Usman et al. Chemistry Central Journal (2017) 11:47 DOI 10.1186/s13065-017-0275-3 REVIEW Open Access Gadolinium‑based layered double hydroxide and graphene oxide nano‑carriers for magnetic resonance imaging and drug delivery Muhammad Sani Usman1, Mohd Zobir Hussein1*, Sharida Fakurazi2,3 and Fathinul Fikri Ahmad Saad4 Abstract Gadolinium (Gd)-based contrasts remain one of the most accepted contrast agents for magnetic resonance imaging, which is among the world most recognized noninvasive techniques employed in clinical diagnosis of patients. At ionic state, Gd is considered toxic but less toxic in chelate form. A variety of nano-carriers, including gadolinium oxide ­(Gd2O3) nanoparticles have been used by researchers to improve the T1 and T2 contrasts of MR images. Even more recently, a few researchers have tried to incorporate contrast agents simultaneously with therapeutic agents using single nano-carrier for theranostic applications. The beneft of this concept is to deliver the drugs, such as anticancer drugs and at the same time to observe what happens to the cancerous cells. The delivery of both agents occurs con- currently. In addition, the toxicity of the anticancer drugs as well as the contrast agents will be signifcantly reduced due to the presence of the nano-carriers. The use of graphene oxide (GO) and layered double hydroxides (LDH) as candidates for this purpose is the subject of current research, due to their low toxicity and biocompatibility, which have the capacity to be used in theranostic researches. We review here, some of the key features of LDH and GO for simultaneous drugs and diagnostic agents delivery systems for use in theranostics applications. Keywords: Layered double hydroxides, Graphene oxide, Drug delivery, Gadolinium contrast, Magnetic resonance imaging (MRI) Background Nanotechnology is a promising feld of research, espe- Tere are various modes of cancer therapy, such as chem- cially in the area of the so-called nanomedicine [2–4]. otherapy, immunotherapy and radiotherapy. Notwith- In recent years, 2D inorganic nanolayers such as layered standing, the challenge of successful cancer therapy is double hydroxides, graphene and graphene oxide, and still existing. Chemotherapy is the most accepted method metal nanoparticles-based nano-carriers have been used of cancer therapy amongst the three modes; this is due in various drug delivery applications. Teir advantages to availability of various chemotherapeutic agents. How- are the reduction in toxicity and improvement of ef- ever, the major challenge of this method is the chemo- cacy of chemotherapeutic drugs, which are known to therapeutic agents, which do not target the cancerous be highly toxic to human cells. Lately, eforts have been cells alone but normal cells are also vulnerable to the made by some researchers to simultaneous dope contrast cytotoxic efects of chemotherapeutic agents [1]. agents such as gadolinium ion into the aforesaid nano- carries for theranostic applications [5–9]. Layered double hydroxide (LDH) is a class of inorganic *Correspondence: [email protected] nanolayers [10] and one of the most commonly used 1 Materials Synthesis and Characterization Laboratory, Institute nano-carriers in drug delivery systems. LDH is an inor- of Advanced Technology (ITMA), Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia ganic 2D layered material with interlayer exchangeable Full list of author information is available at the end of the article anions [11], with the general formula, © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Usman et al. Chemistry Central Journal (2017) 11:47 Page 2 of 10 2+ 3+ + n− ·[ Te slurry obtained is centrifuged/fltered, washed and M1− xMx (OH)2 A x/n mH2O] x oven-dried at 60–80 °C. A variety of anions can be inter- calated between the layers, which lead to the formation of where M2+ and M3+ represent the divalent and trivalent multifunctional nanocomposites [23]. Te ion exchange n− metal cations respectively, and +[A ]x/n represents the technique is much similar to co-precipitation method. interlayer exchangeable anions [11–13]. Te inner layers However, in ion-exchange method, the guest anion solu- also consist of water molecules which assist in uptake of tion is added after the LDH is prepared [22]. As stated molecules [14]. LDH synthesis is usually carried out from earlier, the drug loading capacity of the methods varies precursor solutions of the metal salts under alkali pH based on the nature of the drug or guest anions to be moderator. intercalated. Factors such as hydrothermal treatment, Graphene oxide is a derivative of graphene, a nano- aging process, sonication and microwave assisted syn- material with two dimensions (2D) and an arrangement thesis have been reported to afect the shapes and other of sp2-bonded carbon atoms. It has stupendous proper- physico-chemical properties of the nanocomposites pro- ties such as optical, electronic and thermal stability. GO duced, which in turn infuences the drug loading [24]. is formed when the hydrogen atoms are replaced by oxygen atoms during the chemical synthesis. Te Hum- Application of GO in drug delivery mer’s method is the universally adopted method of GO Te structure of GO consists of sp3-hybridized carbons synthesis from graphite by strong oxidation of the latter which are composed of diferent functional groups, such [15, 16]. Currently, a lot of efort is been put into explora- as hydroxyl, carboxyl, and epoxides. Te groups are con- tion of prospective graphene-based materials in biomedi- nected to the surface of the GO sheets of the sp2 bond- cal applications, such as nano-carriers for drug and gene ing carbon atoms. Tis enables the efcient loading of delivery, biosensing and bioimaging applications [17]. aromatic materials such as anticancer drugs onto the sheets [25]. In similarity with LDH drug delivery sys- Application of LDH in drug delivery tems, GO-based drug delivery system is also a repre- Drug delivery system sentative of a host–guest interactions in supramolecular Drug delivery system refers to the typically the use of chemistry, where the host and the guest molecules or ions nano-carriers as host to accommodate or load therapeutic are bonded non-covalently mostly via hydrogen bonds, agents as guest for delivery to specifc targets. LDH is one ionic bonds, van der Waals interactions and hydropho- of the most commonly used drug delivery agents. LDH bic bonds [26]. In addition, GO contains a stupendous π has a 2D-layered structure which gives it a unique abil- structure that enables noncovalent π–π stacking bond- ity to intercalate and exchange anions with other materi- ing with loaded therapeutics [27]. Due to its composi- als, which enables it to be used as a drug carrier [18–20]. tion, GO is equally capable of OH and COOH hydrogen Another interesting property of LDH is its pH-dependent bonding, hydrophobic bonding, embedding and surface controlled release properties. Tis specifcally makes its absorption [28] with functional groups of various drugs resourceful in pharmaceutical applications. Te synthesis [28]. Tis facilitates drug to GO bonding for the forma- of LDH can be conducted via two major chemical routes, tion of the nanocomposite and eventually release of the which are co-precipitation or ion-exchange method; both drug in the desired pH [29]. methods can be utilized for drug intercalation and have As mentioned earlier, the most commonly used meth- been reported to have high drug loading capacities [21]. ods of GO synthesis are Hummers’ and Hummers’ Nevertheless, some reports indicate diferent percentage modifed methods [30], which are top-down chemi- loading for the methods under the same conditions [22], cal approach of synthesizing GO from graphite fakes. which may be due to the nature of the therapeutic agents. Briefy, graphite fakes and sodium nitrate are frstly Co-precipitation is the most adopted technique for LDH mixed and concentrated sulphuric acid is then added synthesis, due to its drug loading ability and is often under constant stirring and allowed to stir for about an considered as the easiest method. In co-precipitation hour. Appropriate amount of KMnO 4 is slowly added method, an aqueous precursor solution of two diferent to the solution at low temperature. Te solution is metal salts is prepared; to which an anionic guest and then allowed to stir further for 12 h at a temperature of alkaline solution are simultaneously added in drop wise 35–50 °C. Te solution is then diluted with 500 mL of manner. Te set-up is then kept under stirring at room deionized water. Treatment with 30% H 2O2 is followed. temperature with continuous hydrogen fush until a pH Te fnal suspension is then washed with HCl and H2O, between 7 and 10 is attained. Te mixed solution is then fltered and dried at low temperature. GO synthesis is put through aging process for 18 h at 70 °C temperature. conducted with caution to prevent explosion [31]. Usman et al. Chemistry Central Journal (2017) 11:47 Page 3 of 10 Gadolinium‑based nanodelivery system for MR referred to as theranostic drug delivery system (Fig. 1a, imaging and drug delivery b). However, when only a diagnostic agent is loaded on a Magnetic resonance imaging (MRI) is a powerful and nano-carrier, it becomes a diagnostic delivery system [40]. one of the most commonly used clinical approaches Recently, researches have been focused on doping MRI in diagnosis of cancer patients [32].