RESUMO

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.

Assuntos

RESUMO

Breast cancer is one of the most frequent modalities of cancer worldwide, with notable mortality. The medication based on platinum drugs (cisplatin (cddp), carboplatin (cpx), and oxaliplatin (oxa)) is a conventional chemotherapy despite severe side effects and the development of drug resistance. In order to provide a deeper molecular description of the influx and efflux processes of platinum drugs through breast cancer tissues, this study focuses on molecular dynamics (MD) simulations of the passive translocation process through a realistic plasma membrane prototype of human breast cancer cell (c_memb). The results showed that the permeation events were mainly mediated by neutral lipids (DOPC, DOPE, and cholesterol), producing a low and temporary membrane deformation. The drug insertion in the region of polar heads was the most favorable stage of the translocation mechanism, especially for cddp and oxa with potential wells of -8.6 and -9.8 kcal mol-1, respectively. However, the potentials of mean force (PMF) revealed unfavorable kinetics for the permeation of these drugs through lipid tails, with energy barriers of 28.3 (cddp), 32.2 (cpx), and 30.4 kcal mol-1 (oxa). The low permeability coefficients (P) of cpx and oxa, which were 3 and 1 orders of magnitude inferior than for cddp, resulted from the high energy barriers for their traslocation processes through the membrane. The obtained results provide a more accurate picture of the permeation of Pt(II)-based drugs through breast cancer cells, which may be relevant for the design and evaluation of new platinum complexes.

RESUMO

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 (tres) 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 tres = 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.

RESUMO

Cisplatin (cddp)-based chemotherapy is one of the most effective therapeutic alternatives for breast cancer treatment, the most common form of cancer, despite the severe side effects related to the high toxicity and low selectivity of cddp. To circumvent these drawbacks, the encapsulation of cddp into oxidized carbon nanohorns (CNHoxs) has been shown as a promising formulation with biocompatibility and low toxicity. However, there is still a lack of studies regarding the behavior of this cddp@CNHox nanovector on the cell membranes. This study presents an in silico description of the interactions between cddp@CNHox and membrane models of cancer (C_memb) and normal (N_memb) cells referring to a typical human breast. The results revealed the interaction mechanism of the inclusion complex 3cddp@CNHox (three cddp molecules are included in the CNHox cavity) with these biomembranes, which is a multistep process including approach, landing, insertion, and penetration. The 3cddp@CNHox stability was monitored over time, and demonstrated the trapping of cddp molecules inside the CNHox cavity over all simulations. The van der Waals contribution played a primary role (∼74%) for the complex stability. Moreover, the binding free energy calculations indicated that the interaction of the 3cddp@CNHox complex with the C_memb model was slightly more favorable, on average, than with the N_memb model. Analysis of the hydrogen bonds (HBs) formed over simulations of 800 ns explains the selectivity for the C_memb model, since the total number of HBs established between the inclusion complex and the C_memb model was about three times greater than that with the N_memb model. By reinforcing the potentiality of oxidized CNHox as a nanovector of cddp, the results presented in this study may assist and drive new experimental studies with this nanomaterial, focusing on the development of less aggressive formulations for breast cancer treatment.

Assuntos

RESUMO

Carbon nanohorns (CNH) have been considered potential anticancer drug carriers, such as the cisplatin drug (cddp), due to their low toxicity, high purity, drug-loading capacity, and biodegradation routes. However, when it comes to nanomedicine applications, chemical functionalization is an essential step in order to overcome undesirable properties of these nanomaterials, such as the high hydrophobicity, low reactivity, and low dispersibility in polar solvents. In this context, the present study involved the modeling of new CNH topologies based on chemical oxidation and reduction mechanisms and the investigation of the influence of these modified structures on the dynamics and stability of inclusion complexes with cddp. The results indicated that these functionalization strategies lead to the opening of nanowindows on the CNH surfaces, which would constitute the main route for drug release, as reported by experimentalists. Also, our results showed that the insertion of polar functional groups on the oxidized CNH (CNHox-N) contributed to an improvement of the cddp@CNHox-N biocompatibility due to the greater number of hydrogen bonds formed with the solvent. Despite the favorable formation of all complexes, the binding free energies pointed out that the oxidation process made the cddp@CNHox-N complexes slightly less stable than the ones with pristine and reduced CNH. Besides, the results suggest the possibility to tune the complex stability by controlling the oxidation degree, which could be explored by the experimentalists in order to design controlled drug delivery systems based on CNH nanocarriers.

Assuntos

RESUMO

The medication with Pt-based antitumor drug cisplatin has demonstrated effective results against cancer cells, despite the severe side effects due to the high toxicity associated with the low selectivity of these anticancer agents. An alternative to overcome or decrease the side effects is to use drug delivery systems, which can carry high doses of the anticancer drug and promote its slow and targeted release to the tumor sites. Herein, we used molecular dynamics to study prototypes of the complexes formed by the encapsulated cisplatin and carbon nanohorns (CNH), with the purpose to characterize its structures and dynamical behavior in aqueous solution, an important feature to assess the potentiality of using CNH as carrier systems. The results indicated the presence of up to 36 water molecules inside the empty CNH cavity, depending on the cone angle and the presence of the cisplatin. Some of these solvent molecules are expelled out to the bulk upon cisplatin inclusion, although more than 10 molecules remain even for the narrow structures. Moreover, the calculated binding free energy (ΔbG) pointed out that the inclusion complexes formation between CNH structures and up to two cisplatin molecules was thermodynamically favorable in aqueous media, which suggests the potentiality of these carbon nanostructures as drug carriers. For the most likely and narrow host structure the average ΔbG was -92.0 kcal mol-1 for inclusion of two cisplatin, with most of the complex stability coming from the van der Waals contribution.

Assuntos