Almeida Eduardo R, Capriles Priscila V S Z, Dos Santos Hélio F
Núcleo de Estudos em Química Computacional (NEQC), Departamento de Química, Instituto de Ciências Exatas, Universidade Federal de Juiz de Fora (UFJF), Campus Universitário, Martelos, Juiz de Fora, MG 36036-330, Brazil.
Programa de Pós-graduação em Modelagem Computacional (PGMC), Departamento de Ciência da Computação, Instituto de Ciências Exatas, Universidade Federal de Juiz de Fora (UFJF), Campus Universitário, Martelos, Juiz de Fora, MG 36036-330, Brazil.
J Phys Chem B. 2022 Jun 7. doi: 10.1021/acs.jpcb.2c02555.
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 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 (ΔΔ) for the escape from CNHox cavity follows the order oxa > cpx ∼ cddp, with the value for the oxa complex (21-26 kcal mol) found to be about 36 and 30% larger than those for cpx and cddp, respectively. While the approximate residence time () of the oxa drug inside the CNHox cavity was 5.45 × 10 s, the same measure for the cddp and cpx drugs was 5.3 × 10 and 1.60 × 10 s. Simulations also revealed that the escape of oxa with the oxalate group facing the nanowindow was the most unfavorable process, giving = 1.09 × 10 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.
目前应用的所有癌症化疗方法中，约有一半涉及使用三种全球获批的基于Pt(II)的药物进行治疗，即顺铂（cddp）、卡铂（cpx）和奥沙利铂（oxa），因为它们对多种癌症具有显著的抗肿瘤活性。然而，这种广泛应用伴随着严重的副作用，如肾毒性、骨髓抑制和神经毒性，这是由于它们对癌细胞的生物利用度低和选择性差所致。为了减轻这些缺点，使用化学功能化的碳纳米角（CNH）作为纳米载体是一种潜在的制剂，因为CNH因其生物可降解性、生物相容性、低毒性以及与小分子药物尺寸兼容的空腔而受到关注。本文报道了氧化碳纳米角（CNHox）与cddp、cpx和oxa药物形成的复合物的能量和动力学分析。通过无偏分子动力学（MD）模拟，我们表明包封制剂（cddp@CNHox、cpx@CNHox和oxa@CNHox）比吸附制剂（cddp > CNHox、cpx > CNHox和oxa > CNHox）更稳定，稳定性高出约11.0 kcal/mol。这种高稳定性主要由范德华相互作用决定，在整个模拟时间（200 ns）内负责药物的限制。包合物的有偏MD模拟证实了药物释放的非自发性，因为平均力势（PMF）表明该过程具有吸能特征。此外，释放能量曲线指出，从CNHox空腔逃逸的自由能垒（ΔΔ）遵循oxa > cpx ∼ cddp的顺序，发现oxa复合物的值（21 - 26 kcal/mol）分别比cpx和cddp的值大约36%和30%。虽然oxa药物在CNHox空腔内的近似停留时间（）为5.45×10 s，但cddp和cpx药物的相同测量值分别为5.3×10和1.60×10 s。模拟还表明，草酸基团朝向纳米窗口的oxa逃逸是最不利的过程，= 1.09×10 s。除了加强和扩展cddp、cpx和oxa在CNHox中的纳米载药用于癌症化疗外，所考虑的所有特征都可以为实验数据提供解释，并鼓励进行新的研究，旨在为肿瘤疾病提出侵入性较小的治疗方法。
