Abstract

Gold nanoparticles carrying fluorinated ligands in their monolayer are, by themselves, contrast agents for 19F magnetic resonance imaging displaying high sensitivity because of the high density of fluorine nuclei achievable by grafting suitable ligands on the gold core surface. Functionalization of these nanoparticles with Gd(III) chelates allows adding a further functional activity to these systems, developing materials also acting as contrast agents for proton magnetic resonance imaging. These dual mode contrast agents may allow capitalizing on the benefits of 1H and 19F magnetic resonance imaging in a single diagnostic session. In this work, we describe a proof of principle of this approach by studying these nanoparticles in a high field preclinical scanner. The Gd(III) centers within the nanoparticles monolayer shorten considerably the 19F T1 of the ligands but, nevertheless, these systems display strong and sharp NMR signals which allow recording good quality 19F MRI phantom images at nanoparticle concentration of 20 mg/mL after proper adjustment of the imaging sequence. The Gd(III) centers also influence the T1 relaxation time of the water protons and high quality 1H MRI images could be obtained. Gold nanoparticles protected by hydrogenated ligands and decorated with Gd(III) chelates are reported for comparison as 1H MRI contrast agents.

Highlights

  • Gold nanoparticles (AuNPs) are ideal scaffolds to set up prototypes for therapy and diagnosis due to the variety of experimental synthetic procedures to control their size, shape, and dispersion

  • Since 1H and 19F have very similar gyromagnetic ratio 19F magnetic resonance imaging (MRI) can be potentially run on existing 1H imaging hardware, allowing dual imaging in a single diagnostic session, as already available in some clinical instrumentation. 19F MRI requires the use of fluorinated contrast agents to provide the MRI signal, in most cases micelles, dendrimers [23], and nanoemulsions [24,25,26,27]

  • AuNPs are suited as a scaffold to develop nanostructured gadolinium-based MRI contrast agents with improved performance respect to monomeric gadolinium complexes

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Summary

Introduction

Gold nanoparticles (AuNPs) are ideal scaffolds to set up prototypes for therapy and diagnosis due to the variety of experimental synthetic procedures to control their size, shape, and dispersion. Workentin and Hudson reported water soluble AuNPs decorated with triethylene glycol terminated with maleimide conjugated to over 50 Gd(III) chelators prepared via an interfacial Michael addition in aqueous media [16]. In this nanoparticle system, the relaxivity per gadolinium unit was the same scored by the monomeric gadolinium complex: about 2 mM−1 s−1 at 9.4 T. Fluorinated compounds can have relatively long relaxation times, resulting in long acquisition times [32] This problem can be circumvented by introducing in the structure of the 19F CA paramagnetic centers, such as Gd(III) in the proximity of 19F nuclei, shortening T1 and allowing for the acquisition of a larger number of scans in the same experimental. TYimu ean[d33c–o3w6]o.rIknertshrisepcoorntteedxtt,hYatuinanadsmcoawllo, wrkaetresr rseopluobrtleedcothmaptoinunadshmaavliln, gwnaitneer seoqluuibvlaelecnotmflpuoourinnde hataovminsgwnhiniceheqisuaivbaleletnot cflhueolraitneegaatdoomlisnwiuhmichioinssa[b3l7e]tothcehTel1atsehgoartdeonliinngiuemnaiobnlesd[3b7y] tthhee Tp1arsahmoratgenneintigc ecennatbelredsibgynitfhiceapnatlryamimagpnroevtiecdcetnhteersisgignnailfitcoanntolyiseimrpartioov.eAd tshime siilgarnaelffteocnt owisaesraotbisoe.rAvesdiminilaAr ueffNePcst wdeacsoorabtseedrv, evdiainhyAdurNogPesndebcoonrdaste, dw, ivthia fhluyodrriongaetnedbognudasn,idwiinthiuflmuoarminpahteipdhgilueasnaidnidnicuamrryaimngphiniphthileeisr amnodncoalarryyeirnaglsiontthhieoilratmesocnaoplaaybeler oaflscoomthpiolelaxtiensgcGapda(IbIIl)e. oInf cthoims spylestxeimngaG2d7%(IIId)e. cIrneathseisinsy1s9FteTm1 aco2u7l%d dbeecraecahsieevined19F[3T31].coHuoldwbeveearc, hitehveedst[a3b3i]l.ityHoawnedvecro, mthpeasttiabbiliiltiyty oafndthceosme paNtiPbsi,litoybotaf itnheedse fNroPms, opbhtoasipnhedinfer-ostmabpilhizoesdphgionled-sctlaubsitleizresdofgo1l.5d nclmustinersdioafm1e.5tenrm, wiinthdibaimoleotgeirc,awl imthedbiiaolaongdicathl emiredtoiaxiacnitdy twhietihr tcoexllisciwtyewreitnhocteilnlsvwesetrigeantoetdi.nBvaessetdigaotnedth. eBsaeseedviodnenthceesse, weveideexnpcloesr,edwetheexpinlotrroedduthcteioinntroofdGudct(iIoIIn) ocof mGpdl(eIxIIe)scionmtphleexmeosninolathyeermoofnfolulaoyrienraotefdfluAourNinPast,edaimAuinNgPast, daiemcrienagsiantgdtehcereTa1sianngdthTe2 Tre1laaxnadtiTon rtiemlaexsatoiof nprtoimtoens aonf dprfolutoonriannedaflnudotroinaessaensds ttoheasvsieasbsiltihtey voifatbhileistye osyf sthteemsessiynstdeumasl 1inHd/1u9FalM1HRI/1u9FsiMngRaI upsreincglinaicparlescelitnuipc.aFl oserttuhpis. pFuorrpthoisse,ptuhreptowseo,ctlhaesstewsoofclmasisxeesdomf monixoeladymeroAnuoNlaPyesrwAituhNaPgsowlditchoraegsoizlde coofr1e.5s–iz2e.0onfm1.,5r–e2p.0rensmen, treedprinesSecnhteedmien1S,cwheemreed1e,swigenreeddaensdignsyendthanesdizseydn.thesized

F FF F O
Synthesis of NP-C6OF-PEG
Determination of Nanoparticles’ 19F Relaxation Times
Determination of T1 and T2 Values with the 7 T Preclinical Scanner
Dynamic Light Scattering
Results
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