Modeling of nanoparticle coatings for medical applications

Eur. Phys. J. D (2016) 70: 181 DOI: 10.1140/epjd/e2016-70282-6 THE EUROPEAN PHYSICAL JOURNAL D Regular Article Modeling of nanoparticle coatings for medical applications Kaspar Haume1,2,a , Nigel J. Mason1 , and Andrey V. Solov’yov2,b 1 2 Department of Physical Sciences, The Open University, Milton Keynes MK7 6AA, UK MBN Research Center, Altenhöferallee 3, 60438 Frankfurt am Main, Germany Received 20 April 2016 / Received in final form 1 July 2016 Published online 6 September 2016 c The Author(s) 2016. This article is published with open access at Springerlink.com  Abstract. Gold nanoparticles (AuNPs) have been shown to possess properties beneficial for the treatment of cancerous tumors by acting as radiosensitizers for both photon and ion radiation. Blood circulation time is usually increased by coating the AuNPs with poly(ethylene glycol) (PEG) ligands. The effectiveness of the PEG coating, however, depends on both the ligand surface density and length of the PEG molecules, making it important to understand the structure of the coating. In this paper the thickness, ligand surface density, and density of the PEG coating is studied with classical molecular dynamics using the software package MBN Explorer. AuNPs consisting of 135 atoms (approximately 1.4 nm diameter) in a water medium have been studied with the number of PEG ligands varying between 32 and 60. We find that the thickness of the coating is only weakly dependent on the surface ligand density and that the degree of water penetration is increased when there is a smaller number of attached ligands. 1 Introduction Radiotherapy with X-rays or gamma rays is a widespread methodology to treat cancer tumors. However, due to the efficient penetration of tissue by these photons, a considerable fraction of the total dose is deposited in healthy tissue before and after the tumor leading to potentially severe side-effects. In recent years several studies have demonstrated the radiosensitizing effect of metal nanoparticles (NPs) leading to a higher therapeutic index (ratio of therapeutic efficacy to side effects) [1–4]. Dose localization by use of NPs has become a subject of significant scientific interest in the last decade, in part due to the promises of fewer side-effects for cancer patients worldwide, but also due to the exciting interdisciplinary nature involving biology, atomic cluster physics, collision studies, and materials engineering. A core component of this research is computational efforts to model the interactions between radiation, NPs, and biological matter. It is widely accepted that the main cell killing pathway during cancer radiotherapy is mediated by secondary electrons and radicals [3,5–7]. The sensitizing effect of metal NPs is related to an increased emission of secondary electrons compared to a similar volume of water [8]. These electrons in turn activate hydrolysis of the surrounding  Contribution to the Topical Issue “Atomic Cluster Collisions (7th International Symposium)”, edited by Gerardo Delgado Barrio, Andrey Solov’Yov, Pablo Villarreal, Rita Prosmiti. a e-mail: b On leave from A.F. Ioffe Physical Technical Institute, 194021 St. Petersburg, Russian Federation water medium resulting in an increased overall radical yield. For this reason, much effort is currently devoted to understanding and predicting the capabilities of NPs to emit secondary electrons. High-Z elements (high atomic number), such as noble metals, are particularly efficient Auger electron emitters and have been shown to generate radiosensitization through increased radical yield [9–11]. Gold nanoparticles (AuNPs), especially, have become a popular choice since the first demonstration of their radiosensitization properties [1]. In addition a high interaction cross section with photon radiation, their biological inertness, established methods of synthesis in a wide range of sizes and shapes, and possibility to coat their surface with a large catalog of molecules, providing the ability to partially control the behavior of the AuNPs, make them an attractive choice [12–14]. NPs are unstable in physiological conditions and tend to agglomerate and to be eliminated from the bloodstream [15]. For this reason, AuNPs are usually coated with the molecule poly(ethylene glycol) (PEG), a process known as PEGylation, which has been shown to increase blood circulation time (time before the NP is eliminated from the bloodstream) and improve stability (reduce tendency for NPs to aggregate) [16–18]. In the scenario of radiosensitization, however, the effect of the coating is not clear. Although radiosensitization with PEGylated AuNPs has been demonstrated [19,20], Gilles et al. showed that the hydroxyl radical yield was diminished for AuNPs coated with PEG depending on the coating density [21]. In another study, Xiao et al. found a decrease in sensitization through secondary electrons for increasing coating thickness [22]. Page 2 of 7 A better understanding of the structure and dynamics of the coating of AuNPs is therefore necessary to be able to predict their radiosensitizing properties as well as their interaction with the environment. The sizable number of possible coating molecules, including antibodies, proteins, sugars, and other organic compounds such as acids, make for a vast landscape of core-coating combinations. Experimentally investigating all possible combinations in a systematic manner is a staggering task. In this paper, we take an alternative approach by using computer simulations to study a specific combination of coating and NP core, namely the PEGylated AuNP. The presented method is general and is not restricted to the systems considered here thereby providing a convenient framework to study any core-coating combination. Specifically in this paper classical molecular dynamics is used to simulate AuNPs of 135 atoms (approximately 1.4 nm diameter) coated with between 32 and 60 thiolated PEG-amine (S − PEG5 − NH2 ) ligands. The system is fully solvated with water molecules. Using MBN Explorer [23] we report the effect of coating ligand density on the coating layer thickness and density. The paper is structured as follows: after this introduction, the computational details of the simulations are presented, divided into the preparation of the metal core, the preparation of the coating molecules and the solvation of the system, and finally the details of the molecular dynamics simulations. This section is followed by a presentation of the results and a discussion before ending with a summarizing conclusion. Eur. Phys. J. D (2016) 70: 181 [100] [110] h[110] [100] h[110] h[100] h[100] 2.1 Preparation of metal core The AuNP core was created using the Wulff construction plugin of the software Virtual NanoLab1 (version 2015.1). The Wulff construction is a simple theoretical approach in two steps to approximate the shape of a nanosized crystal (e.g. a NP) based on the surface energy of the faces of the crystal. In the first step a vector hj is (...truncated)