Folic-Acid-Functionalized Graphene Oxide Nanocarrier: Synthetic Approaches, Characterization, Drug Delivery Study, and Antitumor Screening

Abstract

In this work, we developed and screened the potential antitumor activity of a nanocarrier based on graphene oxide (GO) and folic acid (FA) for the delivery of chemotherapy drugs. GO was synthesized by the graphite exfoliation process. FA was linked to PEG (4,7,10-trioxa-1,13-tridecanediamine) to form FA–PEG, followed by coupling to the GO surface. Camptothecin (CPT) was further adsorbed on GO for use as a drug model in the delivery study. The synthesis of the intermediate FA–PEG molecule and coupling to GO for the formation of the GO–FA nanocarrier were confirmed by basic and state-of-the-art characterization techniques, including infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), electrospray ionization (ESI) mass spectrometry, transmission electron microscopy (TEM), and magic-angle spinning carbon-13 nuclear magnetic resonance (CP/MAS 13C NMR) spectroscopy. FTIR spectroscopy showed a significant reduction in the signal intensity of the carboxylic groups after the functionalization of GO with FA–PEG. TGA of GO–FA revealed that approximately 20% of the functional groups were from FA–PEG. GO–FA indicated a high CPT loading capacity (37.8%). In vitro studies confirmed prolonged drug release over 200 h. Acidic pH (5.0) slowed the release of CPT from the nanocarrier compared to that at physiological pH (7.4). The toxicity screening of GO–FA and GO–FA + CPT was investigated for two widely studied preclinical cell models: J774, a tumor cell with macrophage phenotype and high proliferation rate; and HepG2, a tumor cell obtained from human hepatocellular carcinoma with folate transporters. The toxicity of the GO–FA nanocarrier without drug loading was dependent on the cell type and presented no toxicity to J774 but high toxicity to HepG2. The presence of FA in the nanocarrier loaded with CPT was crucial to achieve apoptosis in both tumor cell lines. In addition, confocal microscopy revealed both the adhesion and internalization of the FITC-labeled GO–FA by the tumor cell lines.

Understanding the driving forces of camptothecin interactions on the surface of nanocomposites based on graphene oxide decorated with silica nanoparticles

“…Thus, the present study corroborates the discussions regarding CPT release experiments and is in agreement with the data in the literature. 34 The above discussion clearly shows the differences in the nanocomposite based on graphene oxide decorated with silica nanoparticles as a nanocarrier; this material has optimized drug delivery characteristics compared with those of MSN and GO materials. These properties suggest the potential application of GO-MSN nanomaterials as nanocarriers in antitumor treatment.…”

“…Studies related to GO materials comprising CPT as a drug host molecule are still rare and show promising results from the point of view of high encapsulation capacity. 34,35 However, the literature has reported toxic effects of GO, such as cell membrane damage and a high capacity to cause haemolysis, 30,36 thus increasing the chance of toxicity in intravenous applications. There are also studies that show opposite effects, characterized by a low haemolytic effect.…”

Graphene Oxide–PEG–Protocatechuic Acid Nanocomposite Formulation with Improved Anticancer Properties

“…The high affinity of the folate receptor that is preferentially expressed in cancer cells is rarely expressed in normal cells. This has allowed the development of the targeted delivery of anticancer drugs at the cancer at the tumor sites to maximize anticancer efficacy with minimizing side effects to healthy tissues [ 42 , 43 , 44 , 45 ]. The folate targeting of cancerous cells has been reported recently in many studies; e.g., L. Xing et al 2018 used folate targeting for ovary cancer cells, and found that folate receptor alpha (FRα) is overexpressed in ovary cancer cells [ 42 ].…”

Functional Graphene Derivatives for Chemotherapy-Based Synergistic Tumor Therapy

“…Nano-sized GO (nGO) was functionalized by amino terminal branched PEG initially in 2008 by the connecting amino and carboxyl. 12 In addition to PEG, other amineterminated biomaterials such as chitosan (CS), 13 carboxymethyl CS, 14 galactosylated CS, 15 polyethylenimine (PEI), 16 poly(allylamine hydrochloride) (PAH), 17 dextran (DEX), 18 folic acid (FA) 19 and aptamer 20 can be covalently linked to GO by amidation reaction. Despite the lack of amino, hyaluronic acid (HA) can also be grafted to GO…”