Abstract
Nanoparticles (NPs) have been widely used in biomedical research, but the difficulty in determining their in vivo characteristics limits their clinical translation. So far, positron emission tomography (PET), which requires that the NPs are labeled with an appropriate positron nuclide, appears to be the most likely solution to this problem. 64Cu is the most frequently used positron emitter in NP research and 64Cu radiolabeling using chelators is the most commonly used strategy, although this method has some shortcomings in practice. In the present study, we directly integrated 64Cu into the internal cavities of generation 5 polyamidoamine (G5 PAMAM), a commercially available NP, without the need for chelators. The labeling time, pH level, temperature, and amount of precursor were systematically varied to determine the optimum labeling conditions. Preliminary biological evaluation in mice revealed that the 64Cu direct labeling method was feasible for the preparation of labeled PAMAM for in vivo studies. This study introduced a novel idea for 64Cu labeling of dendrimers (and other NPs with a similar structure) and should facilitate the application of NPs in biomedical studies.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Anderson CJ, Ferdani R (2009) Copper-64 radiopharmaceuticals for pet imaging of cancer: advances in preclinical and clinical research. Cancer Biother Radio 24:379–393
Aumanen J, Teobaldi G, Zerbetto F, Korppi-Tommola J (2011) The effect of temperature on the internal dynamics of dansylated POPAM dendrimers. RSC Adv 1:1778–1787. https://doi.org/10.1039/C1RA00625H
Balogh L, Valluzzi R, Laverdure KS, Gido SP, Hagnauer GL, Tomalia DA (1999) Formation of silver and gold dendrimer nanocomposites. J Nanopart Res 1:353–368. https://doi.org/10.1023/A:1010060404024
Bass LA, Wang M, Welch MJ, Anderson CJ (2000) In vivo transchelation of copper-64 from TETA-octreotide to superoxide dismutase in rat liver. Bioconjug Chem 11:527–532. https://doi.org/10.1021/bc990167l
Bose T, Latawiec D, Mondal PP, Mandal S (2014) Overview of nano-drugs characteristics for clinical application: the journey from the entry to the exit point. J Nanopart Res 16:2527. https://doi.org/10.1007/s11051-014-2527-7
Boswell CA, Sun X, Niu W, Weisman GR, Wong EH, Rheingold AL, Anderson CJ (2004) Comparative in vivo stability of copper-64-labeled cross-bridged and conventional tetraazamacrocyclic complexes. J Med Chem 47:1465–1474. https://doi.org/10.1021/jm030383m
Caminade AM, Ouali A, Laurent R, Majoral JP (2015) Phosphorus dendrimers as supports of transition metal catalysts. Inorg Chim Acta 431:3–20. https://doi.org/10.1016/j.ica.2014.10.035
Chen X (2011) Nanoplatform-based molecular imaging. John Wiley & Sons, Inc.
Cheng Z, Al Zaki A, Hui JZ, Muzykantov VR, Tsourkas A (2012) Multifunctional nanoparticles: cost versus benefit of adding targeting and imaging capabilities. Science 338:903–910. https://doi.org/10.1126/science.1226338
Colombo I, Overchuk M, Chen J, Reilly RM, Zheng G, Lheureux S (2017) Molecular imaging in drug development: update and challenges for radiolabeled antibodies and nanotechnology. Methods 130:23–35. https://doi.org/10.1016/j.ymeth.2017.07.018
Crooks RM, Zhao M, Sun L, Chechik V, Yeung LK (2001) Dendrimer-encapsulated metal nanoparticles: synthesis, characterization, and applications to catalysis. Accounts Chem Res 34:181–190. https://doi.org/10.1021/ar000110a
De Silva RA, Jain S, Lears KA, Chong H-S, Kang CS, Sun X et al (2012) Copper-64 radiolabeling and biological evaluation of bifunctional chelators for radiopharmaceutical development. Nucl Med Biol 39:1099–1104. https://doi.org/10.1016/j.nucmedbio.2012.05.009
Erturk AS, Gurbuz MU, Tulu M, Bozdogan AE (2015) Water-soluble TRIS-terminated PAMAM dendrimers: microwave-assisted synthesis, characterization and Cu(II) intradendrimer complexes. RSC Adv 5:60581–60595. https://doi.org/10.1039/c5ra11157a
Ficker M, Petersen JF, Gschneidtner T, Rasmussen A-L, Purdy T, Hansen JS, Hansen TH, Husted S, Moth Poulsen K, Olsson E, Christensen JB (2015) Being two is better than one-catalytic reductions with dendrimer encapsulated copper- and copper-cobalt-subnanoparticles. Chem Commun 51:9957–9960. https://doi.org/10.1039/C5CC00347D
Gajbhiye V, Ganesh N, Barve J, Jain NK (2013) Synthesis, characterization and targeting potential of zidovudine loaded sialic acid conjugated-mannosylated poly(propyleneimine) dendrimers. Eur J Pharm Sci 48:668–679. https://doi.org/10.1016/j.ejps.2012.12.027
Gawande MB, Goswami A, Felpin FX, Asefa T, Huang XX, Silva R, Zou X, Zboril R, Varma RS (2016) Cu and Cu-based nanoparticles: synthesis and applications in review catalysis. Chem Rev 116:3722–3811. https://doi.org/10.1021/acs.chemrev.5b00482
Heidel JD, Davis ME (2011) Clinical developments in nanotechnology for cancer therapy. Pharm Res 28:187–199. https://doi.org/10.1007/s11095-010-0178-7
Hong SH, Sun Y, Tang C, Cheng K, Zhang R, Fan Q, Xu L, Huang D, Zhao A, Cheng Z (2017) Chelator-free and biocompatible melanin nanoplatform with facile-loading gadolinium and copper-64 for bioimaging. Bioconjug Chem 28:1925–1930. https://doi.org/10.1021/acs.bioconjchem.7b00245
Kinnear C, Moore TL, Rodriguez-Lorenzo L, Rothen-Rutishauser B, Petri-Fink A (2017) Form follows function: nanoparticle shape and its implications for nanomedicine. Chem Rev 117:11476–11521. https://doi.org/10.1021/acs.chemrev.7b00194
Klajnert B, Appelhans D, Komber H, Morgner N, Schwarz S, Richter S, Brutschy B, Ionov M, Tonkikh A K, Bryszewska M, Voit B (2008) The influence of densely organized maltose shells on the biological properties of poly(propylene imine) dendrimers: new effects dependent on hydrogen bonding. Chem-Eur J 14:7030–7041. https://doi.org/10.1002/chem.200800342
Liu Y, Welch MJ (2012) Nanoparticles labeled with positron emitting nuclides: advantages, methods, and applications. Bioconjug Chem 23:671–682. https://doi.org/10.1021/bc200264c
Maity P, Yamazoe S, Tsukuda T (2013) Dendrimer-encapsulated copper cluster as a chemoselective and regenerable hydrogenation catalyst. ACS Catal 3:182–185. https://doi.org/10.1021/cs3007318
Murty BSSP, Raj B, Rath BB, Murday J (2013) Application of nanomaterials. In: Textbook of nanoscience and nanotechnology. Springer, Berlin, Heidelberg, pp 107–148
Nemanashi M, Meijboom R (2013) Synthesis and characterization of Cu, Ag and Au dendrimer-encapsulated nanoparticles and their application in the reduction of 4-nitrophenol to 4-aminophenol. J Colloid Interf Sci 389:260–267. https://doi.org/10.1016/j.jcis.2012.09.012
Ottaviani MF, Montalti F, Turro NJ, Tomalia DA (1997) Characterization of starburst dendrimers by the EPR technique. Copper(ii) ions binding full-generation dendrimers. J Phys Chem B 101:158–166. https://doi.org/10.1021/jp962857h
Ottaviani MF, Cangiotti M, Fattori A, Coppola C, Lucchi S, Ficker M, Petersen JF, Christensen JB (2013) Copper(II) complexes with 4-carbomethoxypyrrolidone functionalized PAMAM-dendrimers: an EPR study. J Phys Chem B 117:14163–14172. https://doi.org/10.1021/jp410307z
Padmanabhan P, Kumar A, Kumar S, Chaudhary RK, Gulyas B (2016) Nanoparticles in practice for molecular-imaging applications: an overview. Acta Biomater 41:1–16. https://doi.org/10.1016/j.actbio.2016.06.003
Pelaz B, Alexiou C, Alvarez-Puebla RA, Alves F, Andrews AM, Ashraf S, Balogh LP, Ballerini L, Bestetti A, Brendel C, Bosi S, Carril M, Chan WCW, Chen C, Chen X, Chen X, Cheng Z, Cui D, du J, Dullin C, Escudero A, Feliu N, Gao M, George M, Gogotsi Y, Grünweller A, Gu Z, Halas NJ, Hampp N, Hartmann RK, Hersam MC, Hunziker P, Jian J, Jiang X, Jungebluth P, Kadhiresan P, Kataoka K, Khademhosseini A, Kopeček J, Kotov NA, Krug HF, Lee DS, Lehr CM, Leong KW, Liang XJ, Ling Lim M, Liz-Marzán LM, Ma X, Macchiarini P, Meng H, Möhwald H, Mulvaney P, Nel AE, Nie S, Nordlander P, Okano T, Oliveira J, Park TH, Penner RM, Prato M, Puntes V, Rotello VM, Samarakoon A, Schaak RE, Shen Y, Sjöqvist S, Skirtach AG, Soliman MG, Stevens MM, Sung HW, Tang BZ, Tietze R, Udugama BN, VanEpps JS, Weil T, Weiss PS, Willner I, Wu Y, Yang L, Yue Z, Zhang Q, Zhang Q, Zhang XE, Zhao Y, Zhou X, Parak WJ (2017) Diverse applications of nanomedicine. ACS Nano 11:2313–2381. https://doi.org/10.1021/acsnano.6b06040
Rosenblum LT, Kosaka N, Mitsunaga M, Choyke PL, Kobayashi H (2010) In vivo molecular imaging using nanomaterials: general in vivo characteristics of nano-sized reagents and applications for cancer diagnosis. Mol Membr Biol 27:274–285. https://doi.org/10.3109/09687688.2010.481640
Shi J, Kantoff PW, Wooster R, Farokhzad OC (2016) Cancer nanomedicine: progress, challenges and opportunities. Nat Rev Cancer 17:20–37. https://doi.org/10.1038/nrc.2016.108
Smith BR, Gambhir SS (2017) Nanomaterials for in vivo imaging. Chem Rev 117:901–986. https://doi.org/10.1021/acs.chemrev.6b00073
Svenson S, Tomalia DA (2005) Dendrimers in biomedical applications—reflections on the field. Adv Drug Deliver Rev 57:2106–2129. https://doi.org/10.1016/j.addr.2005.09.018
Taghavi Pourianazar N, Mutlu P, Gunduz U (2014) Bioapplications of poly(amidoamine) (PAMAM) dendrimers in nanomedicine. J Nanopart Res 16:2342. https://doi.org/10.1007/s11051-014-2342-1
Tang YH, Cangiotti M, Kao CL, Ottaviani MF (2017) EPR characterization of copper(ii) complexes of PAMAM-py dendrimers for biocatalysis in the absence and presence of reducing agents and a spin trap. J Phys Chem B 121:10498–10507. https://doi.org/10.1021/acs.jpcb.7b09464
Tiwari A, Mishra AK, Kobayashi H, Turner APF (2012) Intelligent nanomaterials: processes, properties, and applications. John Wiley & Sons, Inc.
Wadas TJ, Anderson CJ (2007) Radiolabeling of TETA- and CB-TE2A-conjugated peptides with copper-64. Nat Protoc 1:3062–3068. https://doi.org/10.1038/nprot.2006.431
Wadas 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. https://doi.org/10.1021/cr900325h
Wang Y, Liu Y, Luehmann H, Xia X, Brown P, Jarreau C, Welch M, Xia Y (2012) Evaluating the pharmacokinetics and in vivo cancer targeting capability of au nanocages by positron emission tomography imaging. ACS Nano 6:5880–5888. https://doi.org/10.1021/nn300464r
Wang S, Cazelles R, Liao W-C, Vázquez-González M, Zoabi A, Abu-Reziq R, Willner I (2017) Mimicking horseradish peroxidase and nadh peroxidase by heterogeneous Cu2+-modified graphene oxide nanoparticles. Nano Lett 17:2043–2048. https://doi.org/10.1021/acs.nanolett.7b00093
Xing Y, Zhao JH, Conti PS, Chen K (2014) Radiolabeled nanoparticles for multimodality tumor imaging. Theranostics 4:290–306. https://doi.org/10.7150/thno.7341
Zhang Y, Xu X, Wang L, Lin J, Zhu Y, Guo Z, Sun Y, Wang H, Zhao Y, Tai R, Yu X, Fan C, Huang Q (2013) Dendrimer-folate-copper conjugates as bioprobes for synchrotron X-ray fluorescence imaging. Chem Commun 49:10388–10390. https://doi.org/10.1039/C3CC46057F
Zhao M, Sun L, Crooks RM (1998) Preparation of Cu nanoclusters within dendrimer templates. J Am Chem Soc 120:4877–4878. https://doi.org/10.1021/ja980438n
Zhao FG, Li WS (2011) Dendrimer/inorganic nanomaterial composites: tailoring preparation, properties, functions, and applications of inorganic nanomaterials with dendritic architectures. Sci China Chem 54:286–301. https://doi.org/10.1007/s11426-010-4205-7
Zhao Y, Sultan D, Detering L, Cho S, Sun G, Pierce R, Wooley KL, Liu Y (2014) Copper-64-alloyed gold nanoparticles for cancer imaging: improved radiolabel stability and diagnostic accuracy. Angew Chem Int Edit 53:156–159. https://doi.org/10.1002/anie.201308494
Funding
The research was financially supported by the National Natural Science Foundation of China (Grant No. 21401025) and Shanghai Engineering Research Center of Molecular Imaging Probes (Grant No. 14DZ2251400).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The animal study was approved by Fudan University Laboratory Animal Ethics Committee.
Conflict of interest
The authors declare that they have no conflicts of interest.
Rights and permissions
About this article
Cite this article
Xu, X., Li, Y., Cao, T. et al. A novel, chelator-free method for 64Cu labeling of dendrimers. J Nanopart Res 20, 204 (2018). https://doi.org/10.1007/s11051-018-4291-6
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s11051-018-4291-6