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

Resultado de la investigación: Article

12 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Páginas (desde-hasta)1689-1701
Número de páginas13
PublicaciónMacromolecular Chemistry and Physics
Volumen216
N.º16
DOI
EstadoPublished - 1 ago 2015

Huella dactilar

Dendrimers
Molecular modeling
dendrimers
Complexation
Fluorouracil
drugs
Polyethylene glycols
Molecular dynamics
Pharmaceutical Preparations
glycols
polyethylenes
Computer simulation
Drug interactions
molecular dynamics
Calorimetry
Titration
Drug delivery
Stoichiometry
Nuclear magnetic resonance
PAMAM-G4

ASJC Scopus subject areas

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

Citar esto

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title = "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-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.",
keywords = "5-fluorouracil, dendrimers, molecular dynamics, PAMAM, PEGylation",
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T1 - Effect of PEGylation on the Structure and Drug Loading Capacity of PAMAM-G4 Dendrimers

T2 - A Molecular Modeling Approach on the Complexation of 5-Fluorouracil with Native and PEGylated PAMAM-G4

AU - Barraza, Luis F.

AU - Jiménez, Verõnica A.

AU - Alderete, Joel B.

PY - 2015/8/1

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N2 - 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.

AB - 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.

KW - 5-fluorouracil

KW - dendrimers

KW - molecular dynamics

KW - PAMAM

KW - PEGylation

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