Molecular modeling of drug delivery systems based on carbon nanostructures: structure, function, and potential applications for anticancer complexes of Pt(II)

Abstract

The medication with Pt(II) drugs (cisplatin, carboplatin, and oxaliplatin) has been an effective alternative for treating cancers due to their notable inhibition of cancer cells growth and the prevention of metastasis. Nevertheless, the low selectivity of these metallodrugs for malignant cells produces severe side effects, which limit this chemotherapy. In this context, carbon nanohorns (CNHs) have been considered potential nanovectors for drugs, since they present low toxicity, drug-loading capacity, biodegradation routes, and biocompatibility when oxidized. However, there is still a lack of studies regarding the molecular behavior of these nanocarriers on cell membranes. The present work aims to characterize the interactions between inclusion complexes drug@CNH, which are formed by platinum drugs encapsulated in CNHs, and plasma membranes by using molecular dynamics simulations. The results demonstrated that the van der Waals contribution played a primary role (∼74%) for the complex stability, which explain the confined dynamics of drugs inside the CNHs. The free energy profiles revealed an endergonic character of the drug release processes from CNHs, in which the energy barrier for oxaliplatin release (~24 kcal mol–1 ) was ~30% larger than those for carboplatin and cisplatin (~18 kcal mol-1 ). The simulations also showed four stages of the interaction mechanism CNH--membrane: approach, insertion, permeation, and internalization. Despite the low structural disturbance of the membranes, the free energy barrier of ∼55 kcal mol-1 for the CNHs translocation indicated that this transport is kinetically unfavorable by passive process. The in silico experiments evidenced that the most likely mechanism of cisplatin delivery from CNHs involve the approach and insertion stages, where the nanovector adheres on the surface of cancer cells, as reported in in vitro studies. After this retention, the drug load may be slowly released in the tumor site. Finally, simulations of the cellular uptake of Pt(II) drugs also pointed out significant energy barriers (~30 kcal mol-1 ) for this process, which reflects their low permeability in membranes as discussed in experimental studies. In addition to reinforcing the potential of CNH as nanovector of Pt(II) drugs, the results presented in this thesis may assist and drive new experimental studies with CNHs, focusing on the development of less aggressive formulations for cancer treatments.