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    U.S. Pat. App. 2012/0258051, entitled "Multistrata Nanoparticles", Published Oct. 11, 2012.

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    U.S. Pat. App. 2012/0258051, entitled "Multistrata Nanoparticles", Published Oct. 11, 2012.

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    U.S. Pat. App. 2012/0258051, entitled "Multistrata Nanoparticles", Published Oct. 11, 2012.

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    U.S. Pat. App. 2012/0258051, Entitled "Multistrata Nanoparticles", Published Oct. 11, 2012.

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    U.S. Pat. App. 2012/0258051, entitled "Multistrata Nanoparticles", Published Oct. 11, 2012.

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    US 2012025805141 cs) United States cz) Patent Application Publication co) pub. No.: US 2012/0258051 Al Bell et al. (43) Pub, Date: Oct. 11, 2012 (S4) MULTISTRATA NANOPARTICLES AND Publication Classification METHODS FOR MAKING MULTISTRA en ual ‘NANOPARTICI AGIK 8 200601) asp 136 (2006.01) (76) Inventors: Charleson S. Bell, Pawleys Island, AGIK $9704 (2006.01) SC (US); Shann Yu, Plano, TX bns2 S00 011.01) (ws) (2) US.C1 24942; 4241932; 427/212; 9717773; 9771927 (21) Apple: 13817,756 on fee (22) Fite: (06t.27,2011 A composition comprising score a iron oxide, a first shell comprising at east one plasmon active metal atleast - oo parially surrounding the core a second shell comprising a Related US. Application Ds Sicleeteic material at least partially surounding the fst shell (60) Provisional application No, 61/473,494, ile on Ape, anda thind shell comprising at last one plasinon ative metal 8.2011 atleast parally surounding the second shell. 02020 2@2@z Patent Application Publication Oct. 11, 2012 Sheet 1 of 7 US 2012/0258051 AL © i FIG.1 = eee Patent Application Publication Oct. 11,2012 Sheet 2 of 7 US 2012/0258051 Al FIG. 2 Patent Application Publication Oct. 11, 2012 Sheet 3 of 7 US 2012/0258051 AL Extinction uorssasBoig voyeouqes FIG.3 Oct. 11, 2012 Sheet 4 of 7 US 2012/0258051 AL Patent Application Publication vol fuss) rae soe gy g| anges Fant EL Patent Application Publication Oct. 11,2012 Sheet 5 of 7 US 2012/0258051 Al 1000 800 FIG. 5 Wavelength (nm) 600 400 US 2012/0258051 Al Oct. 11,2012 Sheet 6 of 7 Patent Application Publication 9 ‘Old (uu) yxGuepeaeny o00L 008 009 oor 31IGrdNBY-SdHL dN5y-SdHL yueig sqv US 2012/0258051 Al Oct. 11,2012 Sheet 7 of 7 Patent Application Publication vst ese ese Ls€ 1033 %OL - yUeIg Lid (wu) yyBuejeaey 008 009 oor US 2012/0258051 AL MULTISTRATA NANOPARTICLES AND. METHODS FOR MAKING MULTISTRATA NANOPARTICLES (CROSS-REFERENCE TO RELATED APPLICATIONS, [0001] This patent application claims priority to US. Pro Visional Patent Application No.61/473,494filadApr 8,201, the entire content of which i inconporated herein by eee. ‘STATEMENT REGARDING FEDERAL FUNDING, 10002] This invention was made with goverament support tinder grant nos. CDMRP_ #WSIXWH08-1-0502. and IDEAS #WSIXWH-05-1-0306 awarded by the Department ‘of Defense. The goverameat has certain right in the iven- INTRODUCTION [0003] Emerging materials and methods in biomedical maging and biophotonies are improving patient outcomes. More specifically the ulization of biomedical diagnostics and therapeutic advaes in methods such as Magnetic Reso fhanee Imaging (MRI), Computed Tomography (CT) imag: ng, Photoacoustic Tomography (PAT, Phosatheemal Optical Coherence Tomography (PTOCT) and targeted Photther- smal Therapy (PTT) have been shown to effectively detet and decrease pathological effets in head-neck cancer, colorectal cancer, and breast cancer. SUMMARY [0004] This disclosure provides compositions including nanoparticle comprising 4 core comprising ion oxide (eg, fn iron oxide comprising « soperpramgnetic iron oxide, suchiasFe.0,, FeO, et.) airs shell comprising leat one plasmon active metal (x. gol, silver, copper, platinum, ‘te. a Least partially surounding the core, second shell comprising a diclctic material (eg, SiO,,among others at Teast partially surrounding the first shel, and a third shell comprising at Teast one plasmon active metal (2, gold, silver, copper, platinum, ete) atleast partially snmounding the second shell. In some embodiments, the nanoparticle has ‘a ciameter less than about 60 nm, [0005], This disclosure also provides methods of making ‘nanoparticles, comprising forming a first sell atleast par dally surrounding «particle comprising iro oxide (eg. an lron oxide comprising asuperparamagnctic iron oxide, such 288 Fe0,, FeO, et), the fest soll comprising at least one plasmon active metal (eg. gold, silver, copper, platinum, ‘forming a second shel atleast partly surrounding the first shell the second shell comprising a dielectric material (ex, Si0,, among others), forming. third shell at least partially surmunding the second shel, the third shell com rising atleast ane plasmon active metal (eg gold, silver opp. platinum ef.) The step of forming the first sell my conprise coating the paniele with an aminosilane (e., APTES, APTMS, APDEMS, APEMS, et.) 0 form au amie ‘ate core, and coating the aminated core with the fst shel ‘The sep of forming the second sbell may comprise coating the first shell with the diclectic material using sonication. ‘The step of forming the third shell may comprise coating the second shell with an aminosilane (ex, APTES, APTMS, Oct, 11, 2012 APDEMS, o APEMS, ora cyclic aminoslane sueh as N-n- butyl-aza-2,2Jimethoxysilaeyelopentane, ete.) to form an minated second shell, and coating the aminated second sell th the third shel. In some emextmints, the thin shell hae fn exterior surface with a diameter less than about 60 nm, [BRIEF DESCRIPTION OF THE DRAWINGS {10006} The patent or application file contains at least one drawing executed in color Copies ofthis patent or patent ‘pplication publication wth color dnwings will be provided by the Office upon aquest and payment ofthe nscewsry fee. 10007] FG. Lisa schomatic showing an exemplary mult strata nanoparticle (MSNP), and an exemplary method for Sabricating the nanoparticle, according to aspects of this dis- closure {0008} FIG. 2 is a series of TEM images of exemplary rhanoparicles at various stages of fabrication of MSNPS accarding t aspects ofthis disclosure, where: () shows the Au—SiO, nanoparticles (¢,-6, 5-6.4520.2,.-7.2203 nm) decorated by surounding Av Dutf colloid of 2S nm radius, where the scale bars {nm and (v)shows PeOx-Au—Si0,— Au MSNPS (,-6, #5645202, fy-8320°5, r5-2125 am), ‘where the sale bari 20 nm, 10009] FG. isplotshowing a series of UV-Vie-NIR spec teaof exemplary nanopareles at various stage of abicaton ‘of MSNPs according to this disclosure, where: () is the spectra for PeOx nanoparticles of radius F,~6 am; (i) is the specta for PeOx-Au nanoparticles (f,-6, 1022 nm): i) Js the spectra for FeOx-Au- SiO, nanoparticles (6-6, 15-6. 4520.2. r5-7.2203 nm): (iv) is the spectra for FeOx-Aw SiO, nanoparticles (6, f, 6.452012. )-7.220.3 am) deco- rated by strounding Au Dut colloid of 2-5 nm radius; and (©) is the spectra for FaOx-Au—SiO,—Au MSNPS ¢ F-64520.2,1)-8.320.5, 2128 am), [0010] FG, 4 sa series of pois showing: (A) the reaxo- metre response of F&OX-Au_SiO, Au MSNPs according to this disclosure at an absorbance of 0.1098 a. (2 ree ation curve fit was conducted with 95% confidence interval )of2.72ms)(B)that differences intheratio between the size ofthe SiO, layer and the size ofthe outer Aw layer for FeOx-Au- SiO, AuMSNPseausesa siftin the extinetion shift in the NIR, where the top plot represents a fist FeOx- Au SiO,—AU_MSNP (y=6, 15°6.45202, 832055, =5.am) and the bottom plot represents a second FeOx: Au_SiO,—-Au MSNP (6, 1645202, 73206, [174 nm); and (C) the diameter histogram ofa sample batch of FeOx-Au-- SiO, At MSNPs base on analysis of| TEM images (average diameter was determined to be about 2683.7 nm. [0011] FG. Sis plot showing the UV-Vis-NIR spectra of thrve different batches of PeOx-g nanoparticles, 10012] FG, 6 is plot showing the UV-Vis-NIR spectra THPC-stbilized Ag nanoparticle pescursors for decors PoOx-Ag~ SiO, nanoparticles with Ag [0013] “FIG. 7isa plot showing the UV-Vis-NIR spocta of Tour different batches of FeOx-An-—SiO, nanoparticles decorated with Ag using THPC-stabilized. Ag nanoparticles, DETAILED DESCRIPTION 10014] Optica, MRI, and CT based imaging contrast of pathologie tissues, therapeutic localization at the site of US 2012/0258051 AL ‘ction atthe cellular level, nd the inability to unite diagnosis fad treatment ino single entity contin 4 mit the pra: jal power and application of these current emerging tech nologies. Ths disclosure provides multi-functional, mult strata nanoparticles (MSNPS) that have tunable dual-pesk (Vis-NIR) extinetion charnetersis, tsmodsl (optical, MRI and CT) imaging contrast, nd small size (less than about 60 fam in diameter), and that are relatively easy to synthesize fndor to modify so as o include surface functional groups. This may provide for coupling disgnostics and therapeutics io a single theranoste material, 10015] Multlayered nanoparticles (Le. nanoparticles hav Inga core with outer surrounding sells) may be classified as Jnorganie or hybrid onganic-inorganic, and may be designed to provide new properties based on the characteristics of each individual layerina synergistic fashion, Rational design rin- ciples ean he employed to create nanomaterials. with ‘enhanced fanctonal applications, sul 2s tissue specific rec- Dpnition, image conttast and thempeutic delivery. Por example, FeOx-Au nanoparticles (:e, nanoparticles having sn on-oxide core anda gold shel), havebsen synthesized ttlize both the magnetic relaxivity ofthe imme and sure plasmon resonance properties ofthe spherical gold Shel. These nanoparticles have been implemented fo simul faneous MR image contst with cancer phototherapy. SiO,—Au nanoparticles (ie, nanopanicles having a silica ‘ore and a old Shell) have been clinically used for tise specific photthennal therapy optimized for in vivo use by design of the surface plasmonic propenics ofthe nanomate- rial Unlike FeOx-Au nanoparticles, which have plasmonic extinction peaks in the vsible spectrum, extnetion peaks in the nearinfrared (NIR, 700-1200 nm) ean be achieved by ‘ontrolof the thickness ratio between the silica core and gold ‘shel. Extinction peaks in the NIR alow forthe optimal eat ing of subdermal tissue for photothermal therapy and eficent optical imaging. Hamessing the surlace plasmon resonance properties of corwshell materials, the nanosphere-n-s ‘hanoshel (the "gold nanomateyushka") was synthesized and demonstrated to provide specific extinetion maxima in the LUV-Vis-NIR spectrum that ar associated withthe nanoscale siructure, A multilayered, metalldielectric nanostructure, the nanomatryushka includes a gold nanosphere surrounded by concentric silia/gold shells. Governed by surface plas sion hybridization theory. concentric metal layers separated by a dielectric spacer layer causes plasmon interactions Which generate mulipeak extinction UV-Vis-NIR spect The location ofthe mull-estinetion peaks are contol bY the metal shell and dielectric ayer geometric ratio allowing Tor spoctie“tunabiiy” of the optical characteristics of the [0016] This disclosure provides muistata nanoparticles (MSNPS) designed to exhibit MRI contrast, Xray contrast Tor CT, photonic eoniest for OCT, absorbance in the NIR for TT, tail of extinction eharsctesties during fabric ton, theranostic potential, easy surface modulation for celli- lar targeting and bincompatiblty. The MSNPs preferably have @ nanostractue diameter of less than about 60 nm 10 support vascular extravasation ability. As dictssed in more {detail below, the MSNPs comprise a superparanagnetie ion oxide coreg, Fe,0, oF FeO, ele.) fist shel formed of ‘one oF more plasmon setive metal (e-gold silver, copper, platinum, etc) surrounding the core, a second shell ormed of A dicletrc material (eg, SiO,, among others) surounding the first shell ands thirdshel formed one ormore peston Oct, 11, 2012 swtive a rounding the second shell FIG. 1 shows an exen and an exemplary method for labricating the MSNP accor Jing to aspects ofthis disclosure. Specifically. FIG. 1 shows a FeOx-Atl_ SiO, Au MSNP (ie.-a MSNP where the plas ‘mon active metal is Au). The MSNP resembles a singlecore, five layered “onion,” where each stata possesses spec Fmetion, 0017] In order to provide nanoparticles having so many Tinetional layers, or stata, while stil having such a stall ‘zo, each sata must be carefully added through controled {abyicaton methods. These methods permit the fabrication of| extremely thin shells (as small as 1-2 nm to maintain an ‘overall partie diameter less than about 100 nm, such as Tess than about 90 nm, less than about 80 nm, less than about 70 ‘mand preferably, ess than about Dam) while til ensuring ‘magnetie material retention throughout the fabrication pro= ‘oss. Generally the methods include coating soperpacamag: hefe iron oxide particle (eg, Fe,O, oF FeO, et) with & frst amiposilane 2, APTES, APTMIS, APDEMS, APEMS, (to fon at aminated ore, cating the ainated ere with alist shell fonnedofone ormor:plasmonactivemetals (eg, gold, silver, copper platinm et.) coating the fist shell with 8 second shell formed of a dielectric material (eg. Si mong others) using sonication, coating the second sell with ‘second aminosilne (eg, APTES, APTMS, APDEMS, or APEMS, # eyelie aminosilane such as Nencbutylaza-2.2- ‘imethoxysilacyetopentaneet.)t form an aminsted ssc sell, and coating the atinsted second shell with third shell formed of one oF more plasmon active metals (eg. gold, silver copper platinum, ee). An exemplary method for fab: ‘cating the nanoparticle of FIG. 1 shawn in FIG. 1 and is farther diseussd in the Examples below. The Examples asa discuss exemplary methods for making FeOx-Ag- Si. Ag MSNPs, 10018] The methods ofthis disclosure may include the preparation of superparamugnetic FeOx nanoparticle cores (eg. Pe,0, oF e,0,, ete). These methodsare well known in ‘heart and may ineldde, boar not limitedto, coprecipitation of eOx (eg. by forminga suspension of Fesalts under basic conditions), microemulsion processes, and thermal decont- Position of organic precursors (eg, Fe(CupB, Fe{CO),, Fefacae)3, et inthe presence of oxygen after aeration anh reflux. FeOx nanoparticles also may he obtained commer: cially. The FeOx nanoparticles may have diameters between about Sand about 98m, suchas diameters less than about 8S fam, less than about 75 am, less than about 65 rand pret erably less than about 5S nm. In some eases, the FeOx nano- particles may be synthesized using surfactants, sh as oleic faci, o Keep the pres from agaregating, and to provide PeOx nanoparticles having surface chemistry that enables subsequent chemieal medication In some cases, the surface ofthe FeOx nanoparticles may be Functionalized using coat Jngs having any of various Faetional groups 10019] ‘The FeOx nanoparticles may be coated with a fst aminosilane to form an aminatedcore (Le. PeOx-NH,).Suit- able aminosilanes may includ, but are not limited. APTES (be, amimnrophethoyslone), APTS, APDEMS, ‘ete. Many methods for coating FeOx ranoparticles ‘ith aminesiae se know, and ae desobedn US. Pa Nos, 4.628087, 4.584.088, 4672040, 4,695,393 anal 4698, 302, the complete teachings of which are herein incorporated iy reference forall purposes, Conventional aminoxysilane reactions, such a those that utilize APTES, may iavolve US 2012/0258051 AL single solvents such ss DIH,0, ethanol (E101), toluene and tetrahydrofuran (THE) and are fully detailed in synthetic chemical literature. For example, in cases, where the FeOx ‘nanoparticles coated with an oleic acid coating. the eminosi Jane may displace the lei aeidin an exchange eacton. One particular modification tothe conventional APTES reaction ‘may inclode the performaake of multiple solvent exchanges throughout the reaction to optimize APTES deposition, ‘NH, availabilty, and magnetic material recovery. THE muy be used as the primary solvent due 10 its ability 10 ‘maximize APTES localization on the surfice of the FeOX cores through both specific and non-specific bonding. The ection solution may be spiked wih a small amount of DI 1,0 to catalyze the reaction and aeotc aid to balance the reaction solution at pH-6 5. The THE may be exchanged al ‘washed with FiO torelensethenon-specific PLES adsorp- fon. When sspendd in E4011 the amined FeOxcores many be highly colloidal and difficult to sediment by centrifuga tion: therefore, the washed cores may be added to hexanes to prepare the material for purification and extraction trough ‘entifygition, Following thee puriieationeyetes, the FeOx- NH, particles may besuspendedand stored in EXO prepa ration fr the deposition of the ist metal layer, Regardless of| the method used to coat the FeOx with aminosilane, the aminositane coating provides NH, groups that have high afiniy for metals (eg, Av, Ag, Co, and Pt ions, among others) and may set as a coupling layer between the FeOx ‘core and the jnitial plasmon active metal layer that ist be applied ws a shell around the FeOx core [0020] -Usilizing the high affinity between NI groups ‘and metal ions, a thin primary strata formed of a plasmon ‘active metal (PAM) may be added to te surface ofthe FeOx- NIL; nanopartile. The PAM may beaded tothe surface by ‘ny’ suitable method including, but not limited to, sonochemical plating or somoplation, method. The sopopla- tion method employs the physiochemical effects of ultra sound which aise from acoustic cavitation (6, sonication). This effect canbe physically described asthe iposive col lapse of bubbles formed at the surface of the FeOx-NH nanoparticles, Though adiabatic compression, this collapse Benerates a Tocalized hotspot due othe formation ofa shock- ‘wave within the gas phase ofthe collapsing bubble. In tir Sonochemistry review, Mason and Lorimal described the ‘empirically determined extreme, transient conditions of $000 K temperatures, pressures of 1800 atm and cooling rates beyond 10°" K "at these hotspots (See Applied Sonochem ‘sty, 2002, New York: Wiley), Ths extreme loca environ ‘ment formed by the sonoplaion reation produces similar conditions generated through conventional “high-thet high Mir rate” nanoparticle and rumnolayer formation methods Jmplemented thoughout nano-literture. Due tothe inherent chelating ability between juxtaposed metal ons and available SNH, groups, thin metal layer may be quickly deposited ‘onto the surface of the FeOX-NH nanoparticle to fem st FeOxPAM nanoparticle (eg, al FeOX-Au nanoparicle, FeOx-Ag nanopanicle, FeOx-Cu. nanoparticle, FeOx-Pt nanoparticle et.) such as though the use of sodium citrate and the sonoplation ultasoni frequency foo21] PAM partiele to form an FeOx-PAM icletre nanopartile Any suitable dielectric may be used, and may be added othe surface by any suitable method. For example, a sonoplation ‘method may be sed where ttraethylorthosliate (TOS) is A dioletric layer may be deposited onto the FeOX- Oct, 11, 2012 ‘mixed with an alkaline initiator (NHOMD under ultrasonic agitation, thereby causing the deposition of a Si0, layer onto the PAM layer. The thickness ofthe SiO, may be carefully controlled by the ratio of FeOx-PAM particle volume to TEOS volume. 10022] Anintermediatesminosilane strata may be added 19 aminate the surfice of the FeOx-PAMdicletrc layer in preparation for deposition of an ational PAM layer. In ome eases the aminosilane may be added according o the ‘methods desribed above, In some eases, a eyelie aminosi- Jane, sueh as N-n-buty.a7a-2.2-dimethoxysilaeyelopentane, may be evated onto the dielectric layer to avoid the multi-step process required by APTES amination and to reduce the possibilty of particle Hooculation dic to the generation of Feaction side products and sel-polymerization, 10023] Following the silanization of the surface of the FoOx-PAM-tiolectie patile (i, 10 form an FeOx-PAM Aiclectie-NHf nanoparticle), the aailable—NH sites may be used to deposit a final PAM strata (ie. 10 fomn to an FeOx-PAM-diclectrie-PAM MSNP). Various methods may be used to deposit the final PAM layer, depending om the desired thickness of the layer, the rate al which deposition is desired, ec. In some embodiments, the final PAM layer may be deposited by frst decorating the FeOx-PAM-diclectric NH; nanoparticle with metal colloids, which may act as rnveieaton or “seed” sites foe subsequent metal deposition through the reduction of metal ions in the presence of reducing open. Por example, theavailable NH, sitesoF the FeOx-PANdielectric-NH, nanoparticles may be decorated With Duff Au colloids (eg, 2-5 nm Dulf Au colloids), and thena complete Aulayer may be catalyzed onto the decorsed pariles through the ection ofa HAAuCI, solution in the presence of 11,CO (i.e, a formaldehyde electroless plating reaction), Aliematively or additional, the — NH, sites my be decorated with THPC-stabilized metal colloids (e2 TTHDC-stabilized Ap) prior depositing the final PAM layer, 0024] In ordr to mits the stability ofthe outer PAM ‘mata, the MSNPs may be resspended in soliton con 8 stabilizing agent, For example, when an PeOx-A— Si0,—Au MSNP was resuspended in a 18 mM solution of| ,GO,,aeta potential of -75.620:992 wag measur, which js consistent withthe existence of —CO,2- ions stabilizing the surface ofthe particle. With respact to MSNPs having PAM layers comprising wo, which present the same surfice chemistry these stabilizing ions are easily place-exchanged With a number of conjugates that proximally preseat amine, ‘ulfhydrl o other functional groups. From a surface mod fication perpective, MSNP behaviors the same as for other pariles, for which many robust methods are wll known 19 provides wide range of molecular coatings andr functional troups. These fabrication reactions yield monodisperse butees of nanoparticles, as shown in PIG, 4(C), Inaction, these reoetions are sealeile, making the fabrication of bul quantities posible 10025] For more than hala decade, PAM-coatednanopar- tiles, such as gold-coated nanoparicies, have been shown 1 act as Xray and CT contast agents, inereasing the wily of | ‘och technique imaging biological samples. MSNP capacity for MRI contrast can be evaluated though elaxometrie me- surements, As discussed inthe Examples below, the exine- tion peak of FeOx-Au—SiO,—Au MSNPs located in the Visible spectrum was measured at 0.1098 au. The MSNPs exhibited « relaxation time st 1141254 ms fit via a 95% confidence interval based on four repetitions. This relaxation US 2012/0258051 AL ne canbe diferetinted from the T2 values of healthy human issue, andare predicted alter the relaxation times oF proximal tsenes. These results support the MR contrast capacity of FeOx-PAMCdilecrie-PAM MSNPs, such as FeOx-Au-- SiO, Au MSNPs, among others [0026] This disclosure provides the fabrication ofa single core, ive layered nanostructure with the potential eapacity for both CT and MR innaging contrast. This contrast agent may allow forthe simultaneous ue of both technologies ad as Well as other hybrid imaging modalities. As described in ‘more detail below, these paricles have ben characterized 0 show their metallodiclecric properties and daal-peak UV= Vis-NIR extinction spectra. This disclosure also provides evi dence of the geometriedependent ‘tunability’ ofthe optical extinction characteristics of the MSNPs, which may allow predictable optimization of performance based om contol lable synthetic conditions. This eehinology’ may be futher spp for se absorption and consequent theme ies in the NIR. Suovessful demonstration of significant tlical abacrplon and het generation is consistent wih re applications in theranosti disease treatment [0027] | Themethods and apparatus disclosure herein are not limited in their applications to the deals of constuction and the arrangement of components deseribed herein. The inven tion is capable of other embodiments and of being practiced for of being carried out in various ways. ATso itis to be "understood tat the phraseology and terminology’ used hein is for the purpose of description only, and should not be regarded limiting. Onlinal indicator, sch as fis, second, ‘nd thir as used inthe description andthe claims to refer 19 ‘various structures, are not meant to be construe to indicate ny specific sictures, or any partieular onder or configu tion to such structures. Al methods described herein can be performed in any suitable order unless otherwise indicted herein or otherwise clearly contradicted by context The use of any and all examples, or exemplary language (eg. “such 1s") provided herein, s intended merely 0 Beitr illuminate the invention and does not pose a limitation onthe scape of | the invention unless otherwise claimed. No language in the specification, andno structures shown inthedrawings, should be construed as indicating that any non-claimed element is essential tothe practice ofthe invention 10028], Recitation of ranges of values horein are merely Inended to serveasa shortand method of weerrng indivi ally to cach separate value falling within the ange, unless otherwise indicated herein, and each separate vale i inooe- poratedimo the specification as it were individ recited herein, For example, ifa concenzation rings stated 2s 1% o 50% it intended that valles such as 2% 0 40%, 10% 10 30%, oF 1% to 3%, et. are expressly enumerated inthis ‘specification, These are only examples of what is specifically ‘ended, and all possible combinations of numerical values berwoon and inching the lowest valve aod the highest value ‘enumerated ae o be considered to be expres’ stated in this pplication [029] Further, no sdmisson is made that any reference, including any non-patent or patent document cited inthis specification, constitutes prioe at In particular, it will be Understood that, unless otherwise sited, reference 10 any ‘document herein does aot eonsiutean admission that any’ oF | these documents forms part ofthe common general knowl- ‘edge inthe artinthe United States orinany other country. Any discussion ofthe references states what their authors aser, Oct, 11, 2012 and the applicant reserves the right o challenge the aeeuraey and pertineney of any ofthe documents eted bere. EXAMPLES, Fxample | Particle Characterization 10030] The MSNPs andthe various precursor nanoparticles described in these Examples were characterized using tans ‘ssion electron microscopy (IPM) with a Pills CM20 microscope, spectroscopy using a Varian Cary 50 UV-Vis- NIR spectrophocomete, andlor rlaxometey using 2 Maran DRX-II0.5T NMR spectroscopic scanner following sample preparation using S lof IxPHS a solvent, Zeta potential measurements were obtained using a Malvem Zetasizer (Malvern Instruments, Westborough, Mass.) following sample preparation sing milo! 1.8mMK,CO, asa solvent Panielesizes and statistical dsteibutons were estimated from TEM iniges using Amt V600 and Imagel software Example 2— Fabrication of FeOx Nanoparticle Cores 0031] _j-Fe,O, panics with 1221 nm diameters were fb: Ficated by a thermal decomposition aeration and relax pr tocol. Briefly, 20 of ecyl ether (Sigma-Aldrich, St Lous, Mo.) ad 1.92 mi of ole seid (Sigma-Aldrich) were sted under N, gs flow and reflux The simple was heated to 100° . prior to addition of 4 mil Fe(CO), (Sigma-Aldrich), The reaction was heated from 150°C. to 280°C, where the ree: tion solution color changed from boil, to orange, orange! colrless, to very dark orange. Sample was aerated at 80° C for 14 hours and refluxed while boiling for 2 hours. The --Fe,0, cores were centrifuged (15min, 70 ef) and washed ‘netianol (EOF, 200 proof, Sigma Aldi) iee, and dried under air, FIG, 2() shows te transmission eletron micros copy (TEM) image ofthe FeOx sanopartcls, and FIG. 36) shows the UV-Vie-NIR Specta ofthe FeOx nanoparticles. Example 3 Amination of FeOx Nanopaticles to Form FeOxNH, 10032] 1S0mgofy-Fe,O,core(FeOx) were costs with he First strata using # modified -aminopropyl)rethoxysiane (APTES, Sigma-Aldrich) funetionalization. Core particles ‘were aude to 40m oftetrbydroflurn (THE, Teno Fisher Scientific, Waltham, Mass.) and tired briskly using a mag- rete sir plate and stirring rod. 5 ml of APTES was added 10 the reaction solution and thereafter spiked with 5 ul of acetic cid (Sigma-Aldrich), $16 lo MiliQ(18 MQ) DIH.O, and ‘ied foe 48 hours. The reaction flask was then placed in a tlycorl bath ad heated 19 80°C, EXOH was used to replace ‘evaporated THF throughout the 2 hour boiling period. Reac- tion solution was concentrated via otowap to 40mlof 10H, Hloxane was added tothe solution ina 41 ati and conti fuged (10 min, 800 re). Recovered FeOx-NH, nanoparticles \wore resuspended in EIOH and stored at room temperature ‘here they remained stable throughout the length of this study (5 mont). Example 4—Gold Plating of FeOx-NHy [Nanoparticles to Form FeOx-Au Nanoparticles 0033]. FeOx-NH, nanoparticles were coated with gold layer, Soniated FeOx-NHL, nanoparticles (-1.8% wt) were sudden equal volunieto DI1,O-based, 19 11AWCL, Sigma Aldrich, dark aged 24-72 hours) under ultasonie perturba US 2012/0258051 AL ‘ion. 20 mM soutium citrate in DI 11,0 was added dropwise ‘under sonication. dstinet color change from a Mlocculated (due to immediate repulsive electrostatic interactions prior to ‘Au liberation by the sin citrate yellow-brown mite tw a black-purple, fully colloidal suspension, fllowing the induction ofthe reducing agent and catalyst, signaled the generation of the FeOx-Auw nanoparticles. The solution was then washed via eenefugation (5 min, 800 rfe) and rests- pended in B(OH and stored foe 18 hours at 4°. where the FeOx-Au nanopanicles remained sable for S months. [0034] "FIG. 2G) shows the transmission electron micros copy (TEM) image of the FeOx-Au nanoparticles, and FIG. 311 shows the UV-Vis-NIR Spectra of the FeOx-Au nano= particles. The ition ofthe gold shell around the FeOx core ‘was substantiated by the appearance of a surface plesmon resonance extinction maxim Qryq-S40-570- nm) in the sample absorbance specra for the FeOx-Au particle (FIG. 134) which isnot evident in the FeOx manopuicles (FIG. 3(). In addition, a comparison of the high-resolution TEM Jmages ofthe FeOx nanoparticles (FIG. 2() and FeOx-Au ‘unoparticles (FIG, 2(7)) clearly shows the formation of gold “plats” on the iron oxide surieo and the development of gold fringe patterns (111 plans, 0.24 nm) consistent with ‘well characterized images in eeeteon microscopy literature, Example SFormation of FsOx-Au—SiO, ‘Nanoparticles 10035] FeOx-Au nanoparticles were costed with a silica layer. I ml of #soltion of FeOx-Aw nanoparticles in OH from Example 4 was added t 5 mil of fresh BYOH. Under Ultrasone perturbation, 35 of0.4%NH,OH and 25-SDlof 10 mM ethanolic tetrethylorthosilcate (TEOS, Sigm-Al- rich) were added. Sonication was continued at room tem perature for 4S minutes and thereafter sored at 4° C. for 24 hours to form the FsOx-Au-—SiO,. FIG. Mil) shows the UV-Nis-NIR Spectr ofthe FeOx-Av-SiO, nanoparticles. ‘The thickness ofthe dielectric layer may be modulated by varying the relative amount of TEOS and FeOx-Au nanopae- tiles in the reaction mixture, As discussed in more detail below, modulation ofthe thickness of the dieleciric layer allots the spectral properties of the MSNPs made according to the present disclosure Example 6 Formation of PeOx-Au—Si0_-NH, Nanoparticles [0036] The FeOx-Au- SiO, nanoparticles were coated with Nen-butyl-azacdimelhonyslseyclopentane — (eyeic silane, Gelest, SIBI982.4), 400 pl of 1 mi ethanolic eyelic silane was aed under ultrsonie perturbation to the ean tlic suspension of FeOx-Au—Si0, nanopatiles to foam FeOx-Au—Si0.—NIi, nanoparticles. The solution ofTeOx ‘Au SiO,—Nii, nanoparticles was stored at 4° C. for 24 hours where they remained stable until completely ulized (C3 months), Example 7 Pormation of PeOx-Au—SiO,—Au ‘SNPs 10037] NH,SiO,—Av-FeOx nanoparticles were deso- ‘ated throvgltemersion in Duff gold colloid (2-4 nm, dark ‘ed for 3 weeks in 4” C.) ina 14, panile to colloid ratio. Briefly, ml of NH, SiO,Au-PeOx was mixed with 4mmlof Au Duif colloid. This mixture was left unperturbed t room, temperature (20-29° C.) for 24 to 96 hours, centefuged (10 Oct, 11, 2012 rin, 800 rP, superatant removed via magnetic sisted aspiration and resuspended in ml of MilliQ DI 11,0 via uliasonic sonication. More specifically, magnetic assisted ‘spiration is conducted via a 1 Tesla neodymium 1" cube ‘magnet (CMS Magnetics, Plano, Tex.)placed tthe botom of the reaction vial in onder to retain magnetic materi in ts pellet form during aspiration. These decorated particles were Smmediately used forthe next step. FIG. 2{) shows the transmission electron miroscopy (TM) imageot the FeOx- Au--SiO, nanoparticles desoraied by surrounding Av Dull colloid of 2-5 am radius, and FIG. 30) shows the UV-Vis NIR Spocim ofthe FeOx-Au—SiO, nanoparticles decorted by sunounding Av Dull colloid 10038] Decorated panicles were vigorously mixed with a 1% HAWCI-K,CO, plating solution ina 1:10 ratio. Brely, 25 mg of K.CO, (Siuma-Aldech) was added to 100 ml of 1,0 where 1% HLAUCL, (dark-aged for 14 days prioe) was audded and dark-aped for 96 hours. 10 ul of HCO (Sigma Aldrich) was added a a catalyst which began the release of ‘Au ions thus causing acolorehiange fom clea to bright pink, Following 10 min eaction time, particles were centriluged (10 min, 800 rf) and the supernatant was removed via mag- neti assisted aspiration. Completed MSNPs were re-ss- pended in ml of FrOH, thus quenching the plating solution, land stored at 4° C. for futher characterization. For slorge longer thao 10 days, MSNPswere resuspended in Im of 18 IM K,CO, st 4° C. The deposition ofthis final PAM layer is supported hy the formation of a mictallic outer layer and change in surface plasmon extnetion spectra (see FIGS. 2(0) and 3(e)-For example, a double-peak spectra ofa mnt ‘red, gold-ielctrie-pold material appeared following elee- trols plating (FIG. 3y), 10039] Asshownin FIG. (4), therelaxometicresponse of PeOx-Au—Si0, Au MSNPs at an absorbance of 0.109% ‘4, wos determined, andthe MSNDs were foun! o exhibit felaxation time at 1141254 ms fit via @ 95% confidence inerval based on four repetitions. This relaxation tim ean be

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