Patent Application: US-74777007-A

Abstract:
a functionalized nanoparticle is provided that comprises a nanoparticle synthesized from a mixture comprising lanthanide ions , a coating of silica or related materials and a presenting substrate . the presenting substrate can be conjugated to the nanoparticle for functionalizing the nanoparticle . the functionalized nanoparticle is less than about 350 nm in diameter .

Description:
herein , we report a general and easy method for the preparation and bioconjugation of silica - coated laf 3 : ln 3 + nanoparticles that display several non - overlapping emission lines that cover the visible to near - infrared region ( 450 - 1900 nm ) through down - conversion as well as up - conversion processes , which can for instance be exploited in multiplexing applications . [ xx ] laf 3 material has second lowest phonon energy of the commonly used ln 3 + - doping matrices ( table 1 [ xix , xxi , xxii ] ) thus minimizing the quenching of the excited state lanthanide ions from lattice vibrations . also the la 3 + ions are easily substituted within the laf 3 matrix upon doping , without the problems associated with either a significant lattice mismatch of two different ions or lanthanide ion clustering . when the term “ nanoparticle ” is used , one of ordinary skill in the art will appreciate that this term encompasses all materials with small size and often associated with quantum size effects , generally the size is less than 100 nm . nanoparticles can comprise a core or a core and a shell , as in core - shell nanoparticles . all nanoparticles may have one or more ln independently selected from the list below and comprise at least one of : ln 2 x 3 ( x = co 3 , c 2 o 4 , so 4 , so 3 ) precursor nanoparticle : a nanoparticle that is used for making a product nanoparticle . the resulting product nanoparticle may or may not be comprised of the precursor nanoparticle . product nanoparticle : a nanoparticle prepared from a precursor nanoparticle and a coating comprising one or more of silica , alumina , zirconia , titania , hafnia , tantalum pentoxide , niobium pentoxide , germanium dioxide , yttrium oxide ( y 2 o 3 ), and gadolinium oxide ( gd 2 o 3 ). the product nanoparticle may or may not comprise precursor nanoparticle . the product nanoparticle can be a core - shell nanoparticle or it may only comprise the core . lanthanides : the term “ lanthanide ” as used herein refers to ce , pr , nd , sm , eu , gd , tb , dy , ho , er , tm , yb , la , lu , y , sc combinations thereof , compounds containing ce , pr , nd , sm , eu , gd , tb , dy , ho , er , tm , yb , la , lu , y , sc and combinations thereof , and ions of ce , pr , nd , sm , eu , gd , tb , dy , ho , er , tm , yb , la , lu , y , sc and combinations thereof . ionic states ranging from + 2 to + 4 are contemplated . presenting substrate : any material that can interact with the silica coating by adhesion , or chemical bonding , including hydrophobic interactions , hydrogen bonding , ionic bonding and covalent bonding , for example , but not to be limiting . presenting materials include , for example , but not limited to avidin , streptavidin , biotin , antibody , polynucleotide , lectin , protein a , polypeptides and any ligands . these can in turn can interact with , for example , but not limited to drugs , antigens , toxins antibodies , streptavidin , protein a , polypeptides , and polynucleotides . functionalized nanoparticle : any combination of a product nanoparticle and a presenting material . ligands : all ligands may have one or more functional group independently selected from the following : organo phosphorous compounds ( phosphonic and phosphinic acids and their esters ), phosphonates , phosphine oxides ; alkyl ammonium compounds ( rnh 3 + , r 1 r 2 nh 2 + , r 1 r 2 r 3 nh + , r 1 r 2 r 3 r 4 n + , with rx = alkyl or aromatic substituent ). chemicals of the highest purity were obtained from aldrich and used without further purification . the fitc - avidin was obtained from invitrogen and used as received . all water used was distilled . all nanoparticles were made with laf 3 at were doped at the respective % atom doping on the total ln 3 + amount . the synthesis is based on our earlier reported procedure to prepare the citrate - stabilized core - shell ( laf 3 : tm 3 + ) laf 3 nanoparticles [ ix , xxiii ] . around 2 g of citric acid was dissolved in 35 ml of water and the ph adjusted to 5 by adding nh 4 oh , then followed by the addition of naf ( 0 . 1 g , 1 . 33 mmol ). the solution was heated to 75 ° c . followed by the addition of la ( no 3 ) 3 . 6h 2 o ( 0 . 54 g , 1 . 26 mmol ) and tm ( no 3 ) 3 . 5h 2 o ( 0 . 02 g , 0 . 05 mmol ) dissolved in 2 ml of methanol . after 10 min , the shell was formed by the addition of 10 drops at a time of la ( no 3 ) 3 . 6h 2 o ( 0 . 6 g , 1 . 33 mmol ) in 2 ml of methanol , and naf ( 0 . 1 g , 1 . 33 mmol ) in 2 ml of water , in sequential order . the reaction was allowed to continue for 2 h and finally the nanoparticles were precipitated by the addition of excess of ethanol to the reaction mixture . they were collected by centrifuge and dried for 24 h . 50 mg of citrate stabilized laf 3 : ln 3 + nanoparticles dissolved in 1 . 44 ml of distilled water was added to ethanol ( 20 ml ) and 30 % nh 4 oh ( 0 . 4 ml ) mixture . 1 . 2 ml of tetraethyl orthosilicate ( teos ) was added to the above mixture . the mixture was stirred for 60 min . white coloured silica beads were centrifuged and washed with ethanol for several times . silica beads were dried under vacuum . silica - coated laf 3 : nd , laf 3 : yb , er , and laf 3 : yb , tm nanoparticles were heated at 800 ° c . for 12 hr in air . surface modification of the silica - coated laf 3 : ln 3 + nanoparticles with 3 - aminopropyltrimethoxysilanes ( aptms ) 10 mg of silica - coated laf 3 : ln 3 + nanoparticles were suspended in 10 ml of ethanol , followed by the addition of 0 . 5 ml ( 2 mmol ) of aptms and stirred for 24 hr at room temperature . the particles were isolated and purified by centrifugation , washed 3 times with ethanol and dried under reduced pressure . 10 mg of aptms modified silica - coated laf 3 : ln 3 + nanoparticles were suspended in 2 ml of dmso , followed by the addition of 10 mg ( 0 . 03 mmol ) of (+)- biotin n - hydroxysuccinimide ester and stirred for 1 . 5 hr at room temperature . the particles were isolated and washed by centrifugation , washed once with water and three times with ethanol , and dried under reduced pressure . biotin - fitc - avidin binding : 10 mg of amine - modified silica - coated laf 3 : ln 3 + nanoparticles were suspended in 10 ml of 10 mm phosphate - buffered saline , ph 7 . 4 , followed by the addition of 0 . 4 ml of fitc - avidin ( final avidin concentration of 0 . 1 mg / ml ) and stirred for 2 . 5 hr at room temperature . the particles were isolated and purified by centrifugation , washed 5 times with 10 mm phosphate - buffered saline solution and resuspended in 10 ml of 10 mm phosphate - buffered saline solution . down - conversion luminescence analyses were done using an edinburgh instruments fls 920 fluorescence system , which was equipped a cw 450w xenon arc lamp via an m300 single grating monochromator and a 10 hz q - switched quantel brilliant , pumped by a nd : yag laser , attached with an optical parametric oscillator ( opo ) with an optical range from 410 to 2400 nm . the excitation source used for up - conversion was a coherent 2 - pin 980 nm cw semiconductor diode laser with p max = 800 mw at 1000 ma . the fiber is coupled to 100 μm ( core ) fiber . a red - sensitive peltier - cooled hamamatsu r955 photomultiplier tube ( pmt ), with a photon - counting interface , was used for analyses between 200 and 850 nm , and a n 2 - cooled (− 80 ° c .) hamamatsu r5509pmt was used for analyses between 800 and 1700 nm . all emission analyses in the visible region were measured with a 1 nm resolution . all emission analyses in the near - infrared region were measured with a 10 nm resolution . all spectra were corrected for detector sensitivity . lifetime analyses for all nanoparticles were done by exciting the solution with a 10 hz q - switched quantel brilliant , pumped by a nd : yag laser , with an optical range from 410 to 2400 nm , and collecting the emission using the respective detector mentioned above . decay curves were measured with a 0 . 01 ms lamp trigger delay for the r955pmt . effective lifetimes were calculated using origin 7 software . the effective lifetimes were calculated using origin 7 software based on the equation [ 1 ], all luminescence studies were carried out as dry powders for unmodified 800 ° c . heated silica - coated laf 3 : nd , laf 3 : er , laf 3 : yb , er and laf 3 : yb , tm nanoparticles . other samples were carried as buffer solutions . tem of the silica - coated laf 3 : ln 3 + nanoparticles was carried out using a hitachi h - 7000 microscope , operated at 100 kv . around 1 - 2 mg of sample was dispersed in 5 ml of ethanol and a drop of this mixture was evaporated on a carbon - coated 300 mesh copper grids . around 45 images were recorded from different region of the same sample and an average particle size was obtained based on a minimum of 100 particles . the transmission electron microscopy ( tem ) image shown in fig1 is of the as - prepared silica - coated laf 3 : nd nanoparticles , which clearly shows that almost all the silica beads have a single core laf 3 : nd nanoparticle (˜ 5 nm ) in the center with an average shell thickness of ˜ 17 nm . the laf 3 : nd core has a slightly higher contrast than the sio 2 shell . fig2 a shows the emission spectrum of the as - prepared silica - coated laf 3 : eu nanoparticles , in which the major emission bands of the eu 3 + ions at 590 nm and 612 nm are assigned to the 5 d 0 to 7 f 1 and 5 d 0 to 7 f 2 transitions , and an effective lifetime of 5 . 9 ms is assigned to the 5 d 0 level ( fig3 ). additionally , the emission spectrum of the as - prepared silica - coated laf 3 : tb 3 + nanoparticles is shown in fig2 b , in which the most intense peak at 545 nm corresponds to 5 d 4 to 7 f 5 transition , and the peaks at 586 and 623 nm correspond to the 5 d 4 to 7 f 4 and 7 f 3 transitions , respectively . an effective lifetime of 3 . 7 ms is attributed to the 5 d 4 level ( fig4 ). fig5 shows the tem image of silica - coated laf 3 : nd nanoparticle heated at 800 ° c . for 12 hr , resulting the beads to contract to an average shell thickness of ˜ 15 nm . fig6 a shows the emission spectrum of the silica - coated laf 3 : nd nanoparticles , where the emission peaks at 870 nm , 1070 nm , and 1330 nm are from 4 f 3 / 2 transitions to 4 i 13 / 2 , 4 i 11 / 2 , and 4 i 9 / 2 , respectively , with a effective luminescent lifetime of 170 μs ( fig7 ). due to the ability of lanthanide ions to be excited indirectly through the sensitized emission of another lanthanide ion , fig6 b shows the emission spectrum of silica - coated laf 3 : yb , er nanoparticles , via sensitized emission from yb 3 + to the er 3 + ions , by direct excitation of the yb 3 + ions at 940 nm . the importance of this spectrum demonstrates that though er 3 + has no absorption lines at this wavelength , this process results in the simultaneous very weak emission of yb 3 + at 980 nm ( attributed to the 2 f 5 / 2 to 2 f 7 / 2 transition ), and the shown sensitized emission of the er 3 + ions at 1540 nm ( 4 i 13 / 2 to 4 i 15 / 2 transition ), with an effective lifetime of 1 . 8 ms from the 4 i 13 / 2 level ( fig8 ). the up - conversion emission spectrum of the 800 ° c . heated silica - coated laf 3 : yb , er nanoparticles , fig9 a shows the emission spectrum of the er 3 + ions by up - conversion , with the peaks at 515 , 540 nm , and 660 nm being assigned to the 2 h 11 / 2 to 4 i 15 / 2 , 4 s 3 / 2 to 4 i 15 / 2 , and 4 f 9 / 2 to 4 i 15 / 2 transitions , respectively . furthermore , fig9 b demonstrates the up - conversion emission spectrum of heated silica - coated laf 3 : yb , tm nanoparticles , in which the emission band around 800 nm is a result of the 3 h 4 to 3 h 6 transition of tm 3 + ions . moreover , a weak tm 3 + emission band at 475 nm was observed and assigned to the 1 g 4 to 3 h 6 transition ( fig1 ), and is also a result of the up - conversion process . preliminary results into the mechanism of the up - conversion process involving tm 3 + suggest that it is occurring via energy transfer ( et ) rather than an excited state absorption ( esa ) or photoavalanche ( pa ) process . [ ix ] some evidence has been gathered that the up - conversion involving er 3 + likely proceeds via a photo - avalanche mechanism , if certain conditions are met . to test the ability for the core - shell silica nanoparticles to be bound to a biological system , surface modification of the silica shell with biotin was used as a model for nanoparticle binding with fitc - avidin , and the extent of binding monitored by the fitc emission intensity . due to the biologically inert nature of silica , the shell had to be modified first in a two - step process in order to impart biotin activity , as shown in scheme 1 . the emission spectra of bioconjugation of silica - coated laf 3 : tb nanoparticles to fitc - avidin , which is overlaid along with non - biotinylated particles as control particles , is shown in the fig1 . the emission spectra show an approximate 25 - fold increase in fitc signal over the control particles , clearly proving that specific binding of avidin to the silica particles has been achieved , and that the signal from the control particles is likely a result of some physical adsorption of avidin onto the particles in a negligible amount . our previous work has shown that coating the surface of laf 3 : ln 3 + nanoparticles with poly ( ethylene glycol )- based ligands minimized the effects of non - specific binding , and we expect the same result with our current silica - coated particles . [ 10 ] fig1 shows the tb 3 + emission spectrum of the particles excited with high excitation power , in which the dominant 544 nm peak of tb 3 + is visible on top of the fitc signal with an effective luminescent lifetime of 3 . 2 ms ( inset in fig1 ), which is in agreement with that of the unmodified and aptms modified particles . the reason for the low tb 3 + signal is due to the fact that lanthanide ions have a very low absorption coefficient when compared to fitc and with an excitation wavelength of 485 nm that excites both the fitc and the tb 3 + ions , the emission spectrum of the fitc will dominate . the same binding experiments were carried on silica - coated laf 3 : nd nanoparticles resulting in a similar increase in fitc emission over the control particles ( fig1 ). fig1 shows the emission spectrum of the silica - coated laf 3 : nd nanoparticles , showing the characteristic peaks at 870 nm , 1064 nm and 1330 nm , with an effective luminescent lifetimes of 178 μs ( inset in fig1 ), which is in agreement with that of the unmodified particles . the formation of the silica coating over the laf 3 : nd and laf 3 : yb , er nanoparticles improved the nir luminescence significantly by minimizing the solvent quenching effect as compared to our previously reported citrate and 2 - aminoethylphosphate stabilized laf 3 : nd nanoparticles . [ 10 ] the preparation of the ( laf 3 : tm ) laf 3 citrate - stabilized nanoparticles followed established procedures resulting in an average particle diameter of 7 - 10 nm . [ ix , xxiii , xxiv ] synthesis of the nanoparticles is outlined in fig1 , which starts from citrate - stabilized laf 3 : ln 3 + precursor nanoparticles as the core matrix , followed by the formation of a laf 3 shell , which is then coated with a silica shell via a modified stöber process . [ xxv ] the resulting particles are fairly monodisperse with an average diameter of 40 ± 5 nm ( tem ). energy dispersive x - ray ( edx ) analysis of the core - shell particles confirmed the presence of the tm 3 + at 1 % relative to la 3 + , meaning the core itself is doped at 2 %, and gave a f to ln ratio of ca . 2 . 8 : 1 confirming that the surface is stabilized with citrate ions . fig1 shows a schematic diagram of the excitation and emission levels of interest from tm 3 + , where excitation of the nanoparticles into the 3 h 4 level at 785 nm result in two emission bands at 1470 nm ( 3 h 4 - 3 f 4 transition ) and 1870 nm ( 3 f 4 - 3 h 6 transition ). the emission and luminescent lifetime spectra of the particles , in d 2 o , are shown in fig1 . the peak intensity of the emission band in fig1 is centered at ca . 1470 nm and is assigned to the 3 h 4 - 3 f 4 transition . the inset in fig1 shows the decay curve of the particles with an effective lifetime of 9 μs . in comparison to a radiative lifetime of 1513 μs for tm 3 + - doped liyf 4 nanoparticles by walsh et al . [ xxvi ] , the short luminescent lifetime of our particles is a result of high level of quenching , and is primarily attributed to the coordination of od groups from the citrate molecules and d 2 o to the nanoparticle surface . additionally , the short lifetime suggests that the laf 3 shell does not completely shield the tm 3 + ions from quenching effects . an estimation of the quantum yield ( φ ) using the formula below results in a value less than 1 %. other reports of tm 3 + - doped systems [ xxvii , xxviii ] such as glasses , silica fibers and ceramics have radiative lifetimes that are within ± 0 . 2 ms of that referenced above , showing that the radiative lifetime ( τ rad ) is not very sensitive to the crystal field . in order to improve the luminescent properties of the nanoparticles , reduction of the non - radiative decay processes was done by the formation of a silica - coating over the particles followed by curing at 900 ° c . for 24 hours . the curing process was found to improve the luminescent properties for two reasons : first , the high temperature removes most surface bound oh groups , such as water and si — oh groups , which are known to quench luminescence . [ ix , xxiii , xxiv ] moreover , the elevated temperatures convert a large portion of the si — oh into sio x groups , further minimizing the number of oh groups in contract with the laf 3 shell . secondly , the heating process also causes the silica shell to contract in diameter , densifying the shell and making it less porous to solvent , which also reduces quenching effects as reported elsewhere . [ xxiv ] fig1 shows the emission spectrum of the particles at 294 k upon excitation at 785 nm , and exhibits a broad set of overlapping peaks centered around 1450 nm , and is attributed to the 3 h 4 - 3 f 4 transition . the broadness of the transition , which has some barely resolved fine structure , is in agreement with other reports [ xxvi ] and is a result of crystal field splitting of the 3 h 4 and 3 f 4 levels . to study further the crystal field splitting , the sample was cooled to 77 k and the emission spectrum was measured at a high resolution ( 2 nm ). shown in fig1 a are the overlaid emission spectra of the 3 h 4 - 3 f 4 transition at ( a ) 294 k and ( b ) 77 k , in which a reduction in the width of the emission band is seen indicating that the 3 h 4 levels are thermally populated at room temperature . an estimation of six crystal field levels by gaussian deconvolution of the overlapped peaks of the 77 k emission was observed , which is similar to studies done by ryba - romanowski et al . [ xxix ] on tm 3 + - doped srgdga 3 o 7 single crystals grown by the czochralski method [ xxx ] , who also observed six of the nine theoretical crystal field levels for the 3 f 4 level . the nine crystal field levels of the 3 f 4 level are derived from the formula 2j + 1 , which is based on the russell - saunders assignment of 2s + 1 l j , where j is the total angular momentum . the decay curves of the samples at 294 k and at 77 k are shown overlaid in fig1 b , with an effective lifetime of 151 ± 10 μs and 188 ± 10 μs , respectively . the difference in the two values suggests that there is a reduction in non - radiative processes for the cooled sample , as its lifetime is slightly longer . finally , the low temperature analysis of the nanoparticles in fig2 shows the emission spectrum of the 3 f 4 - 3 h 6 transition around 1 . 85 μm . luminescent lifetime analysis could not be done due to the low luminescent output at that emission wavelength . in conclusion , a general and facile method for the production of bioconjugated silica - coated laf 3 : ln 3 + nanoparticles with a uniform size distribution has successfully been demonstrated . a wide range of emission lines ( 450 - 1650 nm ) by up - and down - conversion processes have been achieved by doping with different lanthanide ions . in particular , the excitation with 980 nm light on co - doped silica - coated laf 3 : yb , tm nanoparticles resulted in 800 nm emission by up - conversion processes , which is of potential to biological applications . the surface modification of silica - coated nanoparticles with aptms , followed by biotin for biotin - avidin binding , resulted in a 25 - fold increase in the fitc signal over non - biotin functionalized silica - coated nanoparticles . we have also successfully prepared silica - coated , core - shell ( laf 3 : tm ) laf 3 nanoparticles that exhibited 1 . 47 μm and 1 . 87 μm emission . use of the silica shell drastically improved the luminescence of the particles with an estimated quantum yield of 10 % for the 3 h 4 - 3 f 4 transition , and is the highest reported value for any lanthanum trihalide nanoparticle . finally , the 3 f 4 - 3 h 6 transition at 1 . 85 μm was measured at 77 k . the foregoing is a description of embodiments of the technology . as would be known to one skilled in the art , variations would be contemplated that would not alter the scope of the technology . for example , ( laf 3 : tm 3 + ) laf 3 could be synthesized . also , the technology can be applied , but not limited to lights sources for displays , lasers , photonic crystals and light - emitting diodes . a ) m . j . bruchez , m . moronne , p . gin , s . weiss , a . p . alivisatos , science 1998 , 281 , 2013 ; b ) w . c . w . chan , s . nie , science 1998 , 281 , 2016 . 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