Polymer Bulletin

, Volume 74, Issue 6, pp 2159–2184 | Cite as

Synthesis, structural characterization, and antiproliferative/cytotoxic effects of a novel modified poly(maleic anhydride-co-vinyl acetate)/doxorubicin conjugate

  • Gulderen Karakus
  • Abdulilah Ece
  • Ayse Sahin Yaglioglu
  • Haci Bayram Zengin
  • Mesut Karahan
Original Paper

Abstract

Drug carrier, poly(maleic anhydride-co-vinyl acetate) (MAVA or poly[MA-co-VA]) copolymer, was traditionally synthesized by free radical chain polymerization reaction, in methyl ethyl ketone (MEK) organic media at 80 °C, using benzoyl peroxide (BPO) as the radicalic initiator. The purified copolymer was then modified with a chemotherapeutic agent, doxorubicin hydrochloride (DOX) at 75 °C for 72 h, using N-(3-dimethyl-aminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) as the carboxylic acid-activating agent. Structural characterization of the MAVA and the modified MAVA/DOX conjugate was carried out by Fourier transform infrared (FTIR) and nuclear magnetic resonance (1H-NMR and 13C-NMR). Their molecular weights were determined by size-exclusion chromatography (SEC). The spectroscopic and SEC results confirmed that conjugated/modification reaction was successfully carried out. UV spectrophotometric measurements indicated that MAVA/DOX preserved its molecular stability in physiological body fluid, PBS (physiological pH 7.40 at 37 °C). Antiproliferative activities of MAVA/DOX were determined by BrdU cell proliferation ELISA assay using C6 (Rat Brain tumor cells) and HeLa (human uterus carcinoma) cell lines in vitro by comparing with free DOX agent (reference compound). Although MAVA showed low antiproliferative activity, both MAVA/DOX and DOX exhibited greater activity against HeLa and C6. Lactate dehydrogenase (LDH) leakage assay was performed for MAVA/DOX and DOX, which detected a non-toxic effect against C6 even at the highest dose (100 μg/mL). IC50 and IC75 values were also determined using ED50 plus v1.0. Molecular modeling at M06-L/6-31 + G(d,p)//AM1 level showed that the electron density in MAVA/DOX is more localized resulting a higher polarization and thereby a higher dipole moment which shed light on the solubility of MAVA/DOX conjugate.

Graphical abstract

Keywords

Poly(maleic anhydride-co-vinyl acetate) modification Doxorubicin hydrochloride Antiproliferative and cytotoxic activity HeLa and C6 cell lines Computational study Electrostatic potential counter map 

References

  1. 1.
    Thakur VK, Thakur MK, Popescu I (2015) Handbook of polymers for pharmaceutical technologies: processing and applications, vol 2. Scrivener Publishing. doi:10.1002/9781119041412.ch10
  2. 2.
    Florence AT, Siepmann J (2009) Modern pharmaceutics: basic principles and systems, vol 1, 5th edn. CRC Press, Boca RatonGoogle Scholar
  3. 3.
    Bacu E, Chitanu GC, Couture A, Grandclaudon P, Singurel Gh, Carpov A (2002) Potential drug delivery systems from maleic anhydride copolymers and phenothiazine derivatives. Eur Polym J 38:1509–1513CrossRefGoogle Scholar
  4. 4.
    Saad GR, Morsi RE, Mohammady SZ, Elsabee MZ (2008) Dielectric relaxation of monoesters based poly(styrene-co-maleic anhydride) copolymer. J Polym Res 15:115–123. doi:10.1007/s10965-007-9150-6 CrossRefGoogle Scholar
  5. 5.
    Atıcı OG, Akar A, Rahimian R (2001) Modification of poly(maleic anhydride-co- styrene) with hydroxyl containing compounds. Turk J Chem 25:259–266Google Scholar
  6. 6.
    Patel H, Raval DA, Madamwar D, Patel SR (1998) Polymeric prodrug: synthesis, release study and antimicrobial property of poly(styrene-co-maleic anhydride)-bound acriflavine. Angew Makromol Chem 263:25–30CrossRefGoogle Scholar
  7. 7.
    Liu HY, Cao K, Yao Z, Li BG, Hu GH (2007) Variations of the glass-transition temperature in the imidization of poly(styrene-co-maleic anhydride). J Appl Polym Sci 104:2418–2422. doi:10.1002/app.25917 CrossRefGoogle Scholar
  8. 8.
    Kumar N, Langer RS, Domb AJ (2002) Polyanhydrides: an overview. Adv Drug Deliv Rev 54:889–910. doi:10.1016/S0169-409X(02)00050-9 CrossRefGoogle Scholar
  9. 9.
    Chiellini F, Piras AM, Errico C, Chiellini E (2008) Nanomedicine 3:367–393. doi:10.2217/17435889.3.3.367 CrossRefGoogle Scholar
  10. 10.
    Popescu I, Suflet DM, Pelin IM, Chitanu GC (2011) Biomedical applications of maleic anhydride copolymers. Rev Roum Chim 56:173–188Google Scholar
  11. 11.
    Riabtseva A, Mitina N, Grytsyna I, Boiko N, Garamus VM, Stryhanyuk H, Stoika R, Zaichenko A (2016) Functional micelles formed by branched polymeric surfactants: synthesis, characteristics, and application as nanoreactors and carriers. Eur Polym J 75:406–422. doi:10.1016/j.eurpolymj.2016.01.006 CrossRefGoogle Scholar
  12. 12.
    Song F, Li X, Wang Q, Liao L, Zhang C (2014) Nanocomposite hydrogels and their applications in drug delivery and tissue engineering. J Biomed Nanotechnol 10:1–13CrossRefGoogle Scholar
  13. 13.
    Wang L, Kritensen J, Ruffner DE (1998) Delivery of antisense oligonucleotides using HPMA polymer: synthesis of A thiol polymer and its conjugation to water-soluble molecules. Bioconjug Chem 9:749–757CrossRefGoogle Scholar
  14. 14.
    Ulbrich K, Šubr V (2010) Adv Drug Deliver Rev 62:150–166CrossRefGoogle Scholar
  15. 15.
    Kadaji VG, Betageri CV (2011) Water soluble polymers for pharmaceutical applications. Polymers 3:1972–2009. doi:10.3390/polym3041972 CrossRefGoogle Scholar
  16. 16.
    Cho K, Wang X, Nie S, Chen ZG, Shin DM (2008) Therapeutic nanoparticles for drug delivery in cancer. Clin Cancer Res 14:1310–1316. doi:10.1158/1078-0432.CCR-07-1441 CrossRefGoogle Scholar
  17. 17.
    Minko T (2005) Soluble polymer conjugates for drug delivery. Drug Discov Today Tech 2:15–20CrossRefGoogle Scholar
  18. 18.
    Li C, Wallace S (2008) Polymer-drug conjugates: recent development in clinical oncology. Adv Drug Deliv Rev 60:886–898CrossRefGoogle Scholar
  19. 19.
    Duncan R (1999) Polymer conjugates for tumour targeting and intracytoplasmic delivery. The EPR effect as a common gateway? Res Focus Rev 2:441–449Google Scholar
  20. 20.
    Hoste K, Winne KD, Schacht E (2004) Polymeric prodrugs. Int J Pharmaceut 277:119–131CrossRefGoogle Scholar
  21. 21.
    Ringsdorf H (1975) Structure and properties of pharmacologically active polymers. J Polym Sci 51:135–153Google Scholar
  22. 22.
    Breslow DS (1976) Biologically active synthetic polymers. Pure Appl Chem 46:103–113CrossRefGoogle Scholar
  23. 23.
    Dhal PK, Holmes-Farley SR, Huval CC, Jozefiak TH (2006) Polymers as drugs. Adv Polym Sci 192:9–58CrossRefGoogle Scholar
  24. 24.
    Duncan R (2003) The dawning era of polymer therapeutics. Nat Rev Drug Discov 2:347–360CrossRefGoogle Scholar
  25. 25.
    Greish K, Sawa T, Fang J, Akaika T, Maeda H (2004) SMA-doxorubicin, a new polymeric micellar drug for effective targeting to solid tumors. J Control Release 97:219–230CrossRefGoogle Scholar
  26. 26.
    Maeda H, Ueda M, Morinaga T, Matsumoto T (1985) Conjugation of poly(styrene-co-maleic acid) derivatives to the antitumor protein neocarzinostatin: pronounced improvements in pharmacological properties. J Med Chem 28:455–461CrossRefGoogle Scholar
  27. 27.
    Kobayashi A, Oda T, Maeda H (1988) Protein binding of macromolecular anticancer agent SMANCS: characterization of poly(styrene-co-maleic acid) derivatives as an albumin binding ligand. J Bioact Compat Polym 3:319–333CrossRefGoogle Scholar
  28. 28.
    Ohtsuka N, Konno T, Myauchi Y, Meada H (1987) Anticancer effects of arterial administration of the anticancer agent SMANCS with lipiodol on metastatic lymph nodes. Cancer 59:1560–1565CrossRefGoogle Scholar
  29. 29.
    Maeda H, Matsumoto T, Konno T, Iwai K, Ueda M (1984) Tailor-making of protein drugs by polymer conjugation for tumor targeting: a brief review on Smancs. J Protein Chem 3:181–193CrossRefGoogle Scholar
  30. 30.
    Greish K, Fang J, Inutsuka T, Nagamitsu A, Maeda H (2003) Macromolecular Therapeutics: advantages and prospects with special emphasis on solid tumour targeting. Clin Pharmacokinet 42:1089–1105CrossRefGoogle Scholar
  31. 31.
    Maeda H (1991) SMANCS and polymer-conjugated macromolecular drugs: advantages in cancer chemotherapy. Adv Drug Deliv Rev 6:181–202CrossRefGoogle Scholar
  32. 32.
    DiMarco A, Gaetani M, Scarpinato B (1969) Adriamycin (NSC-123, 127): a new antibiotic with antitumor activity. Cancer Chemother Rep 53:33–37Google Scholar
  33. 33.
    Bruch M, Mäder D, Bauers F, Loontjens T, Mülhaupt R (2000) Melt modification of poly(styrene-co-maleic anhydride) with alcohols in the presence of 1,3-oxazolines. J Polym Sci 38:1222–1231. doi:10.1002/(SICI)1099-0518(20000415)38:8<1222:AID-POLA5>3.0.CO;2-Z CrossRefGoogle Scholar
  34. 34.
    Ece A, Boris P (2014) A computational insight into acetylcholinesterase inhibitory activity of a new lichen depsidone. J Enzyme Inhib Med Chem. doi:10.3109/14756366.2014.949256 Google Scholar
  35. 35.
    Dewar MJS, Zoebisch EG, Stewart JJP (1985) The development and use of quantum mechanical molecular models. 76. AMI: a new general purpose quantum mechanical molecular model. J Am Chem Soc 107:3902–3909CrossRefGoogle Scholar
  36. 36.
    Zhao Y, Truhlar DG (2006) A new local density functional for main-group thermochemistry, transition metal bonding, thermochemical kinetics, and noncovalent interactions. J Chem Phys 125:1–17Google Scholar
  37. 37.
    Zhao Y, Truhlar DG (2008) The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: two new functionals and systematic testing of four M06-class functionals and 12 other functionals. Theor Chem Acc 120:215–241CrossRefGoogle Scholar
  38. 38.
    Jacquemin D, Perpete EA, Ciofini I et al (2010) On the performances of the M06 family of density functionals for electronic excitation energies. J Chem Theory Comput 6:2071–2085CrossRefGoogle Scholar
  39. 39.
    Karakus G, Zengin HB, Akin Polat Z, Yenidunya AF, Aydin S (2013) Cytotoxicity of three maleic anhydride copolymers and common solvents used for polymer solvation. Polym Bull 70:1591–1612. doi:10.1007/s00289-012-0860-5 CrossRefGoogle Scholar
  40. 40.
    Nguyen V, Yoshida W, Cohen Y (2003) J Appl Polym Sci 87:300–310CrossRefGoogle Scholar
  41. 41.
    Fles D, Vukovic R, Kuzmic AE, Bogdanic G, Pilizota V, Karlovic D, Markus K, Wolsperger K, Vikic-Topic D (2003) Croat Chem Acta 76:69–74Google Scholar
  42. 42.
    Karakus G, Akin Polat Z, Sahin Yaglioglu A, Karahan M, Yenidunya AF (2013) Synthesis, characterization, and assessment of cytotoxic, antiproliferative, and antiangiogenic effects of a novel procainamide hydrochloride-poly(maleic anhydride-co-styrene) conjugate. J Biomat Sci Polym E 24:1260–1276. doi:10.1080/09205063.2012.750209 CrossRefGoogle Scholar
  43. 43.
    Khaon MK (1982) Synthesis of esters. J Org Chem 47:1962–1965CrossRefGoogle Scholar
  44. 44.
    Lundblad RL et al (1984) Modification of carboxyl groups in proteins. Chem Reag Protein Modif 2:105Google Scholar
  45. 45.
    Chernikova E, Terpugova P, Bui C, Charleux B (2003) Effect of comonomer composition on the controlled free-radical copolymerization of styrene and maleic anhydride by reversible addition-fragmentation chain transfer (RAFT). Polymer 44:4101–4107CrossRefGoogle Scholar
  46. 46.
    Li Y, Richard-Turner S (2010) Free radical copolymerization of methyl substituted stilbenes with maleic anhydride. Eur Polym J 46:821–828CrossRefGoogle Scholar
  47. 47.
    Sundell AM, Luttikhedde HJG (1999) Drug release from ionomer cements based on hydrolyzed poly(vinyl acetate-maleic anhydride). Pure Appl Chem A36:1045–1059Google Scholar
  48. 48.
    Demirtas I, Sahin A, Ayhan B, Tekin S, Telci I (2009) Antiproliferative effects of the methanolic extracts of sideritis libanotica labill. subsp. linearis. Rec Nat Prod 3:104–109Google Scholar
  49. 49.
    Demirtas I, Sahin A (2013) Bioactive volatile content of the stem and root of Centaurea carduiformis DC. subsp. carduiformis var. carduiformis. J Chem 2013:125286-1–125286-6. doi:10.1155/2013/125286 CrossRefGoogle Scholar
  50. 50.
    Sahin-Yaglıoglu A, Akdulum B, Erenler R, Demirtas I, Telci I, Tekin S (2013) Antiproliferative activity of pentadeca-(8E, 13Z) dien 11-yn-2-one and (E)-1,8-pentadecadiene from Echinacea pallida (Nutt.) Nutt. roots. Med Chem Res. doi:10.1007/s00044-012-0297-2
  51. 51.
    Frisch MJ, Trucks GW, Schlegel HB et al (2009) Gaussian 09, Revision C.01. Gaussian, Inc., WallingfordGoogle Scholar
  52. 52.
    Tasdemir IH, Ece A, Kilic E (2012) Experimental and theoretical study on the electrochemical behavior of zofenopril and its voltammetric determination. Curr Pharm Anal 8(4):339–348CrossRefGoogle Scholar
  53. 53.
    (2015) Small-Molecule Drug Discovery Suite 2015-2: QikProp, version 4.4. Schrödinger, LLC, New YorkGoogle Scholar
  54. 54.
    Yoon KJ, Woo JH, Seo YS (2003) Formaldehyde free cross-linking agents based on maleic anhydride copolymers. Fiber Polym 4:182–187CrossRefGoogle Scholar
  55. 55.
    Xiao CM, Tan J, Xue GN (2010) Synthesis and properties of starch-g-poly(maleic anhydride-co-vinyl acetate). Express Polym Lett 4:9–16CrossRefGoogle Scholar
  56. 56.
    Chitanu GC, Popescu I, Carpov A (2006) Synthesis and characterization of maleic anhydride copolymers and their derivatives. 2. New data on the copolymerization of maleic anhydride with vinyl acetate. Rev Roum Chim 51:923–929Google Scholar
  57. 57.
    Krayukhina MA, Kozybakova SA, Samoilava NA, Babak VG, Karaeva SZ, Yamskov IA (2007) Synthesis and properties of amphiphilic maleic acid copolymers. Russ J Appl Chem 80:1145–1150. doi:10.1134/S1070427207070269 CrossRefGoogle Scholar
  58. 58.
    Qiao Z, Xie Y, Chen M, Xu J, Zhu Y, Qian Y (2000) Synthesis of lead sulfide/(polyvinyl acetate) nanocomposites with controllable morphology. Chem Phys Lett 321:504–507CrossRefGoogle Scholar
  59. 59.
    Sunel V, Popa M, Stoican AD, Popa AA, Uglea C (2008) Poly (maleic anhydride-alt-vinyl acetate) conjugate with alkylating agents. Materiale Plastice 45:149–153Google Scholar
  60. 60.
    Rzayev ZMO (2011) Graft copolymers of maleic anhydride and its isostructural analogues: high performance engineering materials. Int Rev Chem Eng 3:153–215Google Scholar
  61. 61.
    Pal J, Singh H, Ghosh AK (2004) Modification of LLDPE using esterified styrene maleic anhydride copolymer: study of its properties and environmental degradability. J Appl Polym Sci 92:102–108CrossRefGoogle Scholar
  62. 62.
    Jeong JH, Byoun YS, Ko SB, Lee YS (2001) Chemical modification of poly(styrene-alt-maleic anhydride) with antimicrobial 4-aminobenzoic acid and 4-hydroxybenzoic acid. J Ind Eng Chem 7:310–315Google Scholar
  63. 63.
    Xiao L, Shimotani H, Ozawa M, Li J, Dragoe N, Saigo K, Kitazawa K (1999) Synthesis of a novel [60]fullerene pearl-necklace polymer, poly(4,4*-carbonylbisphenylene trans-2-[60]fullerenobisacetamide). J Polym Sci Pol Chem 37:3632–3637CrossRefGoogle Scholar
  64. 64.
    John J, Dalal MK, Patel DR, Ram RN (1997) Preparation, properties, and catalytic application of polymer-bound Ru(III) complexes. JMS Pure Appl Chem A34:489–501Google Scholar
  65. 65.
    Tripp RA, Dluhy RA, Zhao Y (2008) Novel nanostructures for SERS biosensing. Nanotoday (Review) 3:31–37CrossRefGoogle Scholar
  66. 66.
    Kaplan Can H, Doğan AL, Rzaev ZMO, Uner AH, Güner A (2005) Synthesis and antitumor activity of poly(3,4-dihydro-2H-pyran-co-maleic anhydride-co-vinyl acetate). J Appl Polym Sci 96:2352–2359CrossRefGoogle Scholar
  67. 67.
    Balaji R, Nanjundan S (1999) Copolymerization of 3-methoxy-4-methacryloyloxybenzal phenylimine with methyl methacrylate. Eur Polym J 35:1133–1138CrossRefGoogle Scholar
  68. 68.
    Sato M, Ohta R, Handa M, Kasuga K (2002) Thermotropic liquid crystalline polymers containing five-membered heterocyclic groups VIII. Synthesis, and liquid crystalline and photoluminescent properties of semi-rigid polyesters based on a distyrylbenzene analogue of 1,3,4-thiadiazole. Liq Cryst 29:1441–1446CrossRefGoogle Scholar
  69. 69.
    Ghosh S, Banthia AK (2003) An approach to novel polyamidoamine (PAMAM) side chain dendritic polyesterurethane (SCDPEU) block copolymer architectures. Eur Polym J 39:2141–2146CrossRefGoogle Scholar
  70. 70.
    Ferruti P, Ranucci E, Trotta F, Gianasi E, Evagorou EG, Wasil M, Wilson G, Duncan R (1999) Synthesis, characterization and antitumour activity of platinum (II) complexes of novel functionalized poly(amido amine)s. Macromol Chem Phys 200:1644–1654CrossRefGoogle Scholar
  71. 71.
    Karakus G, Akin Polat Z, Yenidunya AF, Zengin HB, Karakus CB (2013) Synthesis, characterization and cytotoxicity of novel modified poly[(maleic anhydride)-co-(vinyl acetate)]/noradrenaline conjugate. Polym Int 62:492–500. doi:10.1002/pi.4341 CrossRefGoogle Scholar
  72. 72.
    Zafar F, Sharmin E, Ashraf SM, Ahmad S (2004) Studies on poly(styrene-co-maleic anhydride)-modified polyesteramide-based anticorrosive coatings synthesized from a sustainable resource. J Appl Polym Sci 92:2538–2544CrossRefGoogle Scholar
  73. 73.
    Ak M, Durmus A, Toppare L (2007) Synthesis and characterization of poly(N-(2-(thiophen-3-yl)methylcarbonyloxyethyl) maleimide) and its spectroelectrochemical properties. J Appl Electrochem 37:729–735CrossRefGoogle Scholar
  74. 74.
    Rajput RS, Rupainwar DC, Singh RK, Singh A (2009) Study on characterization and degree of esterification of styrene maleic anhydride by some medicines. Indian J Chem B 48:1597–1600Google Scholar
  75. 75.
    Wang S, Wang M, Lei Y, Zhang L (1999) “Anchor effect” in poly(styrene maleic anhydride)/TiO2 nanocomposites. J Mater Sci Lett 18:2009–2012CrossRefGoogle Scholar
  76. 76.
    Edwards HGM, Hickmott E, Hughes MA (1997) Vibrational spectroscopic studies of potential amidic extractants for lanthanides and actinides in nuclear waste treatment. Spectrochim Acta A 53:43–53Google Scholar
  77. 77.
    Coskun M, Seven P (2011) Synthesis, characterization and investigation of dielectric properties of two-armed graft copolymers prepared with methyl methacrylate and styrene onto PVC using atom transfer radical polymerization. React Funct Polym 71:395–401CrossRefGoogle Scholar
  78. 78.
    Hwang S, Lee CH, Ahn IS (2008) Product identification of guaiacol oxidation catalyzed by manganese peroxidase. J Ind Eng Chem 14:487–492CrossRefGoogle Scholar
  79. 79.
    Lee E, Moon BH, Park Y, Hong S, Lee S, Lee Y, Lim Y (2008) Effects of hydroxy and methoxy substituents on NMR data in flavonols. Bull Korean Chem Soc 29:507–510CrossRefGoogle Scholar
  80. 80.
    Nemtoi G, Beldie C, Tircolea C, Popa I, Cretescu I, Humelnicu I, Humelnicu D (2001) Behaviour of the poly(maleic anhydride-co-vinyl acetate) copolymer in aqueous solutions. Eur Polym J 37:729–735CrossRefGoogle Scholar
  81. 81.
    Sun CZ, Lu CT, Zhao YZ, Guo P, Tian JL, Zhang L, Li XK, Lv HF, Dai DD, Li X (2011) Characterization of the doxorubicin-pluronic F68 conjugate micelles and their effect on doxorubicin resistant human erythroleukemic cancer cells. J Nanomed Nanotechnol 2:2–6Google Scholar
  82. 82.
    Sanmathi CS, Prasannakumar S, Sherigara BS (2004) Terpolymerization of 2-ethoxy ethylmethacrylate, styrene and maleic anhydride: determination of the reactivity ratios. Bull Mater Sci 27:243–249CrossRefGoogle Scholar
  83. 83.
    Ranjbar-Karimi R, Loghmani-Khouzani H (2011) Synthesis of new azines in various reaction conditions and investigation of their cycloaddition reaction. J Iran Chem Soc 8:223–230CrossRefGoogle Scholar
  84. 84.
    Mustata F, Bicu I (2006) P-aminobenzoic acid/cyclohexanon/formaldehyde resins as hardner for epoxy resins. Synthesis and characterization. J Optoelectron Adv M 8:871–875Google Scholar
  85. 85.
    Barron PF, Hill DJT, O’Donnell JH, O’Sullivan PW (1984) Applications of DEPT experiments to the 13C NMR of copolymers: poly(styrene-co-maleic anhydride) and poly (styrene-co-acrylonitrile). Macromol 17:1967–1972CrossRefGoogle Scholar
  86. 86.
    Sanchez CO, Alvarado F, Bustos CJ, Schott E, Gatica N, Valdebenito K (2007) Synthesis, characterization, thermal stability and fluorescence of hybrid polymers prepared from amino-phenyl esters. Polym Bull 59:19–330. doi:10.1007/S00289-007-0776-7 CrossRefGoogle Scholar
  87. 87.
    Ocampo-Fernández M, Herrera AM, Méndez-Bautista T, Garcia-Serrano J (2009) Synthesis and characterization of diethyl-p-vinylbenzyl phosphonate monomer: precursor of ion exchange polymers for fuel cells. Superficies y Vacío 22:6–10Google Scholar
  88. 88.
    Lai MF, Li J, Liu JJ (2005) Thermal and dynamic mechanical properties of poly(propylene carbonate). J Therm Anal Calorim 82:293–298CrossRefGoogle Scholar
  89. 89.
    Yang X, Zhang X, Liu Z, Ma Y, Huang Y, Chen Y (2008) High-efficiency loading and controlled release of doxorubicin hydrochloride on graphene oxide. J Phys Chem C 112:17554–17558CrossRefGoogle Scholar

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© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of Pharmaceutical Chemistry, Faculty of PharmacyCumhuriyet UniversitySivasTurkey
  2. 2.Department of Pharmaceutical Chemistry, Faculty of PharmacyBiruni UniversityIstanbulTurkey
  3. 3.Department of Chemistry, Faculty of ScienceCankırı Karatekin UniversityCankırıTurkey
  4. 4.Department of Chemistry, Faculty of ScienceCumhuriyet UniversitySivasTurkey
  5. 5.Department of Bioengineering, Faculty of Engineering and Natural SciencesÜsküdar UniversityIstanbulTurkey

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