Design of a new drug delivery platform based on surface functionalization 2D covalent organic frameworks

Highlights

• Drug molecules move toward the COFs and form the stable complexes.

• Functionalization of COF with OH group increases its interaction energy with DOX.

• Global minimum is related to formation of the HB and π-π stacking interactions.

Abstract

The adsorption mechanism of doxorubicin (DOX) on pristine covalent organic frameworks (COF) and functionalized COF (F-COF) is investigated by using molecular dynamics (MD) and Metadynamics simulations. MD simulations are performed to explore the loading of DOX into the COFs. To evaluate this process, a set of descriptors, including interaction energies, radial distribution function, and square mean displacement, the number of hydrogen bonds (HB) are calculated throughout the simulation trajectories. It is determined that HB interactions are the most important factors in stability of the investigated systems. The MD results show that the drug molecules move toward the COFs and form the stable complexes. Functionalization of COF with six and three hydroxyl groups increases its interaction energy with DOX from -16.87 to -264.95 and -139.87 kJ/mol, respectively. In this study, the free energy surface (FES) is also calculated by well-tempered metadynamics simulation technique. The PES landscapes confirm that the global minimum could be typically relevant to formation of the HB. The free energy values for the COF/DOX complexes in pristine and functionalization of COFs at their global minima are reached about -229.7, -260.46 (for six OH groups), and -243.37 (for three OH groups) kJ/mol, respectively. In addition, at the acidic condition, protonation of DOX causes that the interactions between DOXs and the COFs become weaker and drug molecules could release from the nanocarrier cavities.

Introduction

Nanocarriers are included nanoparticles such as liposomes, dendrites, polymer-carriers, micelles, and viral, which are recently designed for biomedical applications, including targeted drug delivery [1], [2], [3], cancer treatment[4], gene delivery[5], and the sensory [6]. The use of nanocarriers as drug carriers reduces damage to healthy tissues and also improves the solubility of drug molecules. Smart drug delivery systems (DDSs) can transfer drugs toward the targeted cancer cell and released them in a controlled manner [7]. The release profile of nanocarriers systems is not only dependent on molecular forms but also relevant to the interaction between carriers and drugs. Nanocarriers are investigated as promising DDSs for cancer therapy based on their capability to delay drug circulation periods and reduce drug side effects. The two-dimensional (2D) nano-sheets are a member of nanomaterials that their wide surface space allows excellent absorption of drug molecules [8]. Covalent organic frameworks (COFs) due to well-proportioned cavities [9], stability [10], low density [11], high thermal stability [12], and high specific surface area [13] emerged as new targeted DDSs. The COFs are explored for the first time in 2005 [14] and many researchers have designed a series of intelligent drug delivery systems based on these structures. As well as, several types of COFs along with various linkages and building blocks are designed by using synthetic strategies to achieve a cost-effective synthesis. For example, Zhao and coworkers synthesized two types of COFs via a condensation reaction of amine and aldehyde compounds. Their results showed that COFs have high drug loading capacity and present a good release behavior of the loaded drug with low cytotoxicity [15] Besides, in another study [16], Rozas et al. investigated COFs as a DDS for the first time. They synthesized and designed two new porous crystalline polyamides Covalent Organic Frameworks by combining linear building units and tetrahedral based on the imidization reaction. Their obtained results indicated that these two COFs have exceptionally high drug loading and well-controlled drug release in drug delivery systems [17]. It is worthy to mention that in the present study, the initial structure of the used COFs is taken from the X-ray data, reported by Mitra et al. [18]. They had designed a self-assembly system based on 2D COFs for DOX delivery. These new classes of 2D carriers provided places for the combination of tissue targeting agents into the cavities of COFs to deliver anticancer drugs to the cancer cells. Indeed, COFs are a new class of 2D nanomaterials that are linked together by covalent linkages and made from light atoms such as C, H, O, N, B, and N (or -B-O-, -C-N- and -C-C-). The imine-linked (-C=N-) of 2D COFs exhibits higher stability compared to -B-O- Linkages, due to the existence of π-conjugation in their structures. The aforementioned properties of the organic-based nanocarriers as promising vehicles are discussed in many recently published papers. Hashemzadeh and Raissi performed molecular dynamics (MD) simulations to investigate the interaction of the anticancer drug 5-fluorouracil (5-Fu) with covalent organic frameworks. They showed that the release of the 5-Fu molecule into the COFs is slow, which is an important factor for controlled drug release [19]. Huo et al. used COFs nanospheres for targeted drug delivery and confirmed that COFs exhibited appropriate behavior under acidic conditions. Then, they loaded COFs with the anti-cancer drug doxorubicin (DOX) and achieved a pH-sensitive release [20]. Akyuz synthesized a two-dimensional imine-linked COF and tested it as a drug carrier. They showed this COF has some unique properties including; easy synthesizable, functionality, easy loading of drug molecules, and chemical stability [21]. Doxorubicin is an anthracycline antibiotic that is widely utilized in cancer therapy. At present, it has been reported that DOX is able to interact with nuclear DNA and kill cancer cells [22]. Using its efficacy for overcoming a wide range of cancers, including lung cancer, blood cancer, and various sarcomas, has been beneficial [23]. Although DOX is useful for treat cancer but in some parts of the body, it causes toxicity. It is worth mentioning that recent studies used medical drug carrier systems to eliminate these adverse effects, and we focus attention on the pros and cons of drug delivery carriers. In most cases, DOX adsorbs on the nanocarriers via non-covalent interaction, which is an exothermic and spontaneous process.

In the present work, classical MD and well-tempered metadynamics simulations are used to gain deep insight from the adsorption of DOX on the carrier surface in a biological environment, as a probable smart drug delivery vehicle. In this way, we have investigated the diffusion of DOX into the pristine and functionalized COFs cavities. Besides, the release of the DOX from the COFs cavities is examined in an acidic environment for the most stable system (system B) .Furthermore; the free energy surface (EFS) of adsorption of DOX on COFs and F-COFs surfaces is studied by using well-tempered metadynamics. In general, in considering the functional groups of OH are attached to the carrier's surface, we would like to explore whether it is the functional group's effects which mainly drive the adsorption or not. We hope the obtained results can be useful in future experimental studies to improve COF applications.