PAMAM Dendrimer–Drug Interactions: Effect of pH on the Binding and Release Pattern

Abstract

Understanding the dendrimer-drug interaction is of great importance to design and optimize the dendrimer-based drug delivery system. Using atomistic molecular dynamics (MD) simulations, we have analyzed the release pattern of four ligands (two soluble drugs, namely, salicylic acid (Sal), L-alanine (Ala), and two insoluble drugs, namely, phenylbutazone (Pbz) and primidone (Prim)), which were initially encapsulated inside the ethylenediamine (EDA) cored polyamidoamine (PAMAM) dendrimer using the docking method. We have computed the potential of mean force (PMF) variation with generation 5 (G5)-PAMAM dendrimer complexed with drug molecules using umbrella sampling. From our calculated PMF values, we observe that soluble drugs (Sal and Ala) have lower energy barriers than insoluble drugs (Pbz and Prim). The order of ease of release pattern for these drugs from G5 protonated PAMAM dendrimer was found to be Ala > Sal > Prim > Pbz. In the case of insoluble drugs (Prim and Pbz), because of larger size, we observe much nonpolar contribution, and thus, their larger energy barriers can be reasoned to van der Waals contribution. From the hydrogen bonding analysis of the four PAMAM-drug complexes under study, we found intermolecular hydrogen bonding to show less significant contribution to the free energy barrier. Another interesting feature appears while calculating the PMF profile of G5NP (nonprotonated)-PAMAM-Pbz and G5NP (nonprotonated)-PAMAM-Sal complex. The PMF was found to be less when the drug is bound to nonprotonated dendrimer compared to the protonated dendrimer. Our results suggest that encapsulation of the drug molecule into the host PAMAM dendrimer should be carried out at higher pH values (near pH 10). When such complex enters the human body, the pH is around 7.4 and at that physiological pH, the dendrimer holds the drug tightly. Hence the release of drug can occur at a controlled rate into the bloodstream. Thus, our findings provide a microscopic picture of the encapsulation and controlled release of drugs in the case of dendrimer-based host-guest systems.

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

“…[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.…”

Advanced nanocarriers for an antitumor peptide

“…According to the recent literature, the binding mode of a bioactive compound to the dendrimer was found to be dependent not only on dendrimer's physicochemical characteristics (i.e. size, pKa, nature of functional groups) and structure of the biomolecules, but also on dendrimer generation, core structure and surface charge of dendrimer (D' Emanuele and Attwood, 2005;Gupta et al, 2006;Maingi et al, 2012). For the last reason, we chose ζ-potential in order to extract information on the complexation process of these biomaterials.…”

Rational design of novel, fluorescent, tagged glutamic acid dendrimers with different terminal groups and in silico analysis of their properties

“…By using various monomers to build different topological architectures, it is possible to design their size, their shape, the surface groups available for interaction and overall physicochemical properties. [2][3][4] Similar to other drug delivery systems, one of the key requirements is to have an adequate safety profile. 5 In this regard, peptide dendrimers consisting of natural amino acids are attractive candidates for use in biological systems due to their potential biodegradability and biocompatibility.…”

“…The system was then cooled down in a similar way to 310 K. This also allowed rectifying steric clashes due to inappropriate contacts of water with the dendrimer. 2 …”