Development of the poly(l-histidine) grafted carbon nanotube as a possible smart drug delivery vehicle

Polyhistidine is among the cell-penetrating peptides that in an acidic environment can facilitate membrane transition. Keeping in mind that the pH of the tumor intercellular medium is ∼5.5, in this paper, we examined the functionalization of a convenient drug delivery vehicle with cell-penetrating poly(l-histidine) to provide a smart drug delivery system. Classical molecular dynamics and metadynamics simulations are used to investigate the interactions between doxorubicin, carbon nanotube, poly(l-histidine), and the cell membrane. Metadynamics simulation revealed that not only the global minimum of FES reduced in an acidic environment but also the difference between the free energy of Doxorubicin as being adsorbed on poly(l-histidine) compared to when being freely dissolved in the aqueous medium show a dramatic reduction. MD simulations showed that functionalization of carbon nanotube with poly(l-histidine) groups has no detriment effect in the adsorption of Doxorubicin. The L-J interaction between Doxorubicin and carrier at the equilibrium states reached around -600 kJ/mol, both for the pristine and functionalized carbon nanotube. The coulombic interactions for both complexes were negligible in the neutral environment. At the acidic environment, the L-J interactions retained the same values as the neutral, while the coulombic interactions showed positive values, which suggested its participation in the detachments. At the vicinity of the membrane, the complexes retain their integrity both in neutral and acidic environments. In the present work, we performed metadynamics simulation to investigate the effects of poly(l-histidine) on the adsorption capacity of the carbon nanotubes, and explore the adsorption/desorption processed of Doxorubicin on pristine and poly(l-histidine)-grafted carbon nanotube. The resulted complexes were then subjected to interact with the POPC membrane model in both acidic and neutral environments via molecular dynamic simulations. The results provided here will hopefully help in a better understanding of future drug delivery systems and be helpful in designing more efficient and smart drug delivery systems.