Milk-derived multi-fluorescent graphene quantum dot-based cancer theranostic system.

An economical green-chemistry approach was used for the synthesis of aqueous soluble graphene quantum dots (GQDs) from cow milk for simultaneous imaging and drug delivery in cancer. The GQDs synthesized using one-pot microwave-assisted heating were multi-fluorescent, spherical in shape having a lateral size of ca. 5nm. The role of processing parameters such as heating time and ionic strength showed a profound effect on photoluminescence properties of GQDs. The GQDs were N-doped and oxygen-rich as confirmed by X-ray photoelectron spectroscopy (XPS) analysis. Cysteamine hydrochloride (Cys) was used to attach an anti-cancer drug berberine hydrochloride (BHC) on GQDs forming GQDs@Cys-BHC complex with c.a. 88% drug loading efficiency. In vitro drug release was studied at the acidic-basic environment and drug kinetics was studied using pharmacokinetic statistical models. The GQDs were biocompatible on L929 cells whereas theranostic GQDs@Cys-BHC complex showed a potent cytotoxic effect on different cancerous cell line models: cervical cancer cell lines such as HeLa cells and breast cancer cells such as MDA-MB-231 confirmed by Trypan blue and MTT-based cytotoxic assays. Furthermore, multi-excitation based cellular bioimaging was demonstrated using confocal laser scanning microscopy (CLSM) and fluorescence microscopy using GQDs as well as GQDs@Cys-BHC complex. Thus, drug delivery (therapeutic) and bioimaging (diagnostic) properties of GQDs@Cys-BHC complex are thought to have a potential in vitro theranostic application in cancer therapy.

[1]  Ya‐Ping Sun,et al.  Carbon "quantum" dots for optical bioimaging. , 2013, Journal of materials chemistry. B.

[2]  Bingpo Zhang,et al.  Optical properties of pH-sensitive carbon-dots with different modifications , 2014 .

[3]  M. Sharon,et al.  Synthesis and Centrifugal Separation of Fluorescent Carbon Dots at Room Temperature , 2013 .

[4]  Hui-Fen Wu,et al.  Synthesis of highly fluorescent hydrophobic carbon dots by hot injection method using Paraplast as precursor. , 2015, Materials science & engineering. C, Materials for biological applications.

[5]  M. Sharon,et al.  Antibiotic Conjugated Fluorescent Carbon Dots as a Theranostic Agent for Controlled Drug Release, Bioimaging, and Enhanced Antimicrobial Activity , 2014, Journal of drug delivery.

[6]  W. Duan,et al.  Graphene quantum dots induce apoptosis, autophagy, and inflammatory response via p38 mitogen-activated protein kinase and nuclear factor-κB mediated signaling pathways in activated THP-1 macrophages. , 2015, Toxicology.

[7]  L. Dai,et al.  Highly luminescent carbon nanodots by microwave-assisted pyrolysis. , 2012, Chemical communications.

[8]  Hans Clevers,et al.  The cancer stem cell: premises, promises and challenges , 2011, Nature Medicine.

[9]  Fan Yang,et al.  Carbon-based quantum dots for fluorescence imaging of cells and tissues , 2014 .

[10]  C. Blanpain,et al.  Unravelling cancer stem cell potential , 2013, Nature Reviews Cancer.

[11]  Dong-Ung Lee,et al.  Antimicrobial activity of 8-alkyl- and 8-phenyl-substituted berberines and their 12-bromo derivatives , 1998 .

[12]  Sudhir Ravula,et al.  Pee-dots: biocompatible fluorescent carbon dots derived from the upcycling of urine , 2016 .

[13]  M. Gottesman.  Mechanisms of cancer drug resistance. , 2002, Annual review of medicine.

[14]  Prasanta Chowdhury,et al.  Kinetic modeling on drug release from controlled drug delivery systems. , 2010, Acta poloniae pharmaceutica.

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

[16]  Zhenhui Kang,et al.  Carbon nanodots: synthesis, properties and applications , 2012 .

[17]  Zhaoxu Liu,et al.  Induction of G1 cell cycle arrest and apoptosis by berberine in bladder cancer cells. , 2011, European journal of pharmacology.

[18]  S. Mineshita,et al.  The effect of berberine chloride on experimental colitis in rats in vivo and in vitro. , 2000, The Journal of pharmacology and experimental therapeutics.

[19]  M. Sharon,et al.  Biogenic gold nanoparticles as fotillas to fire berberine hydrochloride using folic acid as molecular road map. , 2013, Materials science & engineering. C, Materials for biological applications.

[20]  Roopa Dharmatti,et al.  Synthesis of mesoporous silica oxide/C-dot complex (meso-SiO2/C-dots) using pyrolysed rice husk and its application in bioimaging , 2014 .

[21]  Yuguo Tang,et al.  Recent advances in carbon nanodots: synthesis, properties and biomedical applications. , 2015, Nanoscale.

[22]  Paul C. Wang,et al.  Circumventing tumor resistance to chemotherapy by nanotechnology. , 2010, Methods in molecular biology.

[23]  Jingyan Zhang,et al.  Graphene: Insight into the Cellular Internalization and Cytotoxicity of Graphene Quantum Dots (Adv. Healthcare Mater. 12/2013) , 2013 .

[24]  Xiangkai Li,et al.  Application of cow milk-derived carbon dots/Ag NPs composite as the antibacterial agent , 2015 .

[25]  Y. Chi,et al.  Electrochemiluminescence of water-soluble carbon nanocrystals released electrochemically from graphite. , 2009, Journal of the American Chemical Society.

[26]  Ya‐Ping Sun,et al.  Carbon dots for optical imaging in vivo. , 2009, Journal of the American Chemical Society.

[27]  Jin Xie,et al.  Nanoparticle-based theranostic agents. , 2010, Advanced drug delivery reviews.

[28]  Young-Chul Lee,et al.  Photoluminescent green carbon nanodots from food-waste-derived sources: large-scale synthesis, properties, and biomedical applications. , 2014, ACS applied materials & interfaces.

[29]  J. Xu,et al.  Effects of Berberine on Cell Cycle, DNA, Reactive Oxygen Species, and Apoptosis in L929 Murine Fibroblast Cells , 2015, Evidence-based complementary and alternative medicine : eCAM.

[30]  Ya‐Ping Sun,et al.  Versatility with carbon dots – from overcooked BBQ to brightly fluorescent agents and photocatalysts , 2013 .

[31]  M. Sharon,et al.  Encapsulation of Berberine in Nano-Sized PLGA Synthesized by Emulsification Method , 2012 .

[32]  M. Sharon,et al.  Swarming carbon dots for folic acid mediated delivery of doxorubicin and biological imaging. , 2014, Journal of materials chemistry. B.

[33]  S. Sahoo,et al.  Cancer nanotechnology: application of nanotechnology in cancer therapy. , 2010, Drug discovery today.

[34]  O. Shenderova,et al.  Evidence of carbon nanoparticle–solvent molecule interactions in Raman and fluorescence spectra , 2015 .

[35]  X. Qu,et al.  Luminescent carbon dot-gated nanovehicles for pH-triggered intracellular controlled release and imaging. , 2013, Langmuir : the ACS journal of surfaces and colloids.

[36]  James M. Tour,et al.  Growth of graphene from food, insects, and waste. , 2011, ACS nano.

[37]  Mira Park,et al.  Synthesis of carbon quantum dots from cabbage with down- and up-conversion photoluminescence properties: excellent imaging agent for biomedical applications , 2015 .

[38]  Jingyan Zhang,et al.  Insight into the Cellular Internalization and Cytotoxicity of Graphene Quantum Dots , 2013, Advanced healthcare materials.

[39]  M. Sharon,et al.  Cysteamine hydrochloride protected carbon dots as a vehicle for the efficient release of the anti-schizophrenic drug haloperidol , 2013 .

[40]  Roopa Dharmatti,et al.  Biogenic Synthesis of Fluorescent Carbon Dots at Ambient Temperature Using Azadirachta indica (Neem) gum , 2015, Journal of Fluorescence.

[41]  Jian-Hua Wang,et al.  Unusual emission transformation of graphene quantum dots induced by self-assembled aggregation. , 2012, Chemical communications.

[42]  Ya‐Ping Sun,et al.  Quantum-sized carbon dots for bright and colorful photoluminescence. , 2006, Journal of the American Chemical Society.

[43]  N. Mishra,et al.  Carbon dots functionalized gold nanorod mediated delivery of doxorubicin: tri-functional nano-worms for drug delivery, photothermal therapy and bioimaging. , 2013, Journal of materials chemistry. B.

[44]  Youfu Wang,et al.  Carbon quantum dots: synthesis, properties and applications , 2014 .

[45]  M. Sharon,et al.  Camphor-mediated synthesis of carbon nanoparticles, graphitic shell encapsulated carbon nanocubes and carbon dots for bioimaging , 2016, Scientific Reports.

[46]  Djordje Klisic,et al.  Graphene quantum dots as autophagy-inducing photodynamic agents. , 2012, Biomaterials.

[47]  Chengzhou Zhu,et al.  Bifunctional fluorescent carbon nanodots: green synthesis via soy milk and application as metal-free electrocatalysts for oxygen reduction. , 2012, Chemical Communications.

[48]  Y. Hsieh,et al.  Inhibitory effect of berberine on the invasion of human lung cancer cells via decreased productions of urokinase-plasminogen activator and matrix metalloproteinase-2. , 2006, Toxicology and applied pharmacology.

[49]  Yitao Wang,et al.  Berberine hydrochloride: anticancer activity and nanoparticulate delivery system , 2011, International journal of nanomedicine.

[50]  Pallavi Sethi,et al.  Tumor microenvironment and nanotherapeutics. , 2013, Translational cancer research.

[51]  N. Mishra,et al.  Green synthesis of biocompatible carbon dots using aqueous extract of Trapa bispinosa peel. , 2013, Materials science & engineering. C, Materials for biological applications.

[52]  S. Ghosh,et al.  Presence of Amorphous Carbon Nanoparticles in Food Caramels , 2012, Scientific Reports.

[53]  Ki Young Choi,et al.  Theranostic nanoplatforms for simultaneous cancer imaging and therapy: current approaches and future perspectives. , 2012, Nanoscale.

[54]  Alicia Fernandez-Fernandez,et al.  Theranostic Applications of Nanomaterials in Cancer: Drug Delivery, Image-Guided Therapy, and Multifunctional Platforms , 2011, Applied biochemistry and biotechnology.