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Multifunctional hydroxyapatite nanoparticles for drug delivery and multimodal molecular imaging

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Abstract

Hydroxyapatite (HAp) is the most important constituent of biological tissues such as bone and teeth and exhibits several characteristic features. HAp nanoparticles (NPs) are good host materials and can be functionalized with various kinds of dopants and substrates. By endowing HAp NPs with desired properties in order to render them suitable for biomedical applications including cellular imaging, non-invasive and quantitative visualisation of molecular process occurring at cellular and subcellular levels becomes possible. Depending on their functional properties, HAp based nanoprobes can be divided into three classes, i.e., luminescent HAp NPs (for both downconversion and upconversion luminescence), magnetic HAp NPs, and luminomagnetic HAp NPs. Luminomagnetic HAp NPs are particularly attractive in terms of bimodal imaging and even multimodal imaging by virtue of their luminescence and magnetism. Functionalised HAp NPs are potential candidates for targeted drug delivery applications. This review (with 166 references) spotlights the cellular imaging applications of three types of HAp NPs. Specific sections cover aspects of molecular imaging and the various imaging modes, a comparison of the common types of nanoprobes for bioimaging, synthetic methods for making the various kinds of HAp NPs, followed by overviews on fluorescent NPs for bioimaging (such as quantum dots, gold nanoclusters, lanthanide-doped or fluorophore-doped NPs), magnetic HAp NPs for use in magnetic resonance imaging (MRI), luminomagnetic HAp NPs for bimodal imaging, and sections on drug delivery as well as cellular imaging applications of HAp based nanoprobes (including targeted imaging).

Hydroxyapatite nanoparticles (HAp NPs) with different functional properties such as luminescence and magnetism are potential candidates for drug delivery as well as multimodal imaging. The review spotlights such applications of luminescent, magnetic and luminomagnetic HAp NPs and discussed their synthesis and characterization.

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References

  1. Hui J, Wang X (2014) Hydroxyapatite nanocrystals: colloidal chemistry, assembly and their biological applications. Inorg Chem Front 1:215–225

    CAS  Google Scholar 

  2. Meyers MA, Chen PY, Lin AYM, Seki Y (2008) Biological materials: structure and mechanical properties. Prog Mater Sci 53:1–206

    CAS  Google Scholar 

  3. Palmer LC, Newcomb CJ, Kaltz SR, Spoerke ED, Stupp SI (2008) Biomimetic systems for hydroxyapatite mineralization inspired by bone and enamel. Chem Rev 108:4754–4783

    CAS  Google Scholar 

  4. Stigter M, Groot K, Layrolle P (2002) Incorporation of tobramycin into biomimetic hydroxyapatite coating on titanium. Biomaterials 23:4143–4153

    CAS  Google Scholar 

  5. Fox K, Tran PA, Tran N (2012) Recent advances in research applications of nanophase hydroxyapatite. Chem Phys Chem 13:2495–2506

    CAS  Google Scholar 

  6. Lafisco M, Delgado-Lopez JM, Varoni EM, Tampieri A, Rimondini L, Gomez-Morales J, Prat M (2013) Cell surface receptor targeted biomimetic apatite nanocrystals for cancer therapy. Small 25:3834–3844

    Google Scholar 

  7. Xu J, White T, Li P, He C, Han Y-F (2010) Hydroxyapatite foam as a catalyst for formaldehyde combustion at room temperature. J Am Chem Soc 132:13172–13173

    CAS  Google Scholar 

  8. Liu TY, Chen SY, Liu DM, Liou SC (2005) On the study of BSA-loaded calcium-deficient hydroxyapatite nano-carriers for controlled drug delivery. J Control Release 107:112–121

    CAS  Google Scholar 

  9. Uskovic V, Uskovic DP (2011) Nanosized hydroxyapatite and other calcium phosphates: chemistry of formation and application as drug and gene delivery agents. J Biomed Mater Res B 96B:152–191

    Google Scholar 

  10. Luo Y, Ling Y, Guo W, Pang J, Liu W, Fang Y, Wen X, Wei K, Gao X (2010) Docetaxel loaded oleic acid-coated hydroxyapatite nanoparticles enhance the docetaxel-induced apoptosis through activation of caspase-2 in androgen independent prostate cancer cells. J Control Release 147:278–288

    CAS  Google Scholar 

  11. Hou C H, Hou S M, Hsueh Y S, Lin J, Wu H C, Lin F H The in vivo performance of biomagnetic hydroxyapatite nanoparticles in cancer hyperthermia therapy. Biomaterials 30:3956–3960

  12. Li J, Yin Y, Yao F, Zhang L, Yao K (2008) Effect of nano-and micro-hydroxyapatite/chitosan-gelatin network film on human gastric cancer cells. Mater Lett 62:3220–3223

    CAS  Google Scholar 

  13. Nazari AG, Tahari A, Moztarzadeh M, Mozafari M, Bahroloom ME (2011) Ion exchange behaviour of silver-doped apatite micro and nanoparticles as antibacterial biomaterial. Micro Nano Lett 6:713–717

    CAS  Google Scholar 

  14. Radovanovic Z, Jokic B, Veljovic D, Dimitrijevic S, Kojic V, Petrovic R, Janackovic D (2014) Antimicrobial activity and biocompatibility of Ag+ - and Cu2+ - doped biphasic hydroxyapatite/ α-tricalcium phosphate obtained from hydrothermally synthesized Ag+ - and Cu2+ - doped hydroxyapatite. Appl Surf Sci 307:513–519

    CAS  Google Scholar 

  15. Remya NS, Syama S, Gayathri V, Varma HK, Mohanan PV (2014) An in vitro study on the interaction of hydroxyapatite nanoparticles and bone marrow mesenchymal stem cells for assessing the toxicological behaviour. Colloids Surf B 117:389–397

    CAS  Google Scholar 

  16. Byrne JD, Betancourt T, Brannon-Peppas L (2008) Active targeting schemes for nanoparticle system in cancer therapeutics. Adv Drug Deliv Rev 60:1615–1626

    CAS  Google Scholar 

  17. Wang SG, Li N, Pan W, Tang B (2012) Advances in functional fluorescent and luminescent probes for imaging intracellular small-molecular reactive species. Trends Anal Chem 39:3–37

    Google Scholar 

  18. Niu J, Wang X, Lv J, Li Y, Tang B (2014) Luminescent nanoprobes for in-vivo bioimaging. Trend Anal Chem 58:112–119

    CAS  Google Scholar 

  19. Kim J, Piao Y, Hyeon Y (2008) Multifunctional nanostructured materials for multimodel imaging, and simultaneous imaging and therapy. Chem Soc Rev 38:372–390

    Google Scholar 

  20. Peer D, Karp JM, Hong S, Farokhzad OC, Margalit R, Langer R (2007) Nanocarrers as an emerging platform for cancer therapy. Nat Nanotechnol 12:751–760

    Google Scholar 

  21. Lee SY, Jeon SI, Jung SH, Chung IJ, Ahn C-H (2014) Targeted multimodal imaging modalities. Adv Drug Deliv Rev 76:60–78

    CAS  Google Scholar 

  22. Norek M, Peters AJ (2011) MRI contrast agents on dysprosium or holmium. Prog Nucl Magn Reson Spectrosc 59:64–82

    CAS  Google Scholar 

  23. Xi D, Dong S, Meng X, Lu Q, Meng L, Ye J (2012) Gold nanoparticles as computerized tomography (CT) contrast agents. RSC Adv 2:12515–12524

    CAS  Google Scholar 

  24. Lusic H, Grinstaff MW (2013) X-ray-computed tomography contrast agents. Chem Rev 113:1641–1666

    CAS  Google Scholar 

  25. Ametamy SM, Honer M, Schubiger PA (2008) Molecular imaging with PET. Chem Rev 108:1501–1516

    Google Scholar 

  26. Li Z, Conti PS (2010) Radiopharmaceutical chemistry for positron emission tomography. Adv Drug Deliv Rev 62:1031–1051

    CAS  Google Scholar 

  27. Wades TJ, Wong EH, Weisman GR, Anderson CJ (2010) Coordinating radiometals of copper, gallium, indium, yttrium and zirconium for PET and SPECT imaging of disease. Chem Rev 110:2858–2902

    Google Scholar 

  28. Gobin AM, Lee MH, Halas NJ, James WD, Drezek RA, Weast JL (2007) Near-infrared resonant nanoshells for combined optical imaging and photothermal cancer therapy. Nano Lett 7:1929–1934

    CAS  Google Scholar 

  29. Fercher AF (2009) Optical coherence tomography-development, principles, applications. Z Med Phys 20:251–276

    Google Scholar 

  30. Pansare VJ, Hejazi S, Faenza W, Prudehomme RK (2012) Review of long-wavelength optical and NIR imaging materials: ontrast agents, fluorophores, and multifunctional nano carriers. Chem Mater 24:812–827

    CAS  Google Scholar 

  31. Harvey CJ, Blomley MJK, Eckersley RJE, Cosgrove DO (2001) Develpoements in ultrasound contrast media. Eur Radiol 11:675–689

    CAS  Google Scholar 

  32. Guo C, Jin Y, Dai Z (2014) Multifunctional ultrasound contrast agents for imaging guided photothermal therapy. Bioconjug Chem 25:840–854

    CAS  Google Scholar 

  33. Lu W, Huang Q, Ku G, Wen X, Zhou M, Guzatov D, Brecht P, Su R, Oraevsky A, Wang LV, Li C (2010) Photoacoustic imaging of living mouse brain vasculature using hollow gold nanospheres. Biomaterials 31:2617–2626

    CAS  Google Scholar 

  34. Savita N, Maitra S, Ravishankar U (2010) Multimodality molecular imaging – an overview with special focus on PET/CT. Apollo Med 7:190–199

    Google Scholar 

  35. Jennings L E, Long N J (2009) Two is better than one-probes for dual-modality molecular imaging. Chem Commun 3511–3524

  36. Frullano L, Meade TJ (2007) Multimodal MRI contrast agents. J Biol Inorg Chem 12:939–949

    CAS  Google Scholar 

  37. Jadvar H, Colletti PM (2014) Competitive advantage of PET/MR. Eur J Radiol 83:84–94

    Google Scholar 

  38. Pichler B, Wehrl HF, Kolb A, Judenhofer MS (2008) Positron emission tomography/ magnetic resonance imaging: the next generation of multimodality imaging? Semin Nucl Med 38:199–208

    Google Scholar 

  39. Debasu ML, Ananias D, Pinho SLC, Geraldes CFGC, Carlos LD, Rocha J (2012) (Gd, Yb, Tb)PO4 up -conversion nanocrystals for bimodal luminescence- MR imaging. Nanoscale 4:5154–5162

    CAS  Google Scholar 

  40. Qiao Z, Shi X (2014) Dendrimer-based molecular imaging contrast agents. Prog Polym Sci. doi:10.1016/j.progpolymsci.2014.08.002

    Google Scholar 

  41. Wolbeis O S (2015) An overview of nanoparticles commonly used in fluorescent bioimaging. doi:10.1039/c4cs00392f

  42. Bae SW, Tan W, Hong J (2012) Fluorescent dye-doped silica nanoparticles: new tools for bioapplications. Chem Commun 48:2270–2282

    CAS  Google Scholar 

  43. Wang X, Meier RJ, Wolfbis OS (2013) Fluorescent pH-sensitive nanoparticles in an agarose matrix for imaging of bacterial growth and metabolism. Angew Chem Int Ed 52:406–409

    CAS  Google Scholar 

  44. Tang R, Feng X (2014) Highly luminescent conjugated polymer nanoparticles for imaging and therapy. Can Chem Trans 1:78–84

    Google Scholar 

  45. Song Y, Zhu S, Yang B (2014) Bioimaging based on fluorescent carbon dots. RSC Adv 4:27184–27200

    CAS  Google Scholar 

  46. Yang Y (2014) Upconversion nanophosphores for use in bioimaging, therapy, drug delivery and bioassays. Microchim Acta 181:263–294

    CAS  Google Scholar 

  47. Cui M, Zhao Y, Song Q (2014) Synthesis, optical properties and applications of ultra-small luminescent gold nanoclusters. Trends Anal Chem 57:73–82

    CAS  Google Scholar 

  48. Caravan P, Ellison JJ, McMurry TJ, Lauffer RB (1999) Gadollinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev 99:2293–2352

    CAS  Google Scholar 

  49. Nicolay K, Strijkers G, Grull H (2013) Gd- Containing nanoparticles as MRI contrast agents. In: Merbach A (ed) The chemistry of contrast agents in medical magnetic resonance imaging, 2nd edn. Wiley, UK, pp 449–483

    Google Scholar 

  50. Sharma P, Brown S, Walter G, Santra S, Moudgil B (2006) Nanoparticles for bioimaging. Adv Colloid Interf Sci 123:471–485

    Google Scholar 

  51. Lu X, Leng Y (2005) Theoretical analysis of calcium phosphate precipitation in simulated body fluid. Biomaterials 26:1097–1108

    CAS  Google Scholar 

  52. Sadat-Shojai M, Khorasani M, Dinpanah-Khoshdargi E, Jamshidi A (2013) Synthesis methods for nanosized hydroxyapatite with diverse structures. Acta Biomater 9:7591–7621

    CAS  Google Scholar 

  53. Liu D-M, Troczynski T, Tseng WJ (2001) Water-based sol–gel synthesis of hydroxyapatite:process development. Biomaterials 22:1721–1730

    CAS  Google Scholar 

  54. Salimi MN, Anuar A (2013) Charecterizations of biocompatible and bioactive hydroxyapatite particles. Procedia Eng 53:192–196

    CAS  Google Scholar 

  55. Wang J, Shaw L L (2009) Synthesis of high purity hydroxyapatite nanopowder via sol–gel combustion process. 20: 1223–1227

  56. Han Y, Li S, Wang X, Chen X (2004) Synthesis and sintering of nanocrystalline hydroxyapatite powders by citric acid sol–gel combustion method. Mater Res Bull 39:25–32

    CAS  Google Scholar 

  57. Ruksudjarit A, Pengpat K, Rujijanagul G, Tunkasiri T (2008) Synthesis and characterization of nanocrystalline hydroxyapatite from natural bovine bone. Curr Appl Phys 8:270–272

    Google Scholar 

  58. Tabakovic A, Kester M, Adair JH (2012) Calcium phosphate- based composite nanoparticles in bioimaging and therapeutic delivery applications. WIREs Nanomed Nanobiotechnol 4:96–112

    CAS  Google Scholar 

  59. Talapin DV, Gaponik N, Borchert H, Rogach AL, Hasse M, Weller H (2002) Etching of colloidal InP nanocrystal with fluorides: photochemical nature of the process resulting in high photoluminescence efficiency. J Phys Chem B 106:12659–12663

    CAS  Google Scholar 

  60. Derfus AM, Chan WCW, Bhatia SN (2003) Probing the cytotoxicity of semiconductor quantum dots. Nano Lett 4:11–18

    Google Scholar 

  61. Zhang J, Fatouros PP, Shu C, Reid J, Qwens LS, Cai T, Gibson HW, Long GL, Corwin FD, Chen ZJ, Dorn HC (2010) High relaxivity trimetallic nitride (Gd3N) metallofullerene MRI contrast agents with optimized functionality. Bioconjug Chem 21:610–615

    Google Scholar 

  62. Bunzil JG (2010) Lanthanide luminescence for biomedical analyse and imaging. Chem Rev 110:2729–2755

    Google Scholar 

  63. Bunzli J-CG, Eliseeva SV (2011) Basics of lanthanide photophysics. In: Haenninen P, Haerma H (eds) Lanthanide Luminescence: Photophysical, Analytical and Biological Aspects, Springer series on Fluorescence, vol 7. Springer, Heidelberg, pp 1–46

    Google Scholar 

  64. Eliseeva SV, Bunzil JG (2009) Lanthanide luminescence for functional materials and bio-sciences. Chem Soc Rev 39:189–227

    Google Scholar 

  65. Zhang Y, Wei W, Das GK, Tan TTY (2014) Engineering lanthanide-based materials for nanomedicine. J Photochem Photobiol C 20:71–96

    Google Scholar 

  66. Werts MHV (2005) Making sense of lanthanide luminescence. Sci Prog 88:101–131

    CAS  Google Scholar 

  67. Bunzil JC (2006) Benefiting from the unique properties of lanthanide ions. Acc Chem Res 39:53–61

    Google Scholar 

  68. Montogomery C P, Murray B S, New E J, Pal R, Parker D (2009) Cell-penetrating metal complex optical probes: targeted and responsive systems based on lanthanide luminescence. 42: 925–937

  69. Wang S, Wang L Lanthanide-doped nanomaterials for luminescence detection and imaging. doi:10.1016/j.trac.2014.07.011

  70. Fang Y, Xu A, Song R, Zhang H, You L, Yu J, Liu H (2003) Systematic synthesis and characterization of single-crystal lanthanide orthophosphate nanowires. J Am Chem Soc 125:16025–16034

    CAS  Google Scholar 

  71. Li C, Quan Z, Yang J, Lin J (2007) Highly uniform and monodisperse β-NaYF4:Ln3 + (Ln = Eu, Tb, Yb/Er, and Yb/Tm) hexagonal microprism crystals: hydrothermal synthesis and luminescent properties. Inorg Chem 46:6329–6337

    CAS  Google Scholar 

  72. Wegh RT, Donker H, Oskam KD, Meijerink (1999) Visible quantum cutting in LiGdF4: Eu3+ through downconversion. Science 283:663–666

    CAS  Google Scholar 

  73. Mader HS, Kele P, Saleh SM, Wolfbeis OS (2010) Upconverting luminescent nanoparticles for use in biocojugation and bioimaging. Curr Opin Chem Biol 14:582–596

    CAS  Google Scholar 

  74. Chen G, Qiu H, Prasad PN, Chen X (2014) Upconversion nanoparticles: design, nanochemistry and applications in theranostics. Chem Rev 114:5161–5214

    CAS  Google Scholar 

  75. Weng M, Abbinei G, Clevenger A, Mao C, Xu S (2011) Upconversion nanoparticles: synthesis, surface modification and biological applications. Nanomed: Nanotechnol Biol Med 7:710–729

    Google Scholar 

  76. Auzel F (2004) Upconversion and anti-stokes processes with f and d ions in solids. Chem Rev 104:139–173

    CAS  Google Scholar 

  77. Heffern MC, Matosziuk LM, Meade TJ (2014) Lanthanide probes for bioresponsive imaging. Chem Rev 114:4496–4539

    CAS  Google Scholar 

  78. Doat A, Fanjul M, Pelle F, Hollande E, Lebugle A (2003) Europium-doped bioapatite: a new photostable biological probe, internalizable by human cells. Biomaterials 24:3365–3371

    CAS  Google Scholar 

  79. Ternane R, Ayedi MT, Ariguib NK, Piriou B (1999) Luminescent properties of Eu3+ in calcium hydroxyapatite. J Lumin 81:165–170

    CAS  Google Scholar 

  80. Cao XY, Wen F, Bian W, Cao Y, Pang C, Zhang W (2009) Preparation and comparison study of hydroxyl apatite and Eu-hydroxyapatite. Front Mater Sci 3:255–258

    Google Scholar 

  81. Kim EJ, Choi S, Hong S (2007) Synthesis and photoluminescence properties of Eu3+ -doped calcium phosphates. J Am Ceram Soc 9:2795–2798

    Google Scholar 

  82. Huang S, Zhu J, Zhou K (2012) Effects of Eu3+ ions on the morphology and luminescence properties of hydroxyapatite nanoparticles synthesized by one-step hydrothermal method. Mater Res Bull 47:24–28. doi:10.1016/j.materresbull.2011.10.013

  83. Long M, Hong F, Li W, Zhao H, Lv Y, Li H, Hu F, Sun L, Yan C, Wei Z (2008) Size-dependent microstructure and europium site preference influence fluorescent properties of Eu3+-doped Ca10(PO4)6(OH)2 nanocrystal. J Lumin 128:428–436

    CAS  Google Scholar 

  84. Andre RS, Paris EC, Gurgel MFC, Rosa ILV, Paiva-Santos CO, Li MS, Varela JA, Longo E (2012) Structural evolution of Eu-doped hydroxyapatite nanorods monitored photoluminescence emission. J Alloys Comp 531:50–54

    CAS  Google Scholar 

  85. Liu Y, Tu D, Zhu H, Chen X (2013) Lanthanide-doped luminescent nanoprobes: controlled synthesis, optical spectroscopy, and bioapplications. Chem Soc Rev 42:6924–6959

    CAS  Google Scholar 

  86. Feng Z, Li Y, Huang Y, Seo HJ (2011) Luminescence properties of Eu2+ and Eu3+ doped calcium- deficient hydroxyapatite prepared in air. J Alloys Comp 509:7087–7092

    CAS  Google Scholar 

  87. Graeve OA, Kanakala R, Madadi A, Williams BC, Glass KC (2010) Luminescence variations in hydroxyapatites doped with Eu2+ and Eu3+ ions. Biomaterials 31:4259–4267

    CAS  Google Scholar 

  88. Sun Y, Yang H, Tao D (2012) Preparation and characterization of Eu3+ doped fluorapatite nanoparticles by a hydrothermal method. Ceram Int 38:6937–6941

    CAS  Google Scholar 

  89. Zhao Y, Zhu J, Zhu S, Huang Y, Li Z, Zhou K (2011) Synthesis and characterization of arginine modified europium-doped hydroxyapatite nanoparticle and its cell viability. Trans Nonferrous Metals Soc China 21:1773–1778

    CAS  Google Scholar 

  90. Wilusz RJ, Bednarkiewicz A, Strek W (2011) Synthesis and optical properties of Eu3+ ion doped nanocrystalline hydroxyapatite embedded in PMMA matrix. J Rare Earths 29:1111–1116

    Google Scholar 

  91. Popa CL, Ciobanu CS, Iconaru SL, Stan M, Dinischiotu A, Negrila CC, Heino MM, Guegan R, Predoi D (2014) Systematic investigation and in vitro biocompatibility studies on mesoporous europium doped hydroxyapatite. Cent Eur J Chem 12:1032–1046

    CAS  Google Scholar 

  92. Kattan AA, Dufour P, Ghys JD, Drouet C (2010) Preparation and physicochemical characteristics of luminescent apatite-based colloids. J Phys Chem C 114:2918–2924

    Google Scholar 

  93. Han Y, Wang X, Dai H, Li S (2013) Synthesis and luminescence of Eu3+ doped hydroxyapatite nanocrystallines: effects of calcinations and Eu3+ content. J Lumin 135:281–287

    CAS  Google Scholar 

  94. Hasna K, Kumar SS, Komath M, Varma MR, Jayaraj MK, Kumar KR (2013) Synthesis of chemically pure, luminescent Eu3+ doped Hap nanoparticles: a promising fluorescent probe for in vivo imaging applications. Phys Chem Chem Phys 15:8106–8111

    CAS  Google Scholar 

  95. Wagner DE, Eisenmann KM, Nester-Kalinoski AL, Bhaduri SB (2013) A microwave-assisted solution combustion synthesis to produce europium-doped calcium phosphate nanowhiskers for bioimaging applications. Acta Biomater 9:8422–8432

    CAS  Google Scholar 

  96. Yang P, Quan Z, Li C, Kang X, Lian H, Lin J (2008) Bioactive, luminescent and mesoporous europium-doped hydroxyapatite as drug carrier. Biomaterials 29:4341–4347

    CAS  Google Scholar 

  97. Yan-zhong Z, Yan-yan H, Jun Z, Shai-hong Z, Zhi-you L, Ke-chao Z (2011) Characteristics of functionalized nano-hydroxyapatite and internalization by human epithelial cell. Nanoscale Res Lett 6:600–607

    Google Scholar 

  98. Sun R, Chen K, Wu X, Zhao D, Sun Z (2013) Controlled synthesis and enhanced luminescence of europium -doped fluorine-substituted hydroxyapatite nanoparticles. Cryst Eng Comm 15:3442–3447

    CAS  Google Scholar 

  99. Escudero A, Calvo ME, Fernandez SR, de la Fuente JM, Ocana M (2013) Microwave-assisted synthesis of biocompatible europium-doped calcium hydroxyapatite and fluoroapatite luminescent nanospindles functionalized with poly(acrylic acid). Langmuir 29:1985–1994

    CAS  Google Scholar 

  100. Doat A, Pelle F, Gardant N, Lebugle A (2004) Synthesis of luminescent bioapatite nanoparticles for utilization as a biological probe. J Solid State Chem 177:1179–1187

    CAS  Google Scholar 

  101. Chen F, Zhu Y-J, Zhang K-H, Wu J, Wang K-W, Tang Q-L, Mo X-M (2011) Europium-doped amorphous calcium phosphate porous nanospheres: preparation and application as luminescent drug carriers. Nanoscale Res Lett 6:67–75

    Google Scholar 

  102. Dembski S, Milde M, Dyrba M, Schweizer S, Gellermann C, Klockenbring T (2011) Effect of pH on the synthesis and properties of luminescent SiO2/calcium phosphate: Eu3+ core-shell nanoparticles. Langmuir 27:14025–14032

    CAS  Google Scholar 

  103. Li X, Zeng H, Teng L, Chen H (2014) Comparative investigation on the crystal structure and cell behavior of rare-earth doped fluorescent apatite nanocrystals. Mater Lett 125:78–81

    CAS  Google Scholar 

  104. Li L, Liu Y, Tao J, Zhang M, Pan H, Xu X, Tang R (2008) Surface modification of hydroxyapatite nanocrystallite by a small amount of terbium provides a biocompatible fluorescent probe. J Phys Chem C 112:12219–12224

    CAS  Google Scholar 

  105. Yang C, Yang P, Wang W, Wang J, Zhang M, Lin J (2008) Solvothermal synthesis and charecterization of Ln (Eu3+, Tb3+) doped hydroxyapatite. J Colloid Interface Sci 328:203–210

    CAS  Google Scholar 

  106. Hui J, Zhang X, Zhang Z, Wang S, Tao L, Wei Y, Wang X (2012) Fluoridated HAp : Ln3+ (Ln = Eu or Tb) nanoparticles for cell imaging. Nanoscale 4:6967–6970

    CAS  Google Scholar 

  107. Lebugle A, Pelle F, Charvillat C, Rousselot I, Chane-Ching J Y (2006) Colloidal and monocrystalline Ln3+ doped apatite calcium phosphate as biocompatible fluorescent probes. Chem Commun 606–608

  108. Zhang X, Hui J, Yang B, Yang Y, Fan D, Liu M, Tao L, Wei Y (2013) PEGylation of fluorinated hydroxyapatite (FAp):Ln3+ nanorods for cell imaging. Polym Chem 4:4120–4125

    CAS  Google Scholar 

  109. Neumeier M, Halis LA, Davis SA, Mann S, Epple M (2011) Synthesis of fluorescent core-shell hydroxyapatite nanoparticle. J Mater Chem 21:1250–1254

    CAS  Google Scholar 

  110. Sun Y, Yang H, Tao D (2011) Microemulsion process synthesis of lanthanide-doped hydroxyapatite nanoparticles under hydrothermal treatment. Ceram Int 37:2917–2920

    CAS  Google Scholar 

  111. Liu H, Xi P, Xie G, Chen F, Li Z, Bai D, Zeng Z (2011) Biocompatible hydroxyapatite nanoparticles as a redox luminescence switch. J Biol Inorg Chem 16:1135–1140

    CAS  Google Scholar 

  112. de Araujo T S, Macedo Z S, de Oliveira P A S C, Valerio M E G (2007) Production and Characterization of pure and Cr3+- doped hydroxyapatite for biomedical applications as fluorescent probes. 42: 2236–2243

  113. Victor SP, Paul W, Jayabalan M, Sharma CP (2014) Supramolecular hydroxyapatite complexes as theranostic near-infrared luminescent drug carriers. Cryst Eng Comm 16:9033–9042

    CAS  Google Scholar 

  114. Liu H, Chen F, Xi P, Chen B, Huang L, Cheng J, Shao C, Wang J, Bai D, Zeng Z (2011) Biocompatible fluorescent hydroxyapatite: synthesis and live cell imaging applications. J Phys Chem C 115:18538–18544

    CAS  Google Scholar 

  115. Ge X, Li C, Fan C, Feng X, Cao B (2013) Enhanced photoluminescence properties of methylene blue dye encapsulated in nanosized hyroyapatite/silica particles with core-shell structure. Appl Phys A 113:583–589

    CAS  Google Scholar 

  116. Morgan TT, Mudddana HS, Altinoglu EI, Rouse SM, Tabakovic A, Tabouillot T, Russin TJ, Shanmugavelandy SS, Butler PJ, Eklund PC, Yun JK, Kester M, Adair JH (2008) Encapsulation of organic molecules in calcium phosphate nanocomposite particles for intracellular imaging and drug delivery. Nano Lett 8:4108–4115

    CAS  Google Scholar 

  117. Altinoglu EI, Russin TJ, Kaiser JM, Barth BM, Eklund PC, Kester M, Adair JH (2008) Near-infrared emitting fluorophore-doped calcium phosphate nanoparticles for in vivo imaging of human breast cancer. ACS Nano 2:2075–2084

    CAS  Google Scholar 

  118. Mokoena PP, Nagpure IM, Kumar V, Kroon RE, Olivier EJ, Neethling JH, Swart HC, Ntwaeaborwa OM (2014) Enhanced UVB emission and analysis of chemical states of Ca5(PO4)3OH:Gd3+, Pr3+ phosphor prepared by co-precipitation. J Phys Chem Solids 75:998–1003

    CAS  Google Scholar 

  119. Zhang C, Cheng Z, Yang P, Xu Z, Peng C, Li G, Lin J (2009) Architectures of strontium hydroxyapatite microspheres: solvothermal synthesis and luminescence properties. Langmuir 25:13591–13598

    CAS  Google Scholar 

  120. Zhang C, Li C, Huang S, Hou Z, Cheng Z, Yang P, Peng C, Lin J (2010) Self- activated luminescet and mesoporous strontium hydroxyapatite nanorods for drug delivery 31: 3374–3383

  121. Naccache R, Rodriguez EM, Bogdan N, Sanz-Rodriguez F, Cruz MCI, Fuente AJ, Vetrone F, Jaque D, Sole JG, Capobianco JA (2012) High resolution fluorescence imaging of cancers using lanthanide ion-doped upconverting nanocrystals. Cancers 4:1067–1105

    CAS  Google Scholar 

  122. Cheng F, Sun K, ZhaoY LY, Xin Q, Sun X (2014) Synthesis and characterization of HA/YVO4: Yb3+, Er3+ up-conversion luminescent nano-rods. Ceram Int 40:1139–11334

    Google Scholar 

  123. Anuradha JJC, Gulati K, Ray A, Roy I (2014) Fluorophore-doped calcium phosphate nanoparticles for non-toxic biomedical applications. RSC Adv 4:40449–40455

    CAS  Google Scholar 

  124. Niemirowicz K, Markiewicz KH, Wilczewska AZ, Car H (2012) Magnetic nanoparticles as new diagnostic tools in medicine. Adv Med Sci 57:196–207

    CAS  Google Scholar 

  125. Yoo D, Lee J, Shin T, Cheon J (2011) Theranostic magnetic nanoparticles. Acc Chem Res 44:863–874

    CAS  Google Scholar 

  126. Laurent S, Forge D, Port M, Roch A, Robic C, Elst LV, Muller RN (2008) Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterization, and biological applications. Chem Rev 108:2064–2110

    CAS  Google Scholar 

  127. Reddy H, Arias JL, Nicolas J, Couvreur (2012) Magnetic nanoparticles: design and characterization, toxicity and biocompatibility, pharmaceutical and biomedical applications. Chem Rev 112:5818–5878

    CAS  Google Scholar 

  128. Singamaneni S, Bliznyuk VN, Binek C, Tsymbal EY (2011) Magnetic nanoparticles: recent advances in synthesis, self-assembly and applications. J Mater Chem 21:16819–16835

    CAS  Google Scholar 

  129. Gallo J, Long NJ, Aboagye EO (2013) Magnetic nanoparticles as contrast agents in the diagnosis and treatment of cancer. Chem Soc Rev 42:7816–7833

    CAS  Google Scholar 

  130. Gao J, Gu H, Xu B (2009) Multifunctional magnetic nanoparticles: design, synthesis, and biomedical applications. Acc Chem Res 42:1097–1107

    CAS  Google Scholar 

  131. Kaygili O, Dorozhkin SV, Ates T, Al-Ghamdi AA, Yakuphanoglu (2014) Dielectric properties of Fe doped hydroxyapatite prepare by sol–gel method. Ceram Int 40:9395–9402

    CAS  Google Scholar 

  132. Mercado DF, Magnacca G, Malandrino M, Rubert A, Montoneri E, Celi L, Prevot A, Gonzales MC (2014) Paramagnetic iron-doped hydroxyapatite nanoparticles with improved metal sorption properties. A bioorganic substrates-mediated synthesis. Appl Mater Interfaces 6:3937–3946

    CAS  Google Scholar 

  133. Liu X, Ma J, Yang J Visible-light-driven amorphous Fe(III)-substituted hydroxyapatite photocatalyst: Charecterization and photocatalytic activity. doi:10.1016/j.matlet.2014.09.018

  134. Li Y, Ooi CP, Cheang PHN (2009) Synthesis and characterisation of neodymium (III) and gadolinium (III)- substituted hydroxyapatite as biomaterials. Int Appl Ceram Technol 4:501–512

    Google Scholar 

  135. Petchsang N, Pon-On W, Hodak JH, Tang IM (2009) Magnetic properties of Co-ferrite-doped hydroxyapatite nanoparticles having a core/shell structure. J Magn Magn Mater 321:1990–1995

    CAS  Google Scholar 

  136. Trandafir DL, Mirestean C, Turcu RVF, Frentiu B, Eniu D, Simon S (2014) Structural characterization of nanostructured hydroxyapatite-iron oxide composites. Ceram Int 40:11071–11078

    CAS  Google Scholar 

  137. Gopi D, Ansari MT, Shinyjoy E, Kavitha L (2012) Synthesis and spectroscopic charecterization of magnetic hydroxyapatite nanocomposite using ultrasonic irradiation. Spectrochim Acta A 87:245–250

    CAS  Google Scholar 

  138. Low HR, Phonthammachai N, Stewart GA, Bastow TJ, Ma LL, White TJ (2008) The crystal chemistry of ferric oxyhydroxyapatite. Inorg Chem 47:11774–11782

    CAS  Google Scholar 

  139. Li Y, Widodo J, Lim S, Ooi CP (2012) Synthesis and cytocompatibility of manganese (II) and iron (III) substituted hydroxyapatite nanaoparticles. J Mater Sci 47:754–763

    CAS  Google Scholar 

  140. Liu Y, Sun Y, Cao C, Yang Y, Wu Y, Ju D, Li F (2014) Long-term biodistribution in vivo and toxicity of radioactive/ magnetic hydroxyapatite nanaorods. Biomaterials 35:3348–3355

    CAS  Google Scholar 

  141. Tampieri A, Iafisco M, Sandri M, Panseri S, Cunha C, Sprio S, Savini E, Uhlarz M, Herrmannsdorfer T (2014) Magnetic bioinspired hybrid nanostructured collagen- hydroxyapatite scaffolds supporting cell proliferation and tuning regenerative process. Appl Mater Interfaces. doi:10.1021/am5050967

    Google Scholar 

  142. Panseri S, Cunha C, Dalessandro T, Sandri M, Giavaresi G, Marcacci M, Hung CT, Tampieri A (2012) Intrinsically superparamagnetic Fe-hydroxyapatite nanoparticles positively influences osteoblast-like cell behaviour. J Nanobiotechnol 10:32–41

    CAS  Google Scholar 

  143. Ruixue S, Kezheng C, Lei X (2013) Preparation and Characterization of Hydroxyapatite/ɤ-FE2O3 Hybrid Nanostructure. J Wuham Univ Technol Mater Sci Edu 215–219

  144. Pon-On W, Meejoo S, Tang I (2008) Substitution of manganese and iron into hydroxyapatite: core/shell nanoparticle. Mater Res Bull 43:2137–2144

    CAS  Google Scholar 

  145. Iafisco M, Sandri M, Panseri S, Delgado-Lopez JM, Gomez-Morales J, Tampieri A (2013) Magnetic bioactive and biodegadable hollow Fe-doped hydroxyapatite coated poly(L-lactic) acid micro-nanospheres. Chem Mater 25:2610–2617

    CAS  Google Scholar 

  146. Tampieri A, DAlessandro T, Sandri M, Sprio S, Landi E, Bertinetti L, Panseri S, Pepponi G, Goettlicher J, Banobre-Lopez M, Rivas J (2012) Intrinsic magnetism and hyperthermia in bioactive Fe-doped hydroxyapatite. Acta Biomater 8:843–851

    CAS  Google Scholar 

  147. Kuda O, Pinchulk N, Iyanchenko L, Parkhomey O, Sych O, Leonowicz WR, Sowka E (2009) Effect of Fe3O4, Fe and Cu doping on magnetic properties and behaviour in physiological solution of biological hydroxyapatite/glass composite. J Mater Process Technol 209:1960–1964

    CAS  Google Scholar 

  148. Tseng C, Chang K, Yeh M, Yang K, Tang T, Lin F (2014) Development of a dual-functional Pt-Fe-HAP magnetic nanoparticles application for chemo-hyperthermia treatment of cancer. Ceram Int 40:5117–5127

    CAS  Google Scholar 

  149. Kanchana P, Lavanya N, Sekar C (2014) Development of amperometric L-tyrosine sensor based on Fe-doped hydroxyapatite nanoparticles. Mater Sci Eng C 35:85–91

    CAS  Google Scholar 

  150. Chandra VS, Baskar G, Suganthi RV, Elayaraja K, Joshy MIA, Beaula WS, Mythili R, Venkataraman G, Kalkura SN (2012) Blood compatibility of iron-doped nanosize hydroxyapatite and its drug release. Appl Mater Interfaces 4:1200–1210

    Google Scholar 

  151. Ashokan A, Menon D, Nair S, Koyakkutty M (2010) A molecular receptor targeted, hydroxyapatite nanocrystals based multi-modal contrast agent. Biomaterials 31:2606–2616

    CAS  Google Scholar 

  152. Liu Z, Wang Q, Yao S, Yang L, Yu S, Feng X, Li F (2014) Synthesis and characterization of Tb3+/Gd3+ dual-doped multifunctional hydroxyapatite nanaoparticle. Ceram Int 40:2613–2617

    CAS  Google Scholar 

  153. Li Z, Liu Z, Yin M, Yang X, Yuan Q, Ren JQX (2012) Aptamer-capped multifunctional mesoporous strontium hydroxyapatite nanovehicle for cancer-cell-responsive drug delivery and imaging. Biomacromolecules 13:4257–4263

    CAS  Google Scholar 

  154. Chen F, Huang P, Zhu Y, Wu J, Zhang C, Cui D (2011) The photoluminescence, drug delivery and imaging properties of multifunctional Eu3+/Gd3+ dual-doped hydroxyapatite nanorods. Biomaterials 32:9031–9039

    CAS  Google Scholar 

  155. Ashokan A, Gowd GS, Somasundaram VH, Bhupathi A, Peethambaran R, Unni AKK, Palaniswami SP, Nair SV, Koyakkutty M (2013) Multifunctional calcium phosphate nano-contrast agent for combined nuclear, magnetic and near-infrared in vivo imaging. Biomaterials 34:7143–7157

    CAS  Google Scholar 

  156. Chen F, Huang P, Zhu Y, Wu J, Cui D (2012) Multifunctional Eu3+/Gd3+ dual-doped calcium phosphate vesicle-like nanospheres for sustained drug release and imaging. Biomaterials 33:6447–6455

    CAS  Google Scholar 

  157. Liu M, Liu H, Sun S, Li X, Zhou Y, Hou Z, Lin J (2014) Multifunctional hydroxyapatite/Na(Y/Gd)F4:Yb3+, Er3+ composite fibres for drug delivery and dual model imaging. Langmuir 30:1176–1182

    CAS  Google Scholar 

  158. Syamchand SS, Priya S, Sony G (2015) Hydroxyapatite nanocrystals dually doped with fluorescent and paramagnetic labels for bimodal (luminomagnetic) cell imaging. Michrochim Acta 182:1213–1221

    CAS  Google Scholar 

  159. Yu MK, Park J, Jon S (2012) Targeting strategies for multifunctional nanoparticles in cancer imaging and therapy. Theranostics 2:3–44

    CAS  Google Scholar 

  160. Veiseh O, Gunn JW, Zhang M (2010) Design and fabrication of magnetic nanoparticles for targeted drug delivery and imaging. Adv Drug Deliv Rev 62:284–304

    CAS  Google Scholar 

  161. Venkatasubbu GD, Ramasamy S, Avadhani GS, Ramakrishnan V, Kumar J (2013) Surface Modification and paclitaxel drug delivery of folic acid modified polyethylene glycol functionalized hydroxyapatite nanoparticles. Powder Technol 235:437–442

    CAS  Google Scholar 

  162. Yang Y, Liu C, Liang Y, Lin F, Wu K (2013) Hollow mesoporous hydroxyapatite nanoparticles (hmHANPs) with enhanced drug loading and pH-responsive release properties for intracellular drug delivery. J Mater Chem B 1:2447–2450

    CAS  Google Scholar 

  163. Wang S, Wang X, Xu H, Abe H, Tan Z, Zhao Y, Guo J, Naito M, Ichikawa H, Fukumori Y (2010) Towards sustained delivery of small molecular drugs using hydroxyapatite microspheres as the vehicles. Adv Powder Technol 21:268–272

    CAS  Google Scholar 

  164. Haifeng G, Zhiqiang Z, Feng Y, Guoping L, Zhiheng Z (2014) Preparation of magnetic, luminescent and mesoporous hydroxyapatite nanospindles with high specific surface area. Rare Metal Mater Eng 43:2647–2651

    Google Scholar 

  165. Vuong QL, Doorslaer SV, Bridot JL, Argante C, Alejandro G, Hermann R, Disch S, Mattea C, Stapf S, Gossum Y (2012) Paramagnetic nanoparticles as potential MRI contrast agents: characterization, NMR relaxation, simulations and theory. Magn Reson Mater Phys 25:467–478

    CAS  Google Scholar 

  166. Guo D, Xu K, Zhao X, Han Y (2005) Development of a strontium - containing hydroxyapatite bone cement. Biomaterials 26:4073–4083

    CAS  Google Scholar 

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Acknowledgments

The authors would like to acknowledge University Grant Commission (UGC) New Delhi, for providing financial assistance through the Teacher Fellowship under Faculty Improvement Programme (FIP) and the Head, Department of Chemistry, University of Kerala (Kariavattom Campus), Trivandrum.

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Syamchand, S.S., Sony, G. Multifunctional hydroxyapatite nanoparticles for drug delivery and multimodal molecular imaging. Microchim Acta 182, 1567–1589 (2015). https://doi.org/10.1007/s00604-015-1504-x

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