Shangetal.NanoscaleResearchLetters2013,8:4 http://www.nanoscalereslett.com/content/8/1/4 NANO EXPRESS Open Access Synthesis and characterization of NIR-responsive Au @pNIPAAm-PEGMA nanogels as vehicles for rod delivery of photodynamic therapy agents Ting Shang1, Cai-ding Wang1, Lei Ren1,2*, Xin-hua Tian3*, Dong-hui Li4, Xue-bin Ke1, Min Chen1 and An-qi Yang1 Abstract A near-infrared (NIR)-responsive Au @pNIPAAm-PEGMA nanogel was synthesized in two steps, growing a rod PEGMA monolayer on the surface of gold nanorods (AuNRs), followed by in situ polymerization and cross-linking of N-iso-propylacrylamide (NIPAAm) and poly-(ethylene glycol)-methacrylate (PEGMA). The AuNRs and Au @pNIPAAm-PEGMAnanogelwerecharacterizedbyUV–visspectroscopy,Ramanspectroscopy,Fouriertransform rod infraredspectroscopy,andtransmissionelectronmicroscopy,respectively.Thelowercriticalsolutiontemperatureofthe Au @pNIPAAm-PEGMAnanogelcouldbetunedbychangingthemolarratioofNIPAAm/PEGMA.TheNIR-mediated rod drug release behavior of the Au @pNIPAAm-PEGMA nanogel was studied with zinc phthalocyanines (ZnPc ) as a rod 4 drug model. It was also demonstrated that the loaded ZnPc could keep the capability of generating singlet 4 oxygen, and the in vitro study showed a great photodynamic therapy (PDT) effect on Hela cells. It thus indicated the potential of this Au @pNIPAAm-PEGMA nanogel for application as a drug carrier in PDT, which might make rod contributions to oncotherapy. Keywords: NIR-responsive, Au @pNIPAAm-PEGMA nanogel, LCST, singlet oxygen, PDT rod Background critical solution temperature (LCST; approximately 32°C) Gold nanoparticles including nanoshells, nanocages, and [12,13].Besides, its LCSTcan be tuned by the addition of nanorods have drawn increasing attention in photo- a comonomer during polymerization [14,15]. Combining dynamic therapy (PDT), drug delivery, and diagnostic this temperature-responsive gel and gold nanoparticles imaging field in recent years [1-5]. Among them, gold together,thetemperature-responsivegelcanbeinduced nanorods (AuNRs) are of particular interest due to their to collapse by the photothermal conversion of gold unique optical properties. With the different aspect nanoparticles, which gives rise to much possibility for ratios and the resulting longitudinal surface plasmon the application of the temperature-responsive gel in resonance (SPR), AuNRs exhibit an absorption band in drug delivery. The composites of Au@pNIPAAm have the near-infrared (NIR) region [6], which conduces to been synthesized and studied in many works [16-18]. higher photothermal conversion and also shows signifi- However, the combination mostly through the physical cant biomedical application in view of the penetration of embedding effect or electrostatic interaction between NIR lightinto biologicaltissues [7,8]. gold nanoparticles and pNIPAAm may make the Poly(N-isopropylacrylamide) (pNIPAAm) gel, as one of composites lack long-term stability, especially in the the mostwidely studied temperature-responsive polymers biologicalenvironment.Ourpreviousworkhasreported [9-11], undergoes phase transition in water when the the synthesis of a core-shell structured multifunctional temperature increases or decreases beyond its lower hybridAu@IPN-pNIPAAmnanogelinwhichthehydro- gel could be chemically grafted onto a single gold *Correspondence:[email protected];[email protected] nanoparticle[19]. 1DepartmentofBiomaterials,ResearchCenterofBiomedicalEngineering, Herein, we developed a new way to immobilize CollegeofMaterials,XiamenUniversity,Xiamen361005,China 3NeurosurgicalDepartmentofAffiliatedZhongshanHospital,Xiamen pNIPAAm combined with poly-(ethylene glycol)- University,Xiamen361004,China methacrylate (PEGMA) on the surface of AuNRs through Fulllistofauthorinformationisavailableattheendofthearticle ©2013Shangetal.;licenseeSpringer.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproduction inanymedium,providedtheoriginalworkisproperlycited. Shangetal.NanoscaleResearchLetters2013,8:4 Page2of8 http://www.nanoscalereslett.com/content/8/1/4 chemical grafting to obtain NIR-responsive Au @ 400 to 1,000 nm. The transmission electron microscopy rod pNIPAAm-PEGMA nanogel. ZnPc a photosensitizer, was (TEM) images were obtained from a JEM 2100 micro- 4, usedasdrugmodeltoinvestigatethedrugloadingandre- scope (JEOL Ltd., Tokyo, Japan) operating at an accel- leasepropertiesoftheAu @pNIPAAm-PEGMAnanogel. eration voltage of 200 kV. Raman spectra were rod The capacity of generating singlet oxygen of ZnPc4 after performed on an UV-1000x instrument (Renishaw, being loaded in the Au @pNIPAAm-PEGMA nanogel Wotton-under-Edge, UK) (path length = 200 nm) using rod wasmeasured,andtheinvitroPDTwasalsostudied.Our a red light-emitting diode laser (λ = 785 nm, 0.5 mW). current results suggested the potential of Au @ A Fourier transform interferometer (AVATAR360, rod pNIPAAm-PEGMAnanogelasacarrierinPDT. Nicolet Instrument Corporation, Madison, WI, USA) was used to record the absorption spectra of AuNRs Methods and Au @pNIPAAm-PEGMA nanogels between 400 rod SynthesisofPEGMA-SHcompound and 4,000 cm−1 at a spectral resolution of 4 cm−1. 0 Concentrations of 1.0 mmol 5,5-dithiobis (2-nitrobenzoic acid) (DTNB) and 2.0 mmol dicyclohexylcarbodiimide LCSTmeasurementofAu @pNIPAAm-PEGMAnanogel rod (DCC)weredissolvedin50mLofdichlormethane,followed In order to investigate the thermal property of the by the addition of 2.2 mmol 4-dimethylaminopyridine Au @pNIPAAm-PEGMA nanogel, nanogels with dif- rod (DMAP) and 2.0 mmol PEGMA. The mixture was de- ferent molar ratios of NIPAAm/PEGMA (1:0, 18:1, 12:1, gassed with nitrogen and then stirred for 48 h at room 9:1, 6:1, 4.5:1) were synthesized. LCSTs of nanogels were temperature. After filtration, the filtrate was washed se- measured through turbidimetric measurement. The con- quentially with water, 5% acetic acid, and water. Then, centration for each Au @pNIPAAm-PEGMA nanogel rod the organic phase was dried over magnesium sulfate, in the deionized water was maintained at 1 mg/mL. The filtered, and evaporated to dryness. The product was lighttransmittancesat600nmwerethenmeasuredbyan dissolved in 100 mL of water/ethanol (V/V, 4/1) with UV–vis spectrophotometer (TU-1901, Beijing Purkinje the addition of 2 mL of 1 M sodium borohydride General Instrument Co. Ltd, Beijing, China) equipped (NaBH ) and stirred for 2 h, and was used without fur- with a temperature-controlled sample holder, and the 4 therpurification. heating rate was set at 0.1°C/min. The LCST was defined as the initial break point in the resulting transmittance SynthesisofAu @pNIPAAm-PEGMAnanogel versustemperaturecurves. rod AuNRs with a length of 50 nm were synthesized using the seed-mediated growth method as reported previ- ZnPc loadingandNIR-mediatedZnPc release 4 4 ously [20]. Subsequently, 0.1 mmol PEGMA-SH was Two milligrams of Au @pNIPAAm-PEGMA nanogels rod added to 25 mL of the as-prepared AuNRs suspension and 2 mg of ZnPc were dispersed in 10 mL of N,N- 4 (1.6 × 10−6 μmol) and continuously stirred for 5 h at dimethyl formamide (DMF) and stirred for 24 h at room room temperature. Au @PEGMA was collected by temperature.TheZnPc -loadedAu @pNIPAAm-PEGMA rod 4 rod centrifugation at 9,500 rpm for 12 min and then re- nanogels were then collected by centrifugation (9,000 rpm dispersed in 15 mL of the deionized water, followed by for 12 min). To determine the amount of unloaded ZnPc , 4 the addition of 1.8 mmol NIPAAm, 0.2 mmol the supernatant was analyzed by an UV–vis spectropho- PEGMA, 86.69 μmol sodium dodecyl sulfate (SDS), tometer (DUTM800, Beckman Coulter) at 680 nm where and 12.97 μmol N,N-methylenebisacrylamide (BIS). ZnPc has a maximum absorption. The loading efficiency 4 The mixture was heated to 75°C with stirring and wascalculatedaccordingtothefollowingformula: maintained in vacuum. After equilibration for 1 h, the polymerization was initiated by adding 109.6 μmol am- Loadingefficiency ¼Wt(cid:2)W0 (cid:3)100%; monium persulfate (APS). The reaction was allowed to Wt proceed for 4 h at 75°C and terminated by opening the system to air. The resulting Au @pNIPAAm- where W represents the total amount of ZnPc and W rod t 4 0 PEGMA nanogels were purified by repeated centrifuga- representstheunloadedamountofZnPc . 4 tion (9,000 rpm for 12 min) and subsequently For the NIR-mediated ZnPc release, 5 mL of the 4 lyophilized for further use. ZnPc -loaded Au @pNIPAAm-PEGMA nanogel 4 rod suspension (1 mg/mL) was placed into dialysis bags Characterization (molecular weight cutoff, 8 to 14 kDa) and irradiated The optical properties of AuNRs and Au @pNIPAAm- by an 808-nm laser (0 to 400 mW/cm2) for different rod PEGMA nanogels were characterized by an UV–vis times (0 to 60 min). To determine the amount of spectrophotometer (DUTM800, Beckman Coulter, Brea, ZnPc released, the dialysate was removed and sub- 4 CA, USA) with a scanning speed of 1,200 nm/min from sequently analyzed by an UV–vis spectrophotometer Shangetal.NanoscaleResearchLetters2013,8:4 Page3of8 http://www.nanoscalereslett.com/content/8/1/4 typical experiment, 0.105 mg of the Au @pNIPAAm- rod PEGMA nanogel loaded with 0.0135 μmol ZnPc was 4 dispersedin3mLofDMF,andthen,0.45μmolDMAwas added. Pure ZnPc (0.0135 μmol) was used as a control. 4 The solutions were then irradiated with a LED lamp (680 nm, 10 mW/cm2) or a NIR laser (808 nm, 400 mW/cm2). Theabsorptionmeasurementsfollowedbyirradiationwere carriedoutevery5min. Light-inducedinvitroPDTeffect Hela cells were seeded into 24-well cell culture plates (1 × 105 cells/well) and incubated for 24 h. After being treated with ZnPc -loaded Au @pNIPAAm-PEGMA 4 rod nanogels (300 μg/mL) in serum-free medium at 37°C for 22 h, chloroquine (10 mg/mL) was added into every well Figure1SchematicdescriptionofthesynthesisofPEGMA-SH. for another 2 h to promote endosomal escape [22]. Then, HelacellswerewashedwithPBSandincubatedina (DUTM800, Beckman Coulter). The release efficiency nanogel-free medium and treated with an 808-nm laser at was calculated as follows: 400 mW/cm2 for 15 min and a 680-nm LED lamp at 10mW/cm2for40min.Forcellsurvivaltest,theirradiated W Release efficiency ¼ r(cid:3)100%; plateswerereturnedtotheincubator,andcellviabilitywas W l colorimetricallymeasured48hlaterwithMTTassay[23]. where W represents the released amount of ZnPc r 4 and W represents the loaded amount of ZnPc . Results and discussion l 4 SynthesisofAu @pNIPAAm-PEGMAnanogel rod Singletoxygendetection The synthesis of PEGMA-SH was shown in Figure 1. Thegenerationofsingletoxygen(1O )fromZnPc loaded PEGMA-DTNB compound was firstly gained by the 2 4 intheAu @pNIPAAm-PEGMAnanogelwasdetermined esterification reaction between the terminal hydroxyl rod by the transformation of 9,10-dimethylanthracene (DMA) group on the PEGMA and the carboxyl group on the whichexhibitsamaximumabsorptionat377nm[21].The DTNB with the DCC as medium and DMAP as catalyst DMA can react irreversibly with 1O to yield an [24,25]. Subsequently, the disulfide bond of PEGMA- 2 endoperoxide. The reaction could be monitored by DTNB was reduced by NaBH to yield the desired 4 recording the decrease in the absorption at 377 nm. In a PEGMA-SHcompound. Figure2PreparationoftheAu @pNIPAAm-PEGMAnanogel.(1,2)Schematicofthesequenceofstepsinthesynthesisofthehybrid rod Au @pNIPAAm-PEGMAnanogels,(3)ZnPc4loadingprocess,and(4)NIR-mediatedZnPc release. rod 4 Shangetal.NanoscaleResearchLetters2013,8:4 Page4of8 http://www.nanoscalereslett.com/content/8/1/4 Figure3TheUV–visspectraof(a)AuNRsand(b) Figure5TheRamanspectraof(a)AuNRsand(b) Aurod@pNIPAAm-PEGMAnanogel. Aurod@pNIPAAm-PEGMAnanogel. ThestrategytopreparetheAu @pNIPAAm-PEGMA shift from 794 to 801 nm occurred (Figure 3b). This red rod nanogel involves two steps, growing a PEGMA mono- shiftofSPR andthepeak shapewidening mightbedueto layer on the surface of a AuNR, followed by in situ achangeforAuNRsinthelocalrefractiveindexproduced polymerization and cross-linking of NIPAAm and bythepNIPAAm-PEGMAshell(Figure4B)[26]. PEGMA, as depicted in Figure 2. In the first step, the Raman spectra were also used to identify the synthesis AuNR surface was modified with a PEGMA self- of the Au @pNIPAAm-PEGMA nanogel. The Raman rod assembled monolayer through a sulfhydryl-gold inter- spectrumoftheas-preparedAuNRs(Figure5a)exhibited action. In the second step, PEGMA-modified AuNRs a band at 190 nm which was ascribable to the Au-Br could be used as a template for in situ formation of bond on the surface of AuNRs [27]. This is because the hydrogel by polymerization and cross-linking of NIPAM as-preparedAuNRswerestabilizedbythe cationicdeter- and PEGMA with BIS as crosslinker, APS as initiator, gent cetyltrimethylammonium bromide (CTAB) in the and SDS as emulsifier. The coating of pNIPAAm- aqueous solution. After being modified with pNIPAAm- PEGMAonAuNRscanbereflectedinthecorresponding PEGMA (Figure 5b), the Au-Br band disappeared, and a UV–vis spectra (Figure 3). AuNRs used in this work had bandat320nmwasobserved,whichwasassignedtothe a length of about 50 nm with an aspect ratio of approxi- Au-S bond [28]. It is thus suggested that PEGMA-SH mately 3.2 (Figure 4A) which exhibited the maximum of might replace CTAB to form PEGMA-modified AuNRs the plasmon peak of 794 nm (Figure 3a). After the through the Au-S bond, and then, PEGMA-SH on the AuNRs were modified with pNIPAAm-PEGMA, a red surface of AuNRs might serve as the template for the Figure4ThetypicalTEMimagesofAuNRs(A)beforeand(B)aftermodificationwithpNIPAAM-PEGMA,respectively. Shangetal.NanoscaleResearchLetters2013,8:4 Page5of8 http://www.nanoscalereslett.com/content/8/1/4 Figure6FTIRspectraof(a)Au@PEGMAand(b)Au @pNIPAAm-PEGMAnanogel. rod following polymerization and cross-linking of NIPAAm NIPAAm/PEGMA,1:0)exhibitedanLCSTofapproximately andPEGMA. 32°C, which was consistent withpurepNIPAAm [13]. It FTIR spectra (Figure 6) were recorded to confirm the is clearly shown in Table 1 that the LCSTs of the structure of the polymer shell. In the FTIR spectrum of Au @pNIPAAm-PEGMA nanogel could be tuned by rod PEGMA-modified AuNRs (Figure 6a), the absorption changing the molar ratio of NIPAAm/PEGMA. Namely, peaks of PEGMA, including ν(C=O) (1,721 cm−1) and as the molar ratio of NIPAAm/PEGMA decreased, the ν(C-O-C) (1,105 cm−1), were observed. The spectrum of LCST of the nanogel increased. For example, when the Au @pNIPAAm-PEGMA nanogels (Figure 6b) exhibited molar ratio of NIPAAm/PEGMA was set at 18:1, the rod the characteristic peaks of polymerized NIPAAm at LCST of Au @pNIPAAm-PEGMA nanogels could be rod 1,650 cm−1 (ν(C=O), amide I) and 1,550 cm−1 (δ(N-H), up to 36°C. The addition of hydrophilic PEGMA amide II). Hence, the FTIR results could provide evidence increased the hydrophilicity of pNIPAAm due to the forthesurfacemodificationandpolymerizationonAuNRs. strong interactions between water and hydrophilic groups on the polymer, which led to an increased LCST [29]. It is thus expected that this attractive property of ThermosensitivepropertyofAu @pNIPAAm-PEGMA rod tunable LCST might make Au @pNIPAAm-PEGMA rod nanogel nanogelsmorepromisingindrugdeliveryapplication. Figure7andTable1showedtheeffectofthemolarratiosof NIPAAm/PEGMA on the LCSTs of the Au @pNIPAAm- rod NIR-mediatedZnPc release 4 PEGMAnanogel.TheAu @pNIPAAm(themolarratioof rod NIR-mediated release of ZnPc loaded in Aurod@ 4 pNIPAAm-PEGMA nanogels was investigated with the irradiation of a NIR laser (808 nm). When the sample was irradiated at 200 mW/cm2, the release efficiency was about 23.5% in the initial 20 min. As the irradiated time was prolonged, the cumulative release efficiency was up to 37.4% within 1 h (Figure 8A). Table1TheLCSTsofAu @pNIPAAm-PEGMAnanogels rod withdifferentmolarratiosofNIPAAm/PEGMA NIPAAm PEGMA NIPAAm/PEGMA LCST(°C) (mmol) (mmol) (mmol/mmol) 1.8 0 1:0 32 1.8 0.1 18:1 36 1.8 0.15 12:1 38 1.8 0.2 9:1 40 Figure7Thetransmittanceversustemperaturecurvesof Au @pNIPAAm-PEGMAnanogels.Withdifferentmolarratiosof 1.8 0.3 6:1 42 rod NIPAAm/PEGMA(1:0,18:1,12:1,9:1,6:1,4.5:1,respectively). 1.8 0.4 4.5:1 44 Shangetal.NanoscaleResearchLetters2013,8:4 Page6of8 http://www.nanoscalereslett.com/content/8/1/4 Figure8NIR-mediatedreleaseofZnPc .(A)Time-and(B)power-dependentofreleaseofZnPc fromAu @pNIPAAm-PEGMA 4 4 rod nanogels,respectively. This can be explained by the AuNRs of Au @ carriers, could offer specific drug delivery to the targeted rod pNIPAAm-PEGMA nanogels absorbing a certain SPR site,suchasatumorzone. wavelength light and converting it into heat [30]. The heat diffused into the polymer shell and caused the Singletoxygendetection shrinkage of the pNIPAAm-PEGMA nanogels and the In PDT, the photosensitizing drugs should preferentially release of ZnPc . accumulate in target tissues and subsequently be 4 The effect of laser power density on drug release was activatedbylightwithamatchingwavelengthtogenerate studied (Figure 8B). Exposure of Au @pNIPAAm- reactive singlet oxygen [32]. The singlet oxygen will rod PEGMA nanogels to an 808-nm laser with the power of causethedestructionoftargetcellsbyacomplexcascade 100 mW/ cm2 for 15 min caused 20% of the loaded of chemical, biological, and physiological reactions [33]. ZnPc released. More loaded ZnPc (43.7%) in Au @ The Au @pNIPAAm-PEGMA nanogels served as ZnPc 4 4 rod rod 4 pNIPAAm-PEGMAnanogels could bereleased upon the carrier in PDT; besides the excellent properties of drug irradiation power of 800 mW/ cm2. This is because loading and release, its effect on the capability of loaded when irradiated with a low-power NIR laser, small ZnPc togeneratesingletoxygenwasalsoinvestigated. 4 shrinkage of nanogels occurred, whereas a laser at high Photo-induced1O ofZnPc wasexaminedbyachemical 2 4 power might make nanogels shrink considerably and methodbyusingDMA,whichcouldreactwith1O toform 2 rapidly[31],consequently moreZnPc couldbereleased. an endoperoxide. The decrease in amount ofDMAcan be 4 It is thus speculated that the NIR-responsive Au @ recorded by measuring the absorption at 377 nm. As rod pNIPAAm-PEGMA nanogel, acting as drug delivery shown in Figure 9, when ZnPc -loaded Au @pNIPAAm- 4 rod PEGMAnanogelsorpureZnPc wasirradiatedbyan808- 4 Figure9ThegenerationprofilesofsingletoxygenfromZnPc - 4 loadedAu @pNIPAAm-PEGMAnanogels(Au/P).Thenanogels Figure10ThephotodynamictherapyeffectofZnPc -loaded rod 4 wereirradiatedbyan808-nmlaseranda680-nmLED Au @pNIPAAm-PEGMAnanogelsonHelacellsatdifferent rod lamp,respectively. irradiatedconditions. Shangetal.NanoscaleResearchLetters2013,8:4 Page7of8 http://www.nanoscalereslett.com/content/8/1/4 nm laser, the absorption of DMA remained unchanged Authors’information withtheincreaseofexposuretimetolight,whereastheab- RL,TXH,andLDHarePh.Ds.andprofessors.ST,WCD,KXB,YAQ,andCMare M.D.studentsintheDepartmentofBiomaterials,CollegeofMaterials, sorption of DMA continuously decreased as the ZnPc - 4 XiamenUniversity. loadedAu @pNIPAAm-PEGMAnanogelsorpureZnPc rod 4 was irradiated by a 680-nm light. This decrease indicated Acknowledgments the production of 1O , which can irreversibly react with ThisworkwasfinanciallysupportedbytheNationalBasicResearchProgram 2 ofChina(2010CB732402,2013CB933703)andtheNationalNaturalScience DMA. Moreover, the generation curve of ZnPc -loaded 4 FoundationofChina(30970733,81171448). Au @pNIPAAm-PEGMA nanogels was similar with rod that of pure ZnPc , demonstrating that the capacity of Authordetails generating 1O of 4ZnPc was hardly affected after being 1DepartmentofBiomaterials,ResearchCenterofBiomedicalEngineering, 2 4 CollegeofMaterials,XiamenUniversity,Xiamen361005,China.2StateKey loaded in Aurod@pNIPAAm-PEGMA nanogels. It is LaboratoryforPhysicalChemistryofSolidSurfaces,XiamenUniversity, thus suggested that the Au @pNIPAAm-PEGMA Xiamen361005,China.3NeurosurgicalDepartmentofAffiliatedZhongshan rod Hospital,XiamenUniversity,Xiamen361004,China.4CollegeofMedicine, nanogel might be a promising drug carrier for photo- XiamenUniversity,Xiamen361005,China. dynamictherapyinthefuture. Received:19November2012Accepted:11December2012 Published:2January2013 InvitroPDTstudyonHelacells The in vitro PDT study, represented in Figure 10, References showed the percentage of cell viability after treatment of 1. HanG,GhoshP,RotelloVM:Functionalizedgoldnanoparticlesfordrug delivery.Nanomedicine2007,2:113–123. Hela cells with the ZnPc -loaded Au @pNIPAAm- 4 rod 2. LalS,ClareSE,HalasNJ:Nanoshell-enabledphotothermalcancertherapy: PEGMA nanogel (300 μg/mL) at different irradiated impendingclinicalimpact.AccChemRes2008,41:1842–1851. conditions. Compared with the cells’group with no light 3. 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