Graphene nanoribbons as a drug delivery agent for lucanthone mediated therapy of glioblastoma multiforme.

We report use of PEG-DSPE coated oxidized graphene nanoribbons (O-GNR-PEG-DSPE) as agent for delivery of anti-tumor drug Lucanthone (Luc) into Glioblastoma Multiformae (GBM) cells targeting base excision repair enzyme APE-1 (Apurinic endonuclease-1). Lucanthone, an endonuclease inhibitor of APE-1, was loaded onto O-GNR-PEG-DSPEs using a simple non-covalent method. We found its uptake by GBM cell line U251 exceeding 67% and 60% in APE-1-overexpressing U251, post 24h. However, their uptake was ~38% and 29% by MCF-7 and rat glial progenitor cells (CG-4), respectively. TEM analysis of U251 showed large aggregates of O-GNR-PEG-DSPE in vesicles. Luc-O-GNR-PEG-DSPE was significantly toxic to U251 but showed little/no toxicity when exposed to MCF-7/CG-4 cells. This differential uptake effect can be exploited to use O-GNR-PEG-DSPEs as a vehicle for Luc delivery to GBM, while reducing nonspecific cytotoxicity to the surrounding healthy tissue. Cell death in U251 was necrotic, probably due to oxidative degradation of APE-1.

[1]  Kai Yang,et al.  Graphene in mice: ultrahigh in vivo tumor uptake and efficient photothermal therapy. , 2010, Nano letters.

[2]  T. Button,et al.  Physicochemical characterization of a novel graphene-based magnetic resonance imaging contrast agent , 2013, International journal of nanomedicine.

[3]  Kofi-Buaku Atsina,et al.  Novel Delivery Strategies for Glioblastoma , 2012, Cancer journal.

[4]  David J. Yang,et al.  Prognostic Effect of Epidermal Growth Factor Receptor and EGFRvIII in Glioblastoma Multiforme Patients , 2005, Clinical Cancer Research.

[5]  J. M. Mason,et al.  Radiation resistance in glioma cells determined by DNA damage repair activity of Ape1/Ref-1. , 2010, Journal of radiation research.

[6]  W. Zong,et al.  Necrotic death as a cell fate. , 2006, Genes & development.

[7]  R. Kaner,et al.  Honeycomb carbon: a review of graphene. , 2010, Chemical reviews.

[8]  Xin Huang,et al.  Multi-functionalized graphene oxide based anticancer drug-carrier with dual-targeting function and pH-sensitivity , 2011 .

[9]  Ralph Weissleder,et al.  A multimodal nanoparticle for preoperative magnetic resonance imaging and intraoperative optical brain tumor delineation. , 2003, Cancer research.

[10]  C. Reutelingsperger,et al.  Annexin V-affinity assay: a review on an apoptosis detection system based on phosphatidylserine exposure. , 1998, Cytometry.

[11]  X. Qin,et al.  Folic acid-conjugated graphene oxide for cancer targeted chemo-photothermal therapy. , 2013, Journal of photochemistry and photobiology. B, Biology.

[12]  Zhuang Liu,et al.  Nano-graphene oxide for cellular imaging and drug delivery , 2008, Nano research.

[13]  M. Kelley,et al.  Role of APE1 in differentiated neuroblastoma SH-SY5Y cells in response to oxidative stress: use of APE1 small molecule inhibitors to delineate APE1 functions. , 2009, DNA repair.

[14]  Mi-Hee Kim,et al.  Biocompatible reduced graphene oxide prepared by using dextran as a multifunctional reducing agent. , 2011, Chemical communications.

[15]  J. Tour,et al.  Longitudinal unzipping of carbon nanotubes to form graphene nanoribbons , 2009, Nature.

[16]  Nancy A Monteiro-Riviere,et al.  Mechanisms of quantum dot nanoparticle cellular uptake. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[17]  M. Berger,et al.  Apurinic/apyrimidinic endonuclease activity is elevated in human adult gliomas. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  Zhuang Liu,et al.  PEGylated nanographene oxide for delivery of water-insoluble cancer drugs. , 2008, Journal of the American Chemical Society.

[19]  Balaji Sitharaman,et al.  Cell specific cytotoxicity and uptake of graphene nanoribbons. , 2013, Biomaterials.

[20]  Hao Hong,et al.  Graphene: a versatile nanoplatform for biomedical applications. , 2012, Nanoscale.

[21]  Samuel H. Wilson,et al.  Lucanthone and Its Derivative Hycanthone Inhibit Apurinic Endonuclease-1 (APE1) by Direct Protein Binding , 2011, PloS one.

[22]  M. Berger,et al.  Apurinic/Apyrimidinic Endonuclease Activity Is Associated with Response to Radiation and Chemotherapy in Medulloblastoma and Primitive Neuroectodermal Tumors , 2005, Clinical Cancer Research.

[23]  D. Begley,et al.  Direct Evidence That Polysorbate-80-Coated Poly(Butylcyanoacrylate) Nanoparticles Deliver Drugs to the CNS via Specific Mechanisms Requiring Prior Binding of Drug to the Nanoparticles , 2003, Pharmaceutical Research.

[24]  M. Berger,et al.  Distribution of Liposomes into Brain and Rat Brain Tumor Models by Convection-Enhanced Delivery Monitored with Magnetic Resonance Imaging , 2004, Cancer Research.

[25]  H. Dai,et al.  Ultrasmall reduced graphene oxide with high near-infrared absorbance for photothermal therapy. , 2011, Journal of the American Chemical Society.

[26]  J. Silber,et al.  The apurinic/apyrimidinic endonuclease activity of Ape1/Ref-1 contributes to human glioma cell resistance to alkylating agents and is elevated by oxidative stress. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[27]  K. Shroyer,et al.  In Vitro Hematological and In Vivo Vasoactivity Assessment of Dextran Functionalized Graphene , 2013, Scientific Reports.

[28]  M. Kelley,et al.  Going APE over ref-1. , 2000, Mutation research.