Improving thermal stability and efficacy of BCNU in treating glioma cells using PAA-functionalized graphene oxide

Abstract

Background: 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a commercial chemotherapeutic drug for treating malignant brain tumors, has poor thermal stability and a short half-life. Immobilization of BCNU on a nanocarrier might increase the thermal stability of BCNU and extend its half-life. Methods: Nanosized graphene oxide (GO) could be modified by polyacrylic acid (PAA) to improve the aqueous solubility and increase the cell penetration efficacy of the nanocarrier. PAA-GO intended as a drug carrier for BCNU was prepared and characterized in this study. The size and thickness of PAA-GO was investigated by transmission electron microscopy and atomic force microscopy, and the presence of PAA functional groups was confirmed by electron spectroscopy for chemical analysis and thermogravimetric analysis. BCNU was conjugated to PAA-GO by covalent binding for specific killing of cancer cells, which could also enhance the thermal stability of the drug. Results: Single layer PAA-GO (about 1.9 nm) with a lateral width as small as 36 nm was successfully prepared. The optimum drug immobilization condition was by reacting 0.5 mg PAA-GO with 0.4 mg BCNU, and the drug-loading capacity and residual drug activity were 198 µg BCNU/mg PAA-GO and 70%, respectively. This nanocarrier significantly prolonged the half-life of bound BCNU from 19 to 43 hours compared with free drug and showed efficient intracellular uptake by GL261 cancer cells. The in vitro anticancer efficacy of PAA-GO-BCNU was demonstrated by a 30% increase in DNA interstrand cross-linking and a 77% decrease in the IC 50 value toward GL261 compared with the same dosage of free drug. Conclusion: Nanosized PAA-GO serves as an efficient BCNU nanocarrier by covalent binding. This nanocarrier will be a promising new vehicle for an advanced drug delivery system in cancer therapy.

Graphene as Cancer Theranostic Tool: Progress and Future Challenges

“…Other cancer types such as Burkitt's lymphoma 33 , colon cancer 34 , 70 , 71 , 78 , 91 , prostate cancer 35 , 64 , 87 , lung cancer 43 , 56 , 63 , 76 , 80 , 87 , skin cancer 57 , 60 , brain cancer 20 , 38 , 46 - 48 , 61 , 62 , glioma 90 and glioblastoma 72 were studied under different drug treatment conjugated with graphene or graphene oxide.…”

“…GO-PVA-CPT exhibited higher cytotoxic activity versus cancer cells compared to CPT alone. A lot of drugs were used in multiple conjugations with graphene such as camptothecin 32 , 66 , 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) 38 , a commercial chemotherapeutic drug for treating malignant brain tumors, tamoxifen citrate 43 , elsinochrome A 44 , adriamycin 40 , β-lapachone 41 , lucanthone 72 , paclitaxel 56 , 76 , anastrozole 65 , 5-fluorouracil 55 , epirubicin 48 , 62 , curcumin 68 , gambogic acid 86 ellagic acid 34 , oxaliplatin (OXA) 91 , cisplatin 91 and thermosensitive nanogel 64 . All these studies showed a great improvement in therapeutic efficacy when the drugs were loaded onto graphene.…”

<p>Polyethylene Glycol-Coated Graphene Oxide Loaded with Erlotinib as an Effective Therapeutic Agent for Treating Nasopharyngeal Cancer Cells</p>

“…For example, chemotherapeutic drugs possessing aromatic ring structures, such as doxorubicin, camptothecin, and SN-38, bind on GO through π–π stacking. 47 Various methods have been developed to functionalize GO for improving its drug carrier function. Lui et al found that GO functionalized with polyethylene glycol (PEG) can carry water-insoluble cancer drugs such as camptothecin and SN38 and showed pH-dependent drug release behavior.…”

“…The PAA–GO–BCNU showed promising anticancer efficacy in in vitro study. 47 Yin et al functionalized GO with PEI and (PEG) as a plasmid-based Stat3 siRNA carrier, which showed a significant regression in tumor growth and tumor weight of mouse malignant melanoma growth in vivo. 50 Yang et al developed epidermal growth factor receptor (EGFR) antibody-conjugated PEGylated nanographene oxide (PEG-NGO) carrying epirubicin (EPI) that was able to target the tumor and kill the cancer cells by its triple-therapeutics (growth signal blocking, chemotherapy, photothermal therapy).…”

Potential Role of Carbon Nanomaterials in the Treatment of Malignant Brain Gliomas

“…Already in 2012 Chen et al had incorporated a chemotherapeutic agent, belonging to the nitrosourea family, into a molecule of oxidized graphene conjugated with polyacrylic acid (1,3-bis(2-chloroethyl)-1-nitrosourea). In vitro studies on GL261 glioma cells demonstrated the drug uptake via endocytosis and the greater efficacy of the drug conjugate compared to the virgin drug [49].…”