Unveiling the Releasing Processes of Pt(II)-Based Anticancer Drugs from Oxidized Carbon Nanohorn: An In Silico Study

About half of all cancer chemotherapies currently applied involve medication with the three worldwide approved Pt(II)-based drugs, cisplatin (cddp), carboplatin (cpx), and oxaliplatin (oxa), due to their notable antitumor activity for several cancers. However, this wide application is accompanied by severe side effects, such as nephrotoxicity, myelosuppression, and neurotoxicity, as a result of their low bioavailability and selectivity for cancer cells. To mitigate these drawbacks, the use of chemically functionalized carbon nanohorns (CNH) as nanocarriers represents a potential formulation since CNH has been noted for their biodegradability, biocompatibility, low toxicity, and cavities dimensionally compatible with small drugs. This work reports energetic and dynamic analyses of complexes formed by oxidized CNH (CNHox) and the cddp, cpx, and oxa drugs. Using unbiased molecular dynamics (MD) simulations, we show that the encapsulated formulations (cddp@CNHox, cpx@CNHox, and oxa@CNHox) were more stable by ∼11.0 kcal mol^-1 than the adsorbed ones (cddp > CNHox, cpx > CNHox, and oxa > CNHox). This high stability, mainly governed by van der Waals interactions, was responsible for the drug confinement during the entire simulation time (200 ns). The biased MD simulations of the inclusion complexes confirmed the nonspontaneity of the drug release since the potentials of mean force (PMF) indicated the endergonic character of this process. Additionally, the releasing energy profiles pointed out that the free energy barrier (ΔΔG^≠) for the escape from CNHox cavity follows the order oxa > cpx ∼ cddp, with the value for the oxa complex (21-26 kcal mol^-1) found to be about 36 and 30% larger than those for cpx and cddp, respectively. While the approximate residence time (t_res) of the oxa drug inside the CNHox cavity was 5.45 × 10⁸ s, the same measure for the cddp and cpx drugs was 5.3 × 10⁵ and 1.60 × 10³ s. Simulations also revealed that the escape of oxa with the oxalate group facing the nanowindow was the most unfavorable process, giving t_res = 1.09 × 10⁹ s. Besides reinforcing and extending the nanovectorization of cddp, cpx, and oxa in CNHox for cancer chemotherapies, all features considered may provide interpretations for experimental data and encourage new investigations aiming to propose less aggressive treatments for oncological diseases.