Effect of the lipid composition and cholesterol on the membrane selectivity of low generations PAMAM dendrimers: A molecular dynamics simulation study

Highlights: • Cholesterol reduced the number of water molecules in the hydration shell of the bilayers. • PAMAM pushed back from the DPPC bilayers; while strongly interacted with DPPC + DPPG. • PAMAM handled the distribution of negatively charged lipids across the membranes. • The presence of cholesterol supported the disruption of the membranes by PAMAM. • The negatively charged lipids may be essential for antitumor activity of PAMAM. Among different nanomaterials, dendrimers stand out because of their inherent broad range of activity against viruses, bacteria, and cancer cells. Herein, a total of 15 molecular systems have been simulated to characterize the structural features and geometry of low generation polyamidoamine (PAMAM) dendrimers (G0-G2) after they attached to various membranes (1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC)/1,2-dipalmitoyl-sn-glycero-3-phosphorylglycerol (DPPG) with a different ratio of cholesterol (CHL) to explain their membrane activity in cancer cells. The results indicated that the local membrane order parameters were increased in membranes containing 20 and 40 mol% cholesterol molecules. Furthermore, the PAMAM dendrimers were able to make a substantial number of holes in the membranes containing cholesterol. The results also showed that hydrogen bonds, and electrostatic interactions, govern the interactions between the PAMAM dendrimers and the membranes. Neutral bilayers could drive back the PAMAM dendrimers from the bilayer surface, whereas phosphatidylcholine (PC) bilayers mixed with phosphatidylglycerol (PG) phospholipids (as mimics of negatively charged cancer cell membranes) bond firmly to the hyperbranched polymers. Moreover, the negatively charged phospholipids crowded in regions where dendrimers interacted with membranes. This investigation provided an explanation and mechanistic insight for the activity of PAMAM dendrimers against the negatively charged cancer cells.