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Gadolinium (III) oxide nanoparticles coated with folic acid-functionalized poly(β-cyclodextrin-co-pentetic acid) as a biocompatible targeted nano-contrast agent for cancer diagnostic: in vitro and in vivo studies

  • Tohid Mortezazadeh
  • Elham Gholibegloo
  • Nader Riyahi AlamEmail author
  • Sadegh Dehghani
  • Soheila Haghgoo
  • Hossein Ghanaati
  • Mehdi KhoobiEmail author
Research Article
  • 4 Downloads

Abstract

Objectives

In this study, a novel targeted MRI contrast agent was developed by coating gadolinium oxide nanoparticles (Gd2O3 NPs) with β-cyclodextrin (CD)-based polyester and targeted by folic acid (FA).

Materials and methods

The developed Gd2O3@PCD–FA MRI contrast agent was characterized and evaluated in relaxivity, in vitro cell targeting, cell toxicity, blood compatibility and in vivo tumor MR contrast enhancement.

Results

In vitro cytotoxicity and hemolysis assays revealed that Gd2O3@PCD–FA NPs have no significant cytotoxicity after 24 and 48 h against normal human breast cell line (MCF-10A) at concentration of up to 50 µg Gd+3/mL and have high blood compatibility at concentration of up to 500 µg Gd+3/mL. In vitro MR imaging experiments showed that Gd2O3@PCD–FA NPs enable targeted contrast T1- and T2-weighted MR imaging of M109 as overexpressing folate receptor cells. Besides, the in vivo analysis indicated that the maximum contrast-to-noise ratio (CNR) of tumor in mice increased after injection of Gd2O3@PCD–FA up to 5.89 ± 1.3 within 1 h under T1-weighted imaging mode and reduced to 1.45 ± 0.44 after 12 h. While CNR increased up to maximum value of 1.98 ± 0.28 after injection of Gd2O3@PCD within 6 h and reduced to 1.12 ± 0.13 within 12 h.

Conclusion

The results indicate the potential of Gd2O3@PCD–FA to serve as a novel targeted nano-contrast agent in MRI.

Keywords

Targeted nano-contrast agent Magnetic resonance imaging Longitudinal relaxivity Contrast enhancement 

Notes

Acknowledgements

This work was supported in part by the research chancellor of Tehran University of Medical Sciences (Grant no. 96-04-30-36739), Tehran, Iran.

Compliance with ethical standards

Conflict of interest

The authors do not have any conflict of interest.

Ethical approval

All in vivo protocols were performed based on the European Community guidelines and was approved by local ethical committee, Tehran University of Medical Sciences (TUMS), Tehran, Iran (Approval number: IR.TUMS.REC0.1394.1461).

References

  1. 1.
    Lee SH, Kim BH, Na HB, Hyeon T (2014) Paramagnetic inorganic nanoparticles as T1 MRI contrast agents. Wiley Interdiscip Rev Nanomed Nanobiotechnol 6(2):196–209Google Scholar
  2. 2.
    Azizian G, Riyahi-Alam N, Haghgoo S, Moghimi HR, Zohdiaghdam R, Rafiei B, Gorji E (2012) Synthesis route and three different core-shell impacts on magnetic characterization of gadolinium oxide-based nanoparticles as new contrast agents for molecular magnetic resonance imaging. Nanoscale Res Lett 7(1):549–559Google Scholar
  3. 3.
    Tegafaw T, Xu W, Lee SH, Chae KS, Cha H, Chang Y, Lee GH (2016) Ligand-size and ligand-chain hydrophilicity effects on the relaxometric properties of ultrasmall Gd2O3 nanoparticles. AIP Adv 6(6):065114Google Scholar
  4. 4.
    Lee N, Hyeon T (2012) Designed synthesis of uniformly sized iron oxide nanoparticles for efficient magnetic resonance imaging contrast agents. Chem Soc Rev 41(7):2575–2589Google Scholar
  5. 5.
    Narmani A, Farhood B, Haghi-Aminjan H, Mortezazadeh T, Aliasgharzadeh A, Mohseni M, Najafi M (2018) Gadolinium nanoparticles as diagnostic and therapeutic agents: their delivery systems in magnetic resonance imaging and neutron capture therapy. J Drug Deliv Sci Technol 44:457–466Google Scholar
  6. 6.
    Abraham J, Thakral C, Skov L, Rossen K, Marckmann P (2008) Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 158(2):273–280Google Scholar
  7. 7.
    Challa R, Ahuja A, Ali J, Khar R (2005) Cyclodextrins in drug delivery: an updated review. AAPS Pharm Sci Tech 6(2):E329–E357Google Scholar
  8. 8.
    Waters EA, Wickline SA (2008) Contrast agents for MRI. Basic Res Cardiol 103(2):114–121Google Scholar
  9. 9.
    McDonald MA, Watkin KL (2003) Small particulate gadolinium oxide and gadolinium oxide albumin microspheres as multimodal contrast and therapeutic agents. Invest Radiol 38(6):305–310Google Scholar
  10. 10.
    Rahman AA, Vasilev K, Majewski P (2011) Ultra small Gd2O3 nanoparticles: absorption and emission properties. J Colloid Interface Sci 354(2):592–596Google Scholar
  11. 11.
    Cheung ENM, Alvares RD, Oakden W, Chaudhary R, Hill ML, Pichaandi J, Mo GC, Yip C, Macdonald PM, Stanisz GJ (2010) Polymer-stabilized lanthanide fluoride nanoparticle aggregates as contrast agents for magnetic resonance imaging and computed tomography. Chem Mater 22(16):4728–4739Google Scholar
  12. 12.
    Ahrén M, La Selegård, Klasson A, Söderlind F, Abrikossova N, Skoglund C, Tr Bengtsson, Engström M, Käll P-O, Uvdal K (2010) Synthesis and characterization of PEGylated Gd2O3 nanoparticles for MRI contrast enhancement. Langmuir 26(8):5753–5762Google Scholar
  13. 13.
    Zohdiaghdam R, Riyahi-Alam N, Moghimi H, Haghgoo S, Alinaghi A, Azizian G, Ghanaati H, Gorji E, Rafiei B (2013) Development of a novel lipidic nanoparticle probe using liposomal encapsulated Gd2O3–DEG for molecular MRI. J Microencapsul 30(7):613–623Google Scholar
  14. 14.
    Akai H, Shiraishi K, Yokoyama M, Yasaka K, Nojima M, Inoue Y, Abe O, Ohtomo K, Kiryu S (2018) PEG-poly (l-lysine)-based polymeric micelle MRI contrast agent: Feasibility study of a Gd-micelle contrast agent for MR lymphography. J Magn Reson Imaging 47(1):238–245Google Scholar
  15. 15.
    Trotta F, Zanetti M, Cavalli R (2012) Cyclodextrin-based nanosponges as drug carriers. Beilstein J Org Chem 8(1):2091–2099Google Scholar
  16. 16.
    Vyas A, Saraf S, Saraf S (2010) Encapsulation of cyclodextrin complexed simvastatin in chitosan nanocarriers: a novel technique for oral delivery. J Incl Phenom Macrocycl Chem 66(3–4):251–259Google Scholar
  17. 17.
    Zhou Q, Guo X, Chen T, Zhang Z, Shao S, Luo C, Li J, Zhou S (2011) Target-specific cellular uptake of folate-decorated biodegradable polymer micelles. J Phys Chem B 115(43):12662–12670Google Scholar
  18. 18.
    Hengerer A, Grimm J (2006) Molecular magnetic resonance imaging. Biomed Imaging Interv J 2(2):e8Google Scholar
  19. 19.
    Achilefu S (2004) Lighting up tumors with receptor-specific optical molecular probes. Technol Cancer Res Treat 3(4):393–409Google Scholar
  20. 20.
    Daryasari MP, Akhgar MR, Mamashli F, Bigdeli B, Khoobi M (2016) Chitosan-folate coated mesoporous silica nanoparticles as a smart and pH-sensitive system for curcumin delivery. RSC Adv 6(107):105578–105588Google Scholar
  21. 21.
    Chen C, Ke J, Zhou XE, Yi W, Brunzelle JS, Li J, Yong E-L, Xu HE, Melcher K (2013) Structural basis for molecular recognition of folic acid by folate receptors. Nature 500(7463):486Google Scholar
  22. 22.
    Conte C, Fotticchia I, Tirino P, Moret F, Pagano B, Gref R, Ungaro F, Reddi E, Giancola C, Quaglia F (2016) Cyclodextrin-assisted assembly of PEGylated polyester nanoparticles decorated with folate. Colloids Surf B Biointerfaces 141:148–157Google Scholar
  23. 23.
    Oyewumi MO, Yokel RA, Jay M, Coakley T, Mumper RJ (2004) Comparison of cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice. J Control Release 95(3):613–626Google Scholar
  24. 24.
    Nakamura T, Kawano K, Shiraishi K, Yokoyama M, Maitani Y (2014) Folate-targeted gadolinium-lipid-based nanoparticles as a bimodal contrast agent for tumor fluorescent and magnetic resonance imaging. Biol Pharm Bull 37(4):521–527Google Scholar
  25. 25.
    Shah SA, Khan MA, Arshad M, Awan S, Hashmi M, Ahmad N (2016) Doxorubicin-loaded photosensitive magnetic liposomes for multi-modal cancer therapy. Colloids Surf B Biointerfaces 148:157–164Google Scholar
  26. 26.
    Kalender W (2004) Classic papers in modern diagnostic radiology. Springer Science & Business Media.Google Scholar
  27. 27.
    Duarte M, Gil M, Peters J, Colet J, Elst LV, Muller R, Geraldes C (2001) Synthesis, characterization, and relaxivity of two linear Gd (DTPA)− polymer conjugates. Bioconjug Chem 12(2):170–177Google Scholar
  28. 28.
    Vahedi S, Tavakoli O, Khoobi M, Ansari A, Faramarzi MA (2017) Application of novel magnetic β-cyclodextrin-anhydride polymer nano-adsorbent in cationic dye removal from aqueous solution. J Taiwan Inst Chem Eng 80:452–463Google Scholar
  29. 29.
    Heydarnezhadi S, Alam NR, Haghgoo S, Ghanaati H, Khoobi M, Gorji E, Rafiei B, Nikfari B, Amirrashedi M (2016) Glycosylated Gadolinium as Potential Metabolic Contrast Agent vs Gd-DTPA for Metabolism of Tumor Tissue in Magnetic Resonance Imaging. Appl Magn Reson 47(4):375–385Google Scholar
  30. 30.
    Anbharasi V, Cao N, Feng SS (2010) Doxorubicin conjugated to D-α-tocopheryl polyethylene glycol succinate and folic acid as a prodrug for targeted chemotherapy. J Biomed Mater Res A 94(3):730–743Google Scholar
  31. 31.
    Richmond JY, McKinney RW (1993) Biosafety in microbiological and biomedical laboratories. DIANE Publishing.Google Scholar
  32. 32.
    Hou W, Xia F, Alfranca G, Yan H, Zhi X, Liu Y, Peng C, Zhang C, de la Fuente JM, Cui D (2017) Nanoparticles for multi-modality cancer diagnosis: simple protocol for self-assembly of gold nanoclusters mediated by gadolinium ions. Biomaterials 120:103–114Google Scholar
  33. 33.
    Akrami M, Khoobi M, Khalilvand-Sedagheh M, Haririan I, Bahador A, Faramarzi MA, Rezaei S, Javar HA, Salehi F, Ardestani SK (2015) Evaluation of multilayer coated magnetic nanoparticles as biocompatible curcumin delivery platforms for breast cancer treatment. RSC Adv 5(107):88096–88107Google Scholar
  34. 34.
    Ahmad MW, Xu W, Kim SJ, Baeck JS, Chang Y, Bae JE, Chae KS, Park JA, Kim TJ, Lee GH (2015) Potential dual imaging nanoparticle: Gd 2 O 3 nanoparticle. Sci Rep 5:8549Google Scholar
  35. 35.
    Kim CR, Baeck JS, Chang Y, Bae JE, Chae KS, Lee GH (2014) Ligand-size dependent water proton relaxivities in ultrasmall gadolinium oxide nanoparticles and in vivo T 1 MR images in a 1.5 T MR field. Phys Chem Chem Phys 16 (37):19866-19873.Google Scholar
  36. 36.
    Ghaghada KB, Ravoori M, Sabapathy D, Bankson J, Kundra V, Annapragada A (2009) New dual mode gadolinium nanoparticle contrast agent for magnetic resonance imaging. PLoS ONE 4(10):e7628Google Scholar
  37. 37.
    Ma J, La LTB, Zaman I, Meng Q, Luong L, Ogilvie D, Kuan HC (2011) Fabrication, structure and properties of epoxy/metal nanocomposites. Macromol Mater Eng 296(5):465–474Google Scholar
  38. 38.
    Yang X, Wang Y, Huang X, Ma Y, Huang Y, Yang R, Duan H, Chen Y (2011) Multi-functionalized graphene oxide based anticancer drug-carrier with dual-targeting function and pH-sensitivity. J Mater Chem 21(10):3448–3454Google Scholar
  39. 39.
    Huang P, Xu C, Lin J, Wang C, Wang X, Zhang C, Zhou X, Guo S, Cui D (2011) Folic acid-conjugated graphene oxide loaded with photosensitizers for targeting photodynamic therapy. Theranostics 1:240Google Scholar
  40. 40.
    Zhao F, Yin H, Zhang Z, Li J (2013) Folic acid modified cationic γ-cyclodextrin-oligoethylenimine star polymer with bioreducible disulfide linker for efficient targeted gene delivery. Biomacromol 14(2):476–484Google Scholar
  41. 41.
    Liu Y, Yang P, Wang W, Dong H, Lin J (2010) Fabrication and photoluminescence properties of hollow Gd 2 O 3: Ln (Ln = Eu3+, Sm3+) spheres via a sacrificial template method. Cryst Eng Comm 12(11):3717–3723Google Scholar
  42. 42.
    Kumar S, Meena VK, Hazari PP, Sharma RK (2016) FITC-Dextran entrapped and silica coated gadolinium oxide nanoparticles for synchronous optical and magnetic resonance imaging applications. Int J Pharm 506(1–2):242–252Google Scholar
  43. 43.
    Rohrer M, Bauer H, Mintorovitch J, Requardt M, Weinmann H-J (2005) Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths. Invest Radiol 40(11):715–724Google Scholar
  44. 44.
    Leng Y, Sato K, Shi Y, Li J-G, Ishigaki T, Yoshida T, Kamiya H (2009) Oxidation-resistant silica coating on gas-phase-reduced iron nanoparticles and influence on magnetic properties. J Phys Chem C 113(38):16681–16685Google Scholar
  45. 45.
    Ahrén M, Selegård L, Söderlind F, Linares M, Kauczor J, Norman P, Käll P-O, Uvdal K (2012) A simple polyol-free synthesis route to Gd 2 O 3 nanoparticles for MRI applications: an experimental and theoretical study. J Nanopart Res 14(8):1006Google Scholar
  46. 46.
    Di W, Ren X, Zhang L, Liu C, Lu S (2011) A facile template-free route to fabricate highly luminescent mesoporous gadolinium oxides. CrystEngComm 13(15):4831–4833Google Scholar
  47. 47.
    Park JY, Baek MJ, Choi ES, Woo S, Kim JH, Kim TJ, Jung JC, Chae KS, Chang Y, Lee GH (2009) Paramagnetic ultrasmall gadolinium oxide nanoparticles as advanced T 1 MRI contrast agent: account for large longitudinal relaxivity, optimal particle diameter, and in vivo T 1 MR images. ACS Nano 3(11):3663–3669Google Scholar
  48. 48.
    Caravan P, Ellison JJ, McMurry TJ, Lauffer RB (1999) Gadolinium (III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev 99(9):2293–2352Google Scholar
  49. 49.
    Fang J, Chandrasekharan P, Liu X-L, Yang Y, Lv Y-B, Yang C-T, Ding J (2014) Manipulating the surface coating of ultra-small Gd2O3 nanoparticles for improved T1-weighted MR imaging. Biomaterials 35(5):1636–1642Google Scholar
  50. 50.
    Shahbazi M-A, Hamidi M, Mäkilä EM, Zhang H, Almeida PV, Kaasalainen M, Salonen JJ, Hirvonen JT, Santos HA (2013) The mechanisms of surface chemistry effects of mesoporous silicon nanoparticles on immunotoxicity and biocompatibility. Biomaterials 34(31):7776–7789Google Scholar
  51. 51.
    Zhang H-W, Wang L-Q, Xiang Q-F, Zhong Q, Chen L-M, Xu C-X, Xiang X-H, Xu B, Meng F, Wan Y-Q (2014) Specific lipase-responsive polymer-coated gadolinium nanoparticles for MR imaging of early acute pancreatitis. Biomaterials 35(1):356–367Google Scholar
  52. 52.
    Y-k Lee (2006) Preparation and characterization of folic acid linked poly (L-glutamate) nanoparticles for cancer targeting. Macromol Res 14(3):387–393Google Scholar
  53. 53.
    Parker N, Turk MJ, Westrick E, Lewis JD, Low PS, Leamon CP (2005) Folate receptor expression in carcinomas and normal tissues determined by a quantitative radioligand binding assay. Anal Biochem 338(2):284–293Google Scholar
  54. 54.
    Lee D-E, Koo H, Sun I-C, Ryu JH, Kim K, Kwon IC (2012) Multifunctional nanoparticles for multimodal imaging and theragnosis. Chem Soc Rev 41(7):2656–2672Google Scholar
  55. 55.
    Xie J, Lee S, Chen X (2010) Nanoparticle-based theranostic agents. Adv Drug Deliv Rev 62(11):1064–1079Google Scholar
  56. 56.
    Mi P, Kokuryo D, Cabral H, Kumagai M, Nomoto T, Aoki I, Terada Y, Kishimura A, Nishiyama N, Kataoka K (2014) Hydrothermally synthesized PEGylated calcium phosphate nanoparticles incorporating Gd-DTPA for contrast enhanced MRI diagnosis of solid tumors. J Control Release 174:63–71Google Scholar

Copyright information

© European Society for Magnetic Resonance in Medicine and Biology (ESMRMB) 2019

Authors and Affiliations

  1. 1.Department of Medical Physic, School of MedicineTabriz University of Medical SciencesTabrizIran
  2. 2.Biomaterials Group, The Institute of Pharmaceutical Sciences (TIPS)Tehran University of Medical SciencesTehranIran
  3. 3.Department of Medical Physics and Biomedical EngineeringTehran University of Medical SciencesTehranIran
  4. 4.Department of Pharmaceutical Biomaterials, Faculty of PharmacyTehran University of Medical SciencesTehranIran
  5. 5.Pharmaceutical Department, Food and Drug Laboratory Research Center, Food and Drug Organization (FDO)Ministry of HealthTehranIran
  6. 6.Medical Imaging Center, Imam Hospital Complex, School of MedicineTehran University of Medical Sciences (TUMS)TehranIran

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