete Joel B.
Publication year - 2015
Publication title -
macromolecular chemistry and physics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.57
H-Index - 112
eISSN - 1521-3935
pISSN - 1022-1352
DOI - 10.1002/macp.201500179
Subject(s) - pegylation , isothermal titration calorimetry , dendrimer , chemistry , polyethylene glycol , peg ratio , drug delivery , molecular dynamics , stoichiometry , drug carrier , polymer chemistry , combinatorial chemistry , organic chemistry , computational chemistry , finance , economics
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.