Polymethyl methacrylate–ovalbumin @ graphene oxide drug carrier system for high anti-proliferative cancer drug delivery

  • Selvakani Prabakaran
  • Murugaraj Jeyaraj
  • Ammavasi Nagaraj
  • Kishor Kumar Sadasivuni
  • Mariappan RajanEmail author
Original Article


High permeable drug delivery mechanism is indispensable for the treatment of various diseases including cancer. Protein-polymeric carriers have enhanced the permeability and therapeutic of bioactive compounds. Here, polymethyl methacrylate (PMMA) as polymer and egg white protein of ovalbumin (OVA) from a natural source of quail egg was developed for the highly permeable biocompatible drug delivery system. A significant anti-cancer drug doxorubicin (DOX) was loaded on this drug delivery system. Graphene oxide (GO)-functionalized OVA–PMMA drug delivery system has increased the surface for an accumulation of drug. The drug-loading capacity and controlled release of the drug were investigated through the dialysis technique with various physiological pH environments. The effect of DOX and GO on the morphology of OVA–PMMA matrix was studied with the help of FT-IR and XRD patterns. Dynamic light scattering study gives the data about the particle size of this OVA–PMMA–GO and OVA–PMMA–GO–DOX. These data matched with the image obtained from SEM and TEM instruments. Cytotoxicity effect and cellular uptaking of DOX-loaded OVA–PMMA and OVA–PMMA–GO were investigated on gastric cancer cell line and normal cell line. All these characterizations of this study reveal that the drug is successfully loaded on this new drug carrier and controlled release was achieved.


Chemotherapy Drug delivery system Doxorubicin Graphene oxide Ovalbumin 



M. Rajan acknowledges major financial support from the Department of Science and Technology, Science and Engineering Research Board (Ref. YSS/2015/001532; New Delhi, India) and also acknowledges the DST-PURSE program for the purchase of SEM and FT-IR, and UPE programs for the purchase of TEM.

Supplementary material

13204_2019_950_MOESM1_ESM.docx (2.6 mb)
Supplementary material 1 (DOCX 2673 KB)


  1. Abdullah K, Ismail M, Hussein-Al-Ali SH, Ibrahim TA, Zakaria ZA (2013) In vitro delivery and controlled release of doxorubicin for targeting osteosarcoma bone cancer. Molecules 18:10580–10598. CrossRefGoogle Scholar
  2. Angelopoulou A, Voulgari E, Diamanti EK, Gournis D, Avgoustakis K (2015) Graphene oxide stabilized by PLA–PEG copolymers for the controlled delivery of paclitaxel. Eur J Pharm Biopharm 93:18–26. CrossRefGoogle Scholar
  3. Aungst BJ (1994) Permeability and metabolism as barriers to transmucosal delivery of peptides and proteins. Drugs Pharm Sci 62:323–343Google Scholar
  4. Chen D, Hongbin F, Jinghong L (2012) Graphene oxide: preparation, functionalization, and electrochemical applications. ACS Chem Rev 112:6027–6053. CrossRefGoogle Scholar
  5. Daniela C, Dmitry V, Jacob M, Alexander S, Zhengzong S, Alexander S, Lawrence B, Wei LU, James M (2010) Improved synthesis of graphene oxide. ACS Nano 4:4806–4814. CrossRefGoogle Scholar
  6. Danmaigoro A, Gayathri Thevi S, Mohd Noor M, Mahmud R, Zakaria Md (2017) Development of Cockleshell (Anadara granosa) derived CaCO3 nanoparticle for doxorubicin delivery. J Comput Theor Nanosci 14:5074–5086. CrossRefGoogle Scholar
  7. Dinesh Pratap S, Herreraa CE, Singhb B, Singhc S, Rajesh Kumar S, Rajesh K (2018) Graphene oxide: an efficient material and recent approach for biotechnological and biomedical applications. Mater Sci Eng C. Google Scholar
  8. Duan G, Zhang C, Li A, Yang X, Lu L, Wang X (2008) Preparation and characterization of mesoporous zirconia made by using a poly(methyl methacrylate) template. Nanoscale Res Lett 3:118–122. CrossRefGoogle Scholar
  9. Elvira C, Fanovich A, Fernández M, Fraile J, San Román J, Domingo C (2004) Evaluation of drug delivery characteristics of microspheres of PMMA–PCL–cholesterol obtained by supercritical-CO2 impregnation and by dissolution-evaporation techniques. J Controlled Released 99:231–240. CrossRefGoogle Scholar
  10. Elzoghby AO, Samy WM, Nazik A (2011) Albumin-based nanoparticles as potential controlled release drug delivery systems. J Controlled Released 157:168–182. CrossRefGoogle Scholar
  11. Fei C, Jinyan L, Yang L, Yanxiu L, Hongjie W, Fei Y, Mengmeng J, Xiangrui Y, Shichao W, Liya X, Shefang Y, Fanghong L, Zhenqing H (2015) Bacillus-shape design of polymer based drug delivery systems with Janus-faced function for synergistic targeted drug delivery and more effective cancer therapy. Mol Pharm 12:1318–1327. CrossRefGoogle Scholar
  12. Feng H, Li Y, Li J (2012) Strong reduced graphene oxide–polymer composites: hydrogels and wires. RSC Adv 2:6988–6993CrossRefGoogle Scholar
  13. Govindaraj D, Rajan M (2017) Binary functional porous multi mineral–substituted apatite nanoparticles for reducing osteosarcoma colonization and enhancing osteoblast cell proliferation. Mater Sci Eng C. Google Scholar
  14. Gunduz U, Keskin T, Tansık G, Mutlu P, Yalcın S, Unsoy G, Yakar A, Khodadust R, Gunduz G (2014) Idarubicin-loaded folic acid conjugated magnetic nanoparticles as a targetable drug delivery system for breast cancer. Biomed Pharm. Google Scholar
  15. Hassan N, Ahad A, Ali M, Ali J (2010) Chemical permeation enhancers for transbuccal drug delivery. Expert Opin Drug Deliv 7:97–112. CrossRefGoogle Scholar
  16. He F, Zhao D (2007) Manipulating the size and dispersibility of zerovalent iron nanoparticles by use of carboxymethyl cellulose stabilizers. Environ Sci Technol 41:6216–6221CrossRefGoogle Scholar
  17. Hillaireau H, Couvreur P (2009) Nanocarriers’ entry into the cell: relevance to drug delivery. Mol Life Sci 66:2873–2896. CrossRefGoogle Scholar
  18. Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP (1998) Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci USA 95:4607–4612CrossRefGoogle Scholar
  19. Jahanshahi M, Babaei Z (2008) Protein nanoparticle: a unique system as drug delivery vehicles. Afr J Biotechnol 7:4926–4934. Google Scholar
  20. John Paul H (1982) Use of Hoechst dyes 33258 and 33342 for enumeration of attached and planktonic bacteria. Appl Environ Microbiol 43:939–944Google Scholar
  21. Kedar U, Prasanna P, Supriya S, Kadam V (2010) Advances in polymeric micelles for drug delivery and tumor targeting. Nanomed Nanotechnol Biol Med 2:714–729. CrossRefGoogle Scholar
  22. Kratz F (2008) Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Controlled Released 132:171–183. CrossRefGoogle Scholar
  23. Lohcharoenkal W, Wang L, Chen YC, Rojanasakul Y (2014) Protein nanoparticles as drug delivery carriers for cancer therapy. Biol Med Res Int. Google Scholar
  24. Luo S, Zhang Y, Cao J, He B, Li S (2016) Arginine modified polymeric micelles as a novel drug delivery system with enhanced endocytosis efficiency. Colloids Surf B 148:181–192. CrossRefGoogle Scholar
  25. Maeda H, Wu J, Sawa T, Matsumura Y, Hori K (2000) Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review. J Controlled Released 65:271–284CrossRefGoogle Scholar
  26. Malafaya PB, Silva GA, Reis RL (2007) Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications. Adv Drug Deliv Rev 59:207–233. CrossRefGoogle Scholar
  27. McCallion C, Burthem J, Rees-Unwin K, Golovanov A, Pluen A (2016) Graphene in therapeutics delivery: problems, solutions and future opportunities. Eur J Pharm Biopharm 104:235–250. CrossRefGoogle Scholar
  28. Monga J, Pandit S, Rajinder Singh C, Chetan Singh C, Shailender Singh C, Sharma M (2013) Growth inhibition and apoptosis induction by (+)-Cyanidan-3-ol in hepatocellular carcinoma. PLoS One 8(7):e68710. CrossRefGoogle Scholar
  29. Moumita Roy C, Schumann C, Bhakta-Guha D, Gunjan G (2016) Cancer nanotheranostics: strategies, promises and impediments. Biomed Pharmacother 84:291–304. CrossRefGoogle Scholar
  30. Nicolazzo JA, Reed BL, Finnin BC (2005) Buccal penetration enhancers—how do they really work? J Controlled Released 105:1–15. CrossRefGoogle Scholar
  31. Nitta SK, Numata K (2013) Biopolymer-based nanoparticles for drug/gene delivery and tissue engineering. Int J Mol Sci 14:1629–1654. CrossRefGoogle Scholar
  32. Norakankorn C, Pan Q, Garry L, Kiatkamjornwong S (2007) Synthesis of poly(methyl methacrylate) nanoparticles initiated by 2,20-azoisobutyronitrile via differential microemulsion polymerization. Macromol Rapid Commun 28:1029–1033CrossRefGoogle Scholar
  33. Patel S, Gheewala N, Suthar A, Shah A (2009) In-vitro cytotoxicity activity of Solanum nigrum extract against Hela cell line and Vero cell line. Int J Pharm Pharm Sci 1:38–46Google Scholar
  34. Praphakar RA, Munusamy MA, Rajan M (2017) Development of extended-voyaging anti-oxidant linked amphiphilic polymeric nanomicelles for anti-tuberculosis drug delivery. Int J Pharm 30:168–177. CrossRefGoogle Scholar
  35. Raj Kumar T, Yongjoo C, Jee-Heon J, Yu SY, Han GC, Chul SY, Jong OK (2016) Folate-mediated targeted delivery of combination chemotherapeutics loaded reduced graphene oxide for synergistic chemo-photothermal therapy of cancers. Pharm Res 33:2815–2827CrossRefGoogle Scholar
  36. Rajan M, Murugan M, Ponnamma D, Kishor Kumar S, Munusamy MA (2016) Poly-carboxylic acids functionalized chitosan nanocarriers for controlled and targeted anti-cancer drug delivery. Biomed Pharmacother 83:201–211. CrossRefGoogle Scholar
  37. Rodríguez-Velázquez E, Alatorre-Meda M, Mano JF (2015) Polysaccharide-based nanobiomaterials as controlled release systems for tissue engineering applications. Curr Pharm Des 21:4837–4850CrossRefGoogle Scholar
  38. Sami M, Orazio V, Giuseppe C, Steffen O, Elizabeth H, Maria K, Bernd B, Michael M, Silke H (2015) Graphene oxide-gelatin nanohybrids as functional tools for enhanced carboplatin activity in neuroblastoma cells. Pharm Res 32:2132–2143. CrossRefGoogle Scholar
  39. Schulz A, Jacksh S, Schubel R et al (2014) Drug-induced morphology switch in drug delivery systems based on poly(2-oxazoline)s. ACS Nano 8:2686–2696CrossRefGoogle Scholar
  40. Senthilraja P, Kathiresan K (2015) In vitro cytotoxicity MTT assay in Vero, HepG2 and MCF-7 cell lines study of marine yeast. J Appl Pharm Sci 5:80–84. CrossRefGoogle Scholar
  41. Tabrizi L, Chiniforoshan H (2017) Designing new iridium(III) arene complexes of naphthoquinone derivatives as anticancer agents: a structure–activity relationship study. Dalton Trans. Google Scholar
  42. Timko BP, Whitehead K, Gao W, Kohane DS, Farokhzad O, Anderson D, Langer D (2011) Advances in drug delivery. Annu Rev Mater Res 41:1–20. CrossRefGoogle Scholar
  43. Torchilin VP (2004) Targeted polymeric micelles for delivery of poorly soluble drugs. Mol Life Sci 61:2549–2559. CrossRefGoogle Scholar
  44. Wang C, Zhang Z, Chen B, Gu L, Li Y, Yu S (2018) Design and evaluation of galactosylated chitosan/graphene oxide nanoparticles as a drug delivery system. J Colloid Interface Sci 516:332–341. CrossRefGoogle Scholar
  45. Wei J, Liu H, Liu M, Wu N, Zhao W, Xiao L, Han L, Edward C, Xiukun L (2012) Oleanolic acid potentiates the antitumor activity of 5-fluorouracil in pancreatic cancer cells. Oncol Rep 28:1339–1345. CrossRefGoogle Scholar
  46. 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 112:17554–17558Google Scholar
  47. Yuan F, Dellian M, Fukumura D, Leunig M, Berk DA, Torchilin VP (1995) Vascular permeability in a human tumor xenograft: molecular size dependence and cutoff size. Cancer Res 55:3752–3756Google Scholar
  48. Zhang B, Yang X, Wang Y, Zhai G (2017) Heparin modified graphene oxide for pH-sensitive sustained release of doxorubicin hydrochloride. Mater Sci Eng C 75:198–206. CrossRefGoogle Scholar

Copyright information

© King Abdulaziz City for Science and Technology 2019

Authors and Affiliations

  1. 1.Biomaterials in Medicinal Chemistry Laboratory, Department of Natural Products Chemistry, School of ChemistryMadurai Kamaraj UniversityMaduraiIndia
  2. 2.National Centre for Nanoscience and NanotechnologyUniversity of Madras, Guindy CampusChennaiIndia
  3. 3.Centre for Advanced MaterialsQatar UniversityDohaQatar

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