Assessment of the effect of external and internal triggers on adsorption and release of paclitaxel from the PEI functionalized silicene nanosheet: A molecular dynamic simulation

https://doi.org/10.1016/j.jmgm.2021.107930Get rights and content

Highlights

  • The drug forms the strong π-π interactions with the nanosheet surface, which is supplemented by X-π interactions.

  • Functionalization of carrier with Polyethylenimine increases the interaction energy via the formation of hydrogen bonds.

  • At acidic pH level, the interaction of the drug and the carrier become weaker.

  • An external electric field leads to an enhance in drug delivery performance of nanosheet.

Abstract

In order to examine the adsorption mechanisms of paclitaxel (PTX) on silicene nanosheet (SNS) molecular dynamics (MD) simulations are carried out. The MD outcomes show that the adsorption of PTX on the pristine SNS is exothermic and spontaneous. The interaction between the PTX molecule and the pristine SNS is mainly due to the formation of π–π interactions through their aromatic rings, which are supplemented by X-π (X = N–H, C–H, and Cdouble bondO) interactions. Upon functionalization of SNS by Polyethylenimine (PEI), drug molecules prefer to bind to the nanocarrier instead of the polymer. In the functionalized SNS (f-SNS), the binding energy of the drug with the nanocarrier becomes stronger in comparison to the SNS case (Eads: −2468.91 vs −840.95 kJ/mol). At the acidic condition, protonation of drug and PEI cause that the interaction between PTX and the nanocarrier become weaker and drug molecules could release from the nanocarrier surface. Finally, two f-SNS and protonated f-SNS (f-pSNS) systems are induced by the electric field (EF). Evaluation of the dynamic properties of these systems (with strengths 0.5 and 1 V/nm) shows that the electric field could be acted as a stimulus for drug release from nanocarriers. The obtained results from this study provide valuable information about the loading/release mechanisms of PTX on/from the SNS surface.

Introduction

The unique electronic, structural, and mechanical properties of two-dimensional (2D) nanomaterials have prepared many aspects for their applications, such as imaging, biosensors, biomedicine, and drug delivery [[1], [2], [3]]. Recently, two-dimensional nanomaterials beyond graphene (G) have received great attention as a drug delivery system because of their special characters like high surface-to-volume ratio, drug-carrying valence, and ability to interpenetrate cell membranes [[4], [5], [6]].

Silicene nanosheet (SNS) is a new member of 2D nanomaterials made from a monolayer of silicon atoms and firmly arranged into a hexagonal honeycomb lattice similar to graphene [7]. In silicene nanosheet, the silicon atoms prefer to form sp3 hybridization over sp2, which makes it highly chemically active [8]. Recently, Saikia et al. [9]. Published a study about the interaction between pyrazinamide (PZA) and many 2D nanocarriers such as hexagonal boron nitride, SNS, silicene carbon, G, and phosphorene to investigate their usage as a candidate for drug delivery. Their results revealed that adsorption of PZA on the surface of SNS is more favorable than other nanocarriers, which consequently has the high drug loading and long retention time. According to previously reported studies, there is the possibility of the modification of 2D nanomaterials [[10], [11], [12]]. The modification can be occurred through noncovalent and covalent functionalization which both of them increase biocompatibility and the solubility of nanomaterials. Modification of silicene by various functional groups leads to increases its efficiency day by day. For example, coating SNS with folic acid is shown to enhances the targeting delivery of anticancer drugs [13]. However, noncovalent functionalization is easily done and prevents nanocarriers from possible damage and control the release of drugs.

Paclitaxel (PTX, Scheme 1) is one of the most widely used chemotherapeutic drugs prescribed to treat many cancers, especially breast and ovarian cancers. PTX is also a known inhibitor of cell proliferation. However, low water solubility, the emergence of drug resistance in patients, and adverse side effects confined its biological use [14]. Hence, in this study, a new drug delivery system is proposed to overcome such limitations.

Polyethylenimine (PEI, Scheme1) is constructed of an amine group and two carbon aliphatic CH2CH2 units and known as a cationic polymer. It is shown that 2D nanomaterials are successfully functionalized with PEI and loaded with various anticancer drugs [15]. For example, Zhang et al. [16] reported functionalization of graphene oxide (GO) with PEI, and used it for the dual transfer of siRNA along the anticancer drug doxorubicin (DOX). Their results showed that the conjugation of PEI with GO had a good performance in delivery of siRNA and DOX. This nanocarrier demonstrated a synergistic effect, and polymer chains lead to a significant enhancement in drug solubility [17].

In many studies, polymers such as polyethylene glycol and PEI have been used to increase solubility and blood-circulation time of drugs [12,18,19]. Furthermore, several variables such as pH condition, temperature, magnetic and electric fields, ultrasound, ionic strength, and chemical species can force these polymers to change their properti [20,21]. pH-responsive polymers such as PEI are interesting type of smart materials that quickly respond to small variations of the pH level by changes in its structure and properties, including chain conformation, solubility, surface activity, and configuration, etc.

There is a difference in the pH level of the physiological environment (~7.4) and near cancer cells (5–5.5), so it can be an effective factor for releasing the drug from the nanocarrier surface in the vicinity of cancer cells. Karnati et al. [22]. studied the pH-sensitive co-loading of PTX and DOX on single-walled carbon nanotube (SWCNT) and non-covalent functionalization with chitosan via the MD simulations. Their obtained results indicated that the π–π interactions are the main factor in PTX/DOX loading. Also, they showed that the non-covalent functionalization of the SWCNT increases the interaction of drug molecules with the carrier. Moreover, they realized that in an acidic environment PTX has good release behavior. The temperature, electric field, and pressure are three effective factors that are able to control drug release from drug delivery systems. Though, the electric field (EF) serves as a much more selective physical trigger [20,23,24]. The electric field has several advantages such as being clean, easily acquirable, and adjustable in both direction and intensity. The electric field is a signal that can be used to trigger drug delivery. One way to accomplish this is to fabricate a pH-sensitive polymer and use the presence or absence of an electric current to change the local pH of the polymer [21]. Shahabi et al. investigated the effect of the external EF on the drug delivery performance of peptide-based metal-organic framework for the 6-mercaptopurine drug by using MD simulations. Their results demonstrated that the strong interaction of drug molecules with MPF is decreased under the influence of the electric field. In other words, they showed that the applied electric field can act as a trigger on the liberation behavior of the drug from the porous nanostructure [23]. Despite the considerable outreach of modern nanomedicine in using the 2D nanomaterials, there is still a lack of comprehensive theoretical models describing the controlled delivery of drugs with the application of electric field on the SNS as the carrier.

In this study, molecular dynamics simulations are performed to investigate the underlying mechanisms of PTX loading on the surfaces of pristine SNS and SNS functionalized with PEI (f-SNS). Besides, the release of the PTX from the surfaces of the studied nanocarriers is examined in an acidic environment. Eventually, the external EF effect on the drug release in the functionalized and protonated f-SNS systems is evaluated. The current systematic investigation gives a deep insight into the distinct interaction mechanisms of PTX with silicene nanosheet, and reveals the effects of noncovalent functionalization and protonation on the drug-carrier interaction. These will eventually help to better understand loading as well as releasing of the anti-cancer drugs.

Section snippets

Systems provision

A silicene nanosheet consisting of 680 silicon atoms terminated with hydrogen atoms is created using the GuassView program [[25], [26], [27], [28], [29], [30]]. The 3D structure of the PTX molecule is downloaded from PubChem (PubChem CID: 36314) [31]. In the f-SNS system, the final orientation of PTX on SNS is extracted and then noncovalently functionalized with PEI chains (each of the PEI chains consists of 6 units). Two protonated systems (i.e., pSNS and f-pSNS) are built as models of cancer

Results and discussions

In order to investigate the process of adsorption, a set of descriptors, including interaction energies, the mean square displacement (MSD), root-mean-square deviation (RMSD), and the radial distribution function (RDF) are calculated throughout the simulation trajectories.

Conclusion

In this molecular dynamic study, the adsorption and releasing of PTX drug on/from the SNS and functionalized SNS are investigated. The MD simulation results revealed that the PTX spontaneously adsorbs on SNS and f-SNS. In the SNS/PTX system, the PTX forms the strong π-π interactions with the nanosheet surface, which is supplemented by X-π interactions. Our theoretical results show that functionalization of the SNS with PEI increases the interaction energy through the formation of hydrogen bond

Funding sources

There is no allocated fund for this work.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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