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.
