Pegylated and folic acid functionalized carbon nanotubes as pH controlled carriers of doxorubicin. Molecular dynamics analysis of the stability and drug release mechanism.

This work deals with an analysis of the covalent functionalization of a carbon nanotube using polyethylene glycol chains terminated by folic acid fragments. The analysis is focused on theoretical predictions, using molecular dynamics simulations, of the properties of such constructs as pH controlled carriers of the anticancer drug doxorubicin. The analyzed systems are expected to hold the doxorubicin in the inner cavity of the carbon nanotube at neutral pH and unload the drug at slightly acidic pH. This property comes from incorporation into the nanotube of some dye molecules (p-phenylenediamine or neutral red) which undergo protonation at slightly acidic pH. We found that both dyes lead to the formation of a stable, co-absorbed phase of a doxorubicin-dye mixture inside the nanotube at physiological pH. At acidic pH we observed a spontaneous release of dyes from the nanotube, leading finally to the state with only doxorubicin encapsulated in the nanotube interior. Thus, the analyzed constructs can be considered as carriers of doxorubicin that are selective to tumor microenvironments (which exhibit reduced pH due to hypoxia and overexpression of folate receptors). However, we also found that the release of doxorubicin from the nanotube at acidic pH is kinetically blocked, at least in the case of the system sizes studied here. Thus, we also discussed some possible ways of reducing the activation barriers against doxorubicin release at acidic pH.