Diffusion of cisplatin molecules in silica nanopores: Molecular dynamics study of a targeted drug delivery system

Highlights

• We model the diffusion of cisplatin in silica nanopores.

• At small pore radii adsorption at the inner wall impedes diffusion.

• At large pore radii (three times the molecule size) we observe free diffusion.

• Results are relevant for target drug delivery.

Abstract

The diffusion and adsorption behavior of cisplatin in silica nanopores is investigated using molecular dynamics simulation. Two different silica conformations are studied in order to characterize the influence of surface polarity and inner pore wall structure. Acceleration techniques are used in order to sample adsorption phase space efficiently. We find a strong influence of the pore diameter on the diffusion coefficient; only for pore diameters larger than roughly 1.6 nm, cisplatin assumes a comparable diffusion coefficient as in bulk water. Our results also allow to estimate escape times of cisplatin from a silica nanopore.

Introduction

Platinum-based drugs are widely used in the treatment of cancer, and here cis-diamminedichloroplatinum(II), Pt(NH₃)₂Cl₂, Fig. 1, – known as cisplatin – is particularly widespread [1]. While it has already been synthesized as early as 1845 by the Italian chemist Peyrone [2], it was only in the 1960s that Rosenberg et al. [3] observed unexpectedly that cisplatin can inhibit cell division in E. coli bacteria. Cisplatin has been used as an antitumor drug after clinical approval by the FDA (US Food and Drug Administration) in 1978. Since then it has been used to treat a wide array of cancers, including head and neck, testicular, cervical, ovarian, colorectal, bladder, and non-small-cell lung cancer [4]. The experimental studies [5] proved that the major target of cisplatin is the DNA. In detail, this drug stops tumor growth by cross-linking guanine bases in DNA double-helix strands. In consequence, the strands are unable to uncoil and separate, and as this is necessary for DNA replication, the cells can no longer divide.

Since the cisplatin molecule is not smart enough to select only cancer cells but damages every cell with a high proliferation rate, it has several severe side effects including nephrotoxicity, neurotoxicity, ototoxicity, nausea and vomiting [6]. One of the most promising ways to attack this problem is to encapsulate the drug and deliver it to the appropriate site close to the tumor cells. This could be done by what is called a targeted drug delivery system. Targeted drug delivery systems seek to concentrate the medication in the tumor cells while reducing the accumulation of the drug in normal cell tissue. This objective can be achieved by using carrier systems that load and transport the drug to the target [7]. Usually the carriers are in the micro- or nanosize, and are based on either inorganic materials like silica or gold, or organic molecules like liposomes and polymers. The common goal of the targeted drug delivery systems is to transport the drugs to the target site in a controlled manner. They should be biocompatible, not stimulate the immune system and deliver the drugs to the appropriate sites [8].

Silica nanopores constitute one of the drug carriers that are able to fulfill the above mentioned properties for drug delivery systems. Silica is considered to have an excellent biocompatibility and can be safely taken up by living cells [[9], [10], [11]]. Lu et al. [12] used fluorescent mesoporous silica nanoparticles as a carrier for a hydrophobic anticancer drug (camptothecin) putting the drug inside the pores and delivering it to the cancer cells. Their results show that the drug remained inside the nanoparticles during transport and was released in the hydrophobic region of the cell compartment inducing cell death. In another study, Watermann and Brieger [8] showed how mesoporous silica nanoparticles could be used as a drug delivery system and were able to improve the efficacy of the drugs and to reduce side effects. They also demonstrated that this nanocarrier is biocompatible and biodegradable. Finally, Cheng et al. [13] designed and constructed mesoporous silica nanoparticles to load the antitumor drug doxorubicin; by using different functionalizations they could tune the enzyme response to the drug delivery system.

Molecular dynamics (MD) is a potent simulation method that allows to study the interaction between molecules on an atomistic basis. This method has been successfully applied to study interactions between carrier systems and drug molecules. In a basic MD study, Yamashita et al. [14] investigated the kinetics of water uptake into a silica nanopore. They could identify different diffusion mechanisms of water molecules in such a nanopore. Mejri et al. [15] investigated the interaction between a single-wall carbon nanotube and cisplatin molecules using MD. They found that rapid release of the cisplatin drug from the tube occurs when the nanotube approaches a cancer cell membrane. Finally, Panczyk et al. [16] studied the mechanism of cisplatin release from carbon nanotubes whose ends are capped by magnetic nanoparticles. They found a significant reduction of the diffusion coefficient inside the nanotube depending on the concentration of cisplatin inside the nanotubes.

In summary, silica nanocontainers are promising materials for targeted drug delivery systems because of their high biocompatibility. In order to assess their usability for transporting and releasing the anti-cancer drug cisplatin, the diffusion of cisplatin in water-filled silica nanopores has to be determined.

In the present paper, we use MD simulation to study the diffusion of cisplatin in silica nanopores and to characterize the (adsorptive) interaction energy between cisplatin and the nanopore wall. In order to allow for some generality, two different pore orientations in the silica are studied, viz. a pore that aligns with the silica dipole moment, and one that lies perpendicular to it. Our simulations report on the diffusivities of cisplatin and the escape times from a pore. The use of accelerated MD (aMD) [17,18] allows us to sample the molecular phase space more efficiently.