Design of a new drug delivery platform based on surface functionalization 2D covalent organic frameworks
Graphical abstract
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.
Section snippets
MD simulations
The MD simulations are applied to examine the potential of COF carriers as DDS. The OH groups are used to modify COF for targeted drug delivery. The 4-aminosalicylhydrazide (ASH) and 4-aminobenzohydrazide (APH), which has been chosen as the linkers units of the COFs and F-COFs carriers, are depicted in Fig. 1.
For this goal, three simulation systems are designed to study the drug loading behavior on the nanocarrier surface. In system-A, the pristine COF is located at the center of a simulation
MD simulation
The MD simulations are carried out to examine the adsorption of the DOX on the carrier surface and investigated the dynamic behavior of the drug molecules into the COF cavities. Three systems (i.e., system-A, -B, and -C) are equilibrated, and then analyzed in the biological environment. The initial and final snapshots of the investigated systems are presented in Figs. S1 and 2, respectively.
As can be seen in the final snapshots, almost all of the DOX molecule adsorbed in inner cavity or outer
Conclusion
In this study, the adsorption behavior of DOX on the COFs is investigated via MD and Metadynamics simulations in an aqueous environment. Our finding reveals that in all investigated systems, the DOX molecules spontaneously adsorbed into the carrier cavities. It is found that the adsorption of drug molecules in the inner and outer cavities of COFs with six hydroxyl groups (system-B) is more than in other systems. In fact, due to the formation of stronger hydrogen bonds in DOX-FCOFs systems, the
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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