The cisplatin encapsulation into carbon nanohorns (CNH) is a promising nanoformulation to circumvent the drug dissipation and to specifically accumulate it in tumor sites. Herein, biased molecular dynamics simulations were used to analyze the transmembrane transport of the CNH loaded with cisplatin through a breast cancer cell membrane prototype. The simulations revealed a four-stage mechanism: approach, insertion, permeation, and internalization. Despite the lowest structural disturbance of the membrane provided by the nanocarrier, the average free energy barrier for the translocation was 55.2 kcal mol-1, suggesting that the passive process is kinetically unfavorable. In contrast, the free energy profiles revealed potential wells of -6.8 kcal mol-1 along the insertion stage in the polar heads region of the membrane, which might enhance the retention of the drug in tumor sites; therefore, the most likely cisplatin delivery mechanism should involve the adsorption and retention of CNH on the surface of cancer cells, allowing the loaded cisplatin be slowly released and passively transported through the cell membrane.
Keywords: carbon nanohorn; cell membrane; cisplatin; molecular dynamics; permeation; potential of mean force; umbrella sampling.