No 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.

Native and PEGylated poly-amidoamine-G4 (PAMAM-G4) dendrimers with PEGylation degrees of 0%, 28%, 34%, 67%, and 100% are evaluated as potential drug carriers for methotrexate (MTX). A maximum complex stoichiometry of 47:1 is obtained for the system with 34% of PEGylation, with an estimated binding constant of 1.2 × 10 4 mol −1 per binding site, as derived from aqueous solubility profi les. 2D-NOESY experiments reveal a preferential complexation of MTX within PAMAM-G4 branches, suggesting that high PEGylation ratios restrict drug diffusion toward innermost PAMAM cavities. On the other hand, high PEGylation degrees considerably decrease the rate of MTX release, which can be attributed to a reduced dendrimer swelling due to surface polyethylene glycol crowding. All release profi les follow fi rst-order kinetics, suggesting a diffusion-controlled mechanism for MTX release. These results can be helpful to understand the molecular basis underlying the complexation and release of MTX with PEGylated PAMAM dendrimers aimed at designing more effi cient drug delivery systems.

The complexation of mefenamic acid (MA) with poly(amido amine) dendrimers of the second and third generation (PAMAM‐G2 and PAMAM‐G3) at pH 7.0 is studied by aqueous solubility experiments, DOSY and 2D‐NOESY spectroscopy, and fully atomistic molecular dynamics (MD) simulations. Solubility profiles account for the formation of MA:PAMAM complexes of the type 10:1 and 15:1, for PAMAM‐G2 and PAMAM‐G3, respectively, with a maximum solubilization enhancement of 14.6 mol of MA per mol dendrimer. Diffusion ordered sepectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY) experiments suggest that MA association occurs through both external electrostatic interactions with the PAMAM surface and internal encapsulation into the deep dendrimer cavities. MD simulations are consistent with these experimental findings and show that the internal drug encapsulation is enhanced as the dendrimer generation increases. The involvement of internal and external interactions in the complexation of MA with low‐generation PAMAM dendrimers differs from the general behavior expected for acidic anionic guests, for which external electrostatic contacts with the positively charged PAMAM surface have been postulated as the most relevant factor for drug association.

No abstract

PEGylated PAMAM dendrimers (PEG-PAMAM) have been extensively studied as versatile vehicles for drug delivery. Nevertheless, little information has been reported regarding the effect of the PEGylation degree on the drug-loading properties of these systems, aimed at maximizing their performance as drug carrier nanocarrriers. In this work, fully atomistic molecular dynamics (MD) simulations were employed to examine the association of methotrexate (MTX) with native and diversely PEGylated PAMAM-G4 dendrimers, using 2 kDa PEG chains with substitution degrees from 25 to 100% and 100:1 drug:dendrimer ratios to mimic experimental conditions of drug excess in saturated solution. MD results regarding complex stoichiometries and preferential binding sites were compared to experimental data retrieved from aqueous solubility profiles and 2D-NOESY experiments showing an outstanding level of agreement. The maximum theoretical drug loading capacity was achieved by the system with 34% PEGylation (42:1) through the simultaneous complexation of MTX within internal PAMAM-G4 branches and external PEG chains. On the other hand, higher PEGylation degrees were found to be detrimental for drug complexation due to PEG chains crowding on the dendrimer surface. These results provide valuable information to design more efficient PAMAM-based drug nanocarriers and explain the positive effect that partial PEGylation exerts on the drug-loading capacity of PAMAM-G4 over native and fully PEGylated systems.

No abstract

No abstract