PEGylated PAMAM dendrimers as eptifibatide nanocarriers: An atomistic view from molecular dynamics simulations

Acetylation and PEGylation can decrease cytotoxicity, improve biocompatibility, and reduce the rate of PAMAM dendrimers elimination from systemic circulation. However, there is scarce information on the microstructure and drug loading capacity of PEGylated dendrimers at atomic level. We have performed molecular dynamics simulations in order to explore the association of eptifibatide (EPT) with native acetyl-terminated G4-PAMAM dendrimer and its partially (25, 50, and 75 %) PEGylated analogues. The impact of PEG length was investigated using chains with molecular weight of 500 and 1000 Da. Maximum loading capacity was achieved by G4-16PEG1000 system (1:7) through the encapsulation of 4 EPT in internal cavities and conjugation of 3 EPT on surface. Potential of mean force calculations revealed that G4-48PEG500 tightly holds EPT molecules. In view of loading capacity, preferential binding sites of drug molecules, and release patterns, G4-16PEG1000 can be considered as the most promising carrier for EPT.