Design of new drug delivery platform based on surface functionalization of black phosphorus nanosheet with a smart polymer for enhancing the efficiency of doxorubicin in the treatment of cancer

The development of drug delivery systems (DDSs) has raised hopes for targeted cancer therapy. Smart polymers can be conjugated with several nanoparticles and increase their efficiency in biomedical applications. In this work, the classical molecular dynamics and well-tempered metadynamics simulations are performed to study the behavior of black phosphorus (BPH) nanosheet functionalized with polyethylenimine (PEI) in adsorption, diffusion, and release of doxorubicin (DOX) anticancer drug. Adsorption of the drug on PEI-BPH surface is mainly due to the formation of strong pi-pi interaction between the drug and BPH. The drug-binding to the nanosheet is enhanced by the intermolecular hydrogen bond that formed between DOX and PEI. The energy values for the interaction of DOX with BPH and PEI are calculated to be about - 180 and - 50 kJ/mol, respectively. The obtained results indicated that the adsorption of the drug molecules on the nanosheet destroyed the hydration layer around the BPH- PEI surface. The free energy calculation for DDS shows a global minimum in which the distances of DOX from BPH surface and PEI are about 1.0 and 0.5 nm, respectively. Furthermore, the diffusion of DDS into the membrane has a macropinocytosis pathway that is in line with experimental observations. Moreover, it is found that, unlike the isolated DOX, the drug in complex with BPH-PEI can be easily penetrated membrane cells. The study of the pH-responsive release of the drug shows the high solubility of the polymer in the water environment plays the main role in swelling of DDS and the release of the DOX molecules.