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

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.

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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):196–209

    CAS  PubMed  Article  Google 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):549–559

    PubMed  PubMed Central  Article  Google 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):065114

    Article  CAS  Google 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):2575–2589

    CAS  PubMed  Article  Google 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 44:457–466

    CAS  Article  Google 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):273–280

    CAS  PubMed  Article  Google 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–E357

    Article  Google Scholar 

  8. 8.

    Waters EA, Wickline SA (2008) Contrast agents for MRI. Basic Res Cardiol 103(2):114–121

    CAS  PubMed  Article  Google 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):305–310

    CAS  PubMed  Google Scholar 

  10. 10.

    Rahman AA, Vasilev K, Majewski P (2011) Ultra small Gd2O3 nanoparticles: absorption and emission properties. J Colloid Interface Sci 354(2):592–596

    Article  CAS  Google 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):4728–4739

    CAS  Article  Google 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):5753–5762

    PubMed  Article  CAS  Google 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):613–623

    CAS  PubMed  Article  Google 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):238–245

    PubMed  Article  Google Scholar 

  15. 15.

    Trotta F, Zanetti M, Cavalli R (2012) Cyclodextrin-based nanosponges as drug carriers. Beilstein J Org Chem 8(1):2091–2099

    CAS  PubMed  PubMed Central  Article  Google 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):251–259

    CAS  Article  Google 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):12662–12670

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Hengerer A, Grimm J (2006) Molecular magnetic resonance imaging. Biomed Imaging Interv J 2(2):e8

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Achilefu S (2004) Lighting up tumors with receptor-specific optical molecular probes. Technol Cancer Res Treat 3(4):393–409

    CAS  PubMed  Article  Google 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):105578–105588

    CAS  Article  Google 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):486

    CAS  PubMed  PubMed Central  Article  Google 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 141:148–157

    CAS  PubMed  Article  Google 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):613–626

    CAS  PubMed  Article  Google 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):521–527

    CAS  PubMed  Article  Google 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 148:157–164

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Kalender W (2004) Classic papers in modern diagnostic radiology. Springer Science & Business Media.

  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):170–177

    CAS  PubMed  Article  Google 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 80:452–463

    CAS  Article  Google 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):375–385

    CAS  Article  Google 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):730–743

    PubMed  Google Scholar 

  31. 31.

    Richmond JY, McKinney RW (1993) Biosafety in microbiological and biomedical laboratories. DIANE Publishing.

  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 120:103–114

    CAS  PubMed  Article  Google 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):88096–88107

    CAS  Article  Google 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 5:8549

    CAS  PubMed  PubMed Central  Article  Google 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.

  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):e7628

    PubMed  PubMed Central  Article  CAS  Google 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):465–474

    CAS  Article  Google 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):3448–3454

    CAS  Article  Google 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 1:240

    CAS  PubMed  PubMed Central  Article  Google 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):476–484

    CAS  Article  Google 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):3717–3723

    CAS  Article  Google 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):242–252

    CAS  PubMed  Article  Google 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):715–724

    PubMed  Article  Google 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):16681–16685

    CAS  Article  Google 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):1006

    Article  CAS  Google 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):4831–4833

    CAS  Article  Google 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):3663–3669

    CAS  PubMed  Article  Google 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):2293–2352

    CAS  PubMed  Article  Google 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):1636–1642

    CAS  PubMed  Article  Google 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):7776–7789

    CAS  PubMed  Article  Google 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):356–367

    PubMed  Article  CAS  Google 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):387–393

    Article  Google 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):284–293

    CAS  PubMed  Article  Google 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):2656–2672

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Xie J, Lee S, Chen X (2010) Nanoparticle-based theranostic agents. Adv Drug Deliv Rev 62(11):1064–1079

    CAS  PubMed  PubMed Central  Article  Google 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 174:63–71

    CAS  PubMed  Article  Google Scholar 

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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.

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Correspondence to Nader Riyahi Alam or Mehdi Khoobi.

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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).

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Mortezazadeh, T., Gholibegloo, E., Alam, N.R. et al. 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. Magn Reson Mater Phy 32, 487–500 (2019). https://doi.org/10.1007/s10334-019-00738-2

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Keywords

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