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

Abstract

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.

Modeling the Cellular Uptake of Functionalized Carbon Nanohorns Loaded with Cisplatin through a Breast Cancer Cell Membrane

“…The spatial distributions of the cddp clusters as a function of time also show the encapsulation of cddp into the nanocarriers during all simulations (Figure S8). These results are in agreement with our previous observations, , which described the cddp release from a CNHox model as an endothermic process characterized by an average energy barrier of 18.2 ± 2.4 kcal mol –1 . This data might be compared to the experimental release rate for cddp@CNHox, 0.18 h –1 , which gives a free energy barrier of ∼24 kcal mol –1 …”

“…80 Under physiological conditions (310 K, 1 bar, and 150 mM NaCl) without considering a membrane, our estimative points out that the cddp release time from the CNHox is greater than 5.3 × 10 5 s (∼6 days). 80 We speculate that this kinetics of cddp release may be modified in the presence of a membrane. Ultimately, the free cddp molecules in the tumor microenvironment should finally undergo to the cellular uptake process through the membrane, which also involves an energy barrier of about 17 kcal mol −1 .…”

“…The high stability of the inclusion complexes implies that the cddp molecules do not spontaneously release the CNH cavity at physiological conditions. In fact, in our previous paper, we showed that the cddp releasing from the CNHox cavity needs an additional energy of ∼22 kcal mol −1 , 80 which cannot be obtained from the unbiased simulation conditions.…”

Translocation Processes of Pt(II)-Based Drugs through Human Breast Cancer Cell Membrane: In Silico Experiments

“…Regarding the drugs, we used the same parametrization procedure described in our previous work for cddp, cpx, and oxa . In brief, the intramolecular parameters were derived from the optimized structures at the MP2/6-31G­(d,p)/LANL2DZ level of theory. − The polarizable continuum model (PCM) with the integral equation formalism (IEF) variant was employed to consider the aqueous solution in these calculations .…”

Theoretical investigation of triplet potential energy surfaces for (C^C*) cyclometalated platinum(ii) complexes and the corresponding control strategies

“…In the application of anticancer drugs, previous studies report that some derivatives have been conjugated to Pt(II) drugs to elicit promising anticancer effects. [1][2][3][4][5][6] The oxaliplatin scaffold was chosen based on the findings that tetracarboxylato Pt(IV) compounds are generally stable toward reduction. 7,8 This prodrug supposedly exists in its intact Pt(IV) form in the dark but is activated to release oxaliplatin and PPA under the irradiation of red light.…”