Functionalized graphene oxides for drug loading, release and delivery of poorly water soluble anticancer drug: A comparative study
Graphical abstract
Introduction
The exponentially emergent call for advances in the efficient diagnosis and treatment of various malignant diseases has stimulated a wide range of interdisciplinary science community to innovate an efficient and undisruptive drug delivery system. Graphene, with a sp2-hybrirdized 2D framework has produced pioneering results and attracted a great research interest across the globe owing to its remarkable mechanical strength, electrical as well as thermal conductivity and large specific surface area [1], [2], [3], [4]. Because of these extraordinary properties, graphene provides essentially infinite prospective for various applications such as green energy, biomedical, electronics, and nanocomposites etc. Graphene oxides (GOs) develop during oxidation of graphene, which have oxygenated hydrophilic functionalities at the surface of GO such as hydroxyl (-OH), epoxy (>O), and at the edges such as carboxylic (-COOH) groups. These functional groups promote the intercalation of water molecules into the covered passage and they can be easily detached by ultra-sonication that helps to produce highly dispersible GO sheets in aqueous medium [5], [6], [7], [8]. The exfoliated GO can be further functionalized for drug delivery applications. Owing to these potent hydrophilic groups present on the surface of GO, the assistance of being high dispersion in water and physiological environments is attained by GO. Due to these oxygen containing groups, GO can be further functionalized covalently or noncovalently for its required applications accordingly [9]. Importantly, GO has specific and large surface area which is exclusively accessible from top and bottom sides of GO sheets and offer effective immobilization/loading of various chemicals as well as biomolecules (drugs, genes, proteins, etc.). Graphene has enormous potential to penetrate through the plasma membrane resulting into the enhanced cellular uptake of desired micro [10], [11] and macromolecules [12], [13] with excellent biocompatibility made GO a magical vehicle for drug delivery applications. The targeted drug delivery concept predominantly shows potential application in the biomedical field, where the developments of different therapeutic systems are significant to get better efficacy, reduces dose amount and eliminate adverse effects.
As we know, the majority of anticancer drugs are either insoluble or sparingly soluble in water as well as in biological medium due to their hydrophobic nature. But, they can acquire the hydrophilic nature by combining with highly polarized groups. This is one of the reasons why there is exponentially growing interest in exploring the potential of GO in drug delivery systems (DDSs).
The capability of polymer grafted GO sheets to stack and deliver anticancer drugs to the targeted cells has been confirmed previously [10], [11], [12], [13], [14]. Several research groups have demonstrated the potential of carbon nanomaterials for loading and delivery of anticancer drugs [15], [16], [17], [18], [19]. For example, Pan et al. [20] functionalized GO with adipic acid and sodium alginate and loaded the anticancer drug doxorubicin hydrochloride (DOX·HCl) on it. They reported that their developed nanocarrier exhibited better cytotoxicity to Hela cells compared to pure drug.
Bao et al. [21] synthesized chitosan-functionalized graphene oxide and showed that this nanocarrier was effective vehicle for anticancer drug delivery of camptothecin (CPT). Sahoo et al. [22] developed the two nanocarrier systems such as polyvinyl alcohol (PVA) functionalized multi walled carbon nanotubes (MWCNT) and GO in order to achieve efficient loading and targeted delivery of anticancer drug and investigated the cytotoxic effect of both systems on various cancer cells. The cytotoxicity of CPT was better in MWCNT-PVA compared to GO-PVA.
However, in drug delivery applications, the role of functionalized GO with hydrophilic and biocompatible polymers and other excipients are in core interest as they have suitable attaching sites to combine with drugs through noncovalent interaction.
In the present work, we synthesized GO by expanded graphite powder by using modified Hummer’s method. The resulting GO is soluble in water due to highly polar hydroxyl, epoxy and carboxyl groups. Due to these polar and chemically reactive groups, GO further modified with hydrophilic and biocompatible polymer PVP covalently to improve the solubility of GO in biological mediums. We have also developed the other nanocarrier system based on GO and β-CD to compare the loading and cytotoxicity effect of drug. Later, the anticancer drug SN-38 (active metabolite of irrinotecan, an analog of camptothecin) was loaded onto GO functionalized with PVP and β-CD. SN-38 is a cytotoxic quinolone alkaloid, which is known to have anticancer activities. Being an aromatic drug SN-38 has a sparingly soluble nature in physiological solutions which is the main cause for its low bioavailability. The drug SN-38 was stacked noncovalently (via π-π stacking and intermolecular hydrogen bonding) onto PVP and β-CD grafted GO. Subsequently, in view of the biological importance of those SN-38 loaded nanocarriers, it was designed to check in-vitro cytotoxicity study against human breast cancer cells using MTT assay. This research work is dedicated to developing a rationale by comparing various parameters such as loading capacity, release profile and cell killing efficiency of SN-38 by using two different carriers GO-PVP and GO-β-CD.
Section snippets
Materials
Expanded Graphite powder with particle size (∼100 μm) was acquired from Sigma-Aldrich. Potassium permanganate (KMnO4), sodium nitrate (NaNO3), sulphuric acid (H2SO4), hydrogen peroxide (H2O2, 30% aq.) were purchased from Himedia; polyvinylpyrrolidone (PVP, Mw ∼ 40000), betacyclodextrin (β-CD, Mw ∼ 1135) were purchased from Calbiochem; DCC (N,N’,Dicyclohexyl Carbodiimide), DMAP (4-Dimethylaminopyridine) were purchased from SRL andSN-38 (7-ethyl-10-hydroxy camptothecin)were acquired from Sigma.
Synthesis and characterization of GO and functionalized GO
The functionalization of GO with PVP and β-CD was established by FT-IR spectroscopy as depicted in Fig. 1. The spectrum of GO was regular with the previous reported results. The IR peaks appeared at 3435, 1732, 1635, 1412, 1222 and 1048 cm−1, which were corresponded to oxygen containing hydroxy, carbonyl of COOH, aromatic carbonyl, carboxy CO, epoxy COC and alkoxy stretching, respectively. Frequencies at 2927 cm−1 and 2862 cm−1 can be assigned to the asymmetric and symmetric methylene
Conclusion
In summary, we have successfully developed biocompatible polymer PVP and excipient β-CD functionalized GO for efficient loading, release and cell killing activity of a poorly water soluble aromatic anticancer drug, SN-38. The polymer functionalized GO were able to discover drug delivery vehicle with SN-38 via hydrophobic and π-π interactions. GO-PVP-SN-38 possesses maximum masking action; and evidence is mounting that it is more cytotoxic compared to GO-βCD-SN-38 as well as SN-38 to the breast
Acknowledgements
Authors acknowledge the financial assistance from NMHS research grantKU/NMHS/MG/2016/002/8603/007, GBPIHED, Kosi-Katarmal, Almora, India.
References (38)
- et al.
Multifunctional graphene quantum dots for simultaneous targeted cellular imaging and drug delivery
Colloids Surf. B
(2014) - et al.
Carboxylated graphene oxide functionalized with (-cyclodextrin—Engineering of a novel nanohybrid drug carrier
Int. J. Biol. Macromol.
(2016) - et al.
Facile synthesis of manganese ferrite/graphene oxide nanocomposites for controlled targeted delivery
J. Magn. Magn. Mater.
(2016) - et al.
Pegylated folate and peptide-decorted graphene oxide nanovehicle for in vivo targeted delivery of anticancer drugs and therapeutic self-monitoring
Biosens. Bioelectron.
(2016) - et al.
Green synthesis of Au-Ag-In-rGO nanocomposites and its α-glucosidase inhibition and cytotoxicity effects
Mater. Lett.
(2018) - et al.
Biosynthesis of gold decorated reduced graphene oxide and its biological activities
Mater. Lett.
(2016) - et al.
Biocompatible nanocomposite ofcarboxymethyl cellulose and functionalized carbon-norfloxacin intercalated layered double hydroxides
Carbohydr. Polym.
(2018) - et al.
Effect of Hydrogen Plasma pretreatment on growth of carbon nanotubes by MPECVD
Mater. Sci. Eng. C
(2006) - et al.
Synthesis of graphene based nanosheets via chemical reduction of exfoliated graphite oxide
Carbon
(2007) - et al.
Graphene-based composite materials
Nature
(2006)