Molecular dynamics simulations of PPI dendrimer–drug complexes

Abstract

Dendrimeric nanoparticles are potential drug delivery devices which can enhance the solubility of hydrophobic drugs, thus increasing their bioavailability and sustained release action. A quantitative understanding of the dendrimer-drug interactions can give valuable insight into the solubility and release profile of hydrophobic drug molecules in various solvent conditions. Fully atomistic molecular dynamics (MD) simulations have been performed to study the interactions of G5 PPI EDA (G5 ethylenediamine cored poly(propylene imine)) dendrimer and two well known drugs (Famotidine and Indomethacin) at different pH conditions. The study suggested that at low pH the dendrimer-drug complexes are thermodynamically unstable as compared to neutral and high pH conditions. Calculated Potential of Mean Force (PMF) by umbrella sampling showed that the release of drugs from the dendrimer at low pH is spontaneous, median release at neutral pH and slow release at high pH. In addition, Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) binding free energy calculations were also performed at each umbrella sampling window to identify the various energy contributions. To understand the effect of dendrimer chemistry and topology on the solubility and release profile of drugs, this study is extended to explore the solubility and release profile of phenylbutazone drug complexed with G3 poly(amidoamine) and G4 diaminobutane cored PPI dendrimers. The results indicate that the pH-induced conformational changes in dendrimer, ionization states, dendrimer type and pK a of the guest molecules influence the free energy barrier and stability of complexation, and thus regulate drug loading, solubility and release.

Association of the anti-tuberculosis drug rifampicin with a PAMAM dendrimer

“…This is in line with previous studies that support that, at low pH, there is a triggered simultaneous release in contrast to a medially sustained release observed at neutral pH. [73,[100][101][102] A c c e p t e d M a n u s c r i p t…”

“…Therefore, at neutral pH, the simulation suggests a reasonably stable complex, which is consistent with the observed medially sustained release profile. [73] Considering the simulation at low pH, RIF 20 PAMAM L (bottom panel), one can observe a completely different picture. The distances (19 out of 20) rise rapidly and almost simultaneously to values above 4 nm, indicating that the RIF molecules are rapidly expelled from the dendrimer cavities as the simulation proceeds.…”

“…At low pH, the RIF molecules were rapidly and simultaneously expelled to the solvent bulk, agreeing with the observed triggered simultaneous release. [73] This pH switch is desirable in terms of the application of dendrimers as drug delivery systems towards acidic cellular structures such as the macrophage. One should keep in mind that this pH based vectorization may impose administration restrictions as for example in the case of oral administration due to the low pH of the stomach.…”

“…[55,[58][59][60][61][62][63][64][65][66][67] Molecular dynamics (MD) simulation, which is a powerful tool for investigating properties of molecular systems relevant in physics, chemistry and biology [68][69][70][71], has been the major technique used in this respect. In terms of the drug-dendrimer association phenomena, MD simulations have been used to study the association of ibuprofen with G3-PAMAM, [55] nicotinic acid with G3-PAMAM, [57] four drug molecules (salicylic acid, L-alanine, primidone and phenylbutazone) with G5-PAMAM, [72] three drug molecules (famotidine, indomethacin and phenylbutazone) with poly(propylene imine) (PPI) dendrimers [73] and piroxicam with G3-PAMAM. [74] The main goal of the present work is to study the stability of the RIF-PAMAM complexes under different pH conditions using MD simulations in order to evaluate the suitability of PAMAM as a pH-based DDS for RIF molecules.…”

Association of small aromatic molecules with PAMAM dendrimers

“…23,24 Goddard and co-workers have extensively investigated the properties of G0-G10 PAMAM dendrimers in vacuum 25 and G4-G6 PAMAM dendrimers in the presence of explicit water solvent using MD simulations. 29 From a comparison of the encapsulation ability of G4 PPI and G3 PAMAM dendrimers, the authors inferred that non-polar interactions with dendrimer pockets was a primary mechanism of encapsulation. 11 Their results emphasized the importance of hydrogen bonding and ionic interactions for ibuprofen-dendrimer complexes.…”