Near IR (NIR) sensitive Au-Au2S nanocolloids were prepared by mixing HAuCl4 and Na2S in aqueous solutions. An anti-tumor drug, cis-platin, was adsorbed onto Au-Au2S nanoparticle surface via the 11-mercaptoundecanoic acid (MUA) layers. The results show that the degree of adsorption of cis-platin onto Au-Au2S nanoparticles was controlled by the solution pH value, and the drug release was sensitive to near-infrared irradiation. The cis-platin-loaded Au-Au2S nanocolloids can be potentially applied as NIR activated drug delivery carrier. (C) 2002 Elsevier Science B.V All rights reserved

Chow, GM

Ren, L

任磊

Materials Science and Engineering C

Xiamen University Institutional Repository

Synthesis of nir-sensitive Au–Au2S nanocolloids for drug deliveryL. Rena,*, G.M. Chowa,baMolecular Engineering of Biological and Chemical Systems, Singapore–Massachusetts Institute of Technology Alliance (SMA),National University of Singapore, 10 Kent Ridge Crescent 119260, SingaporebDepartment of Materials Science, National University of Singapore, 10 Kent Ridge Crescent 119260, SingaporeAbstractNear IR (NIR) sensitive Au–Au2S nanocolloids were prepared by mixing HAuCl4 and Na2S in aqueous solutions. An anti-tumor drug,cis-platin, was adsorbed onto Au–Au2S nanoparticle surface via the 11-mercaptoundecanoic acid (MUA) layers. The results show that thedegree of adsorption of cis-platin onto Au–Au2S nanoparticles was controlled by the solution pH value, and the drug release was sensitive tonear-infrared irradiation. The cis-platin-loaded Au–Au2S nanocolloids can be potentially applied as NIR activated drug delivery carrier.D 2002 Elsevier Science B.V. All rights reserved.Keywords: Drug delivery; Near-infrared; Au–Au2S; Nanoparticles; cis-platin1. IntroductionChemotherapy for the cancer treatment cannot be used toits full potential because it involves saturating the body withtoxic drugs that produce harmful side effects such asreduced immune response to infection [1]. Drug deliverysystems (DDS), in which the carriers incorporate the drugeither through chemical bonding or passive adsorption, candeliver the drug to specific cells or release drugs optimallyat predetermined rates [2,3]. The near-infrared (NIR) radi-ation, which is nondestructive to human tissues, has beendeveloped as a DDS approach for cancer therapy [4,5]. Inthis approach, the photosensitizing drug is activated whenirradiated by the NIR light during treatment. Moreover,tissue hyperthermia induced by NIR light, can be synergizedfor the release of photosensitizing drug. However, thetraditional NIR photosensors are organic dyes that areharmful to human tissue, limiting the use of NIR radiationfor cancer therapy.In this study, NIR sensitive Au–Au2S nanocolloids wereinvestigated as drug delivery carriers. Zhou et al. [6] andAveritt et al. [7] reported that NIR sensitivity of Au–Au2Snanoparticles, where Au2S dielectric core was encapsulatedby a thin gold shell, depended on the particle geometry. Goldis essentially a bio-inert material with applications rangingfrom dental surgery to arthritis treatments [8,9], Au (shell)–Au2S (core) nanocolloids may also take advantage of theinherent biocompatibility of gold. Moreover, when usingnanoparticles as drug carriers, the reduction of particle sizeto nanoscale not only enables an intravenous injection andminimizes possible irritant reactions at the injection site [10],but also allows the carriers to penetrate the membranes of thediseased cells, and delivers drugs to cancerous tumors [11].In this paper, we report a preliminary study of theadsorption of cis-platin, a common drug applied in treatmentof a broad range of solid cancers and lymphomas [12], toNIR sensitive Au–Au2S nanocolloids. In order to function-alize the surface of NIR sensitive Au–Au2S nanoparticles,11-mercaptoundecanoic acid (MUA) was immobilized onthe colloidal carriers before drug adsorption. The chemicalstructures of MUA and cis-platin are shown in Fig. 1. MUAmolecules maybe adsorbed onto Au–Au2S nanoparticlesbecause the thiol (–SH) group is active to gold surface[13]. Another terminal –COOH group of MUA may providefurther reactivity with cis-platin. The release of cis-platinfrom the Au–Au2S nanocolloids under NIR light is alsoaddressed.2. Experimental2.1. SynthesisChloroauric acid (HAuCl44H2O) was obtained fromAcros Organics. Sodium sulfide (Na2S9H2O), 11-mercap-0928-4931/02/$ - see front matter D 2002 Elsevier Science B.V. All rights reserved.PII: S0928 -4931 (02 )00247 -3* Corresponding author. Singapore –MIT Alliance, E4-04-10, 4Engineering Drive 3, National University of Singapore, Singapore117576, Singapore. Tel.: +65-68761266; fax: +65-67763604/67752920.E-mail address: smarenl@nus.edu.sg (L. Ren).www.elsevier.com/locate/msecMaterials Science and Engineering C 23 (2003) 113–116toundecanoic acid (HS(CH2)10COOH), and cis-platin (cis-[Pt(NH3)2Cl2]) were obtained from Sigma. All reagentswere used as purchased without further purification. Theglassware were thoroughly cleaned and rinsed with deion-ized water. Following the literatures [6,7], the growth ofAu–Au2S nanocolloids was initiated when aqueous solu-tions of HAuCl4 and Na2S were mixed. Briefly, 20 ml of 1mM Na2S was mixed with 20 ml of 2 mM HAuCl4, andstored at 25 jC for 1 day. The reaction was monitored usinga UV–visible spectrophotometer at a range of 400–1100nm. After centrifuging at 15,000 r.p.m., the Au–Au2Snanoparticles were redispersed in a 100 mM 11-mercap-toundecanoic acid (MUA) solution in ethanol for 3 days at40 jC. Excess MUAwere removed from solution by at leastthree repeated cycles of centrifuging at 15,000 r.p.m., andsubsequent redispersing in water. Finally, 10 mg of cis-platin was mixed with 10 ml MUA-modified Au–Au2Snanocolloids by sonication. Afterwards, the flask containingthe drug carriers was capped and left to stand for 2 days.Determination of the degree of loading cis-platin ontonanoparticles was carried out by separating the free cis-platin molecules from the supernatant fraction after centri-fuging at 15,000 r.p.m. for 30 min. The concentration of cis-platin in supernatant was measured by high performanceliquid chromatography (HPLC) method.2.2. Drug release under NIR lightAfter centrifuging and rinsing, the cis-platin-loaded Au–Au2S nanoparticles were transferred to glass vials contain-ing 2 ml of water. Each vial was then irradiated along itslong axis with a pulsed Nd:YAG laser (1064 nm, 100 mJ/pulse, 7 ns per pulse length, 10 Hz repetition rate, SureliteII, Continuum). The entire colloidal solution was exposed tothe cross-sectional area of the beam. During the irradiationof 1 h, samples were moved from vials at different timeintervals, and the amount of cis-platin released was sub-sequently determined using HPLC. Control experimentswithout laser irradiation were also performed.2.3. CharacterizationSamples for UV–Vis study were placed in quartz crystalcuvettes (path length 1 cm) and the absorption spectra wereacquired at room temperature using a UV-1601 spectropho-tometer (Shimadzu). Samples for TEM measurements wereprepared by placing a drop of solution onto carbon-coatedcopper grids (200 mesh; 3 mm, Pelco) and left to dry priorto investigation using a microscope by JEOL 100CX (100kV accelerating voltage). For Fourier transform infraredspectroscopy, nanoparticles were recovered from solutionby centrifugation at 15,000 r.p.m. and completely dried byfreeze-drying. The FTIR spectra were obtained by formingthin (f 100 Am) transparent KBr pellets containing thematerials of interest. The transmission spectra were recordedby using a Bio-red spectrometer (FTS 135) at a resolution of4 cm 1, and 256 scans were taken in the range of 400–4000 cm 1. HPLC measurements were carried out in aliquid chromatograph instrument with a constant-flow-ratepump and diode array detector (model HP 1050, HewlettPackard, USA). Samples were chromatographed using ananalytical APS-Hypersyl column (Hewlett Packard of 20-cm length, 4.6-mm internal diameter). The mobile phase hada flow rate of 1.0 ml/min under isocratic conditions ofacetonitrile–water (90:10). The UV detector was set at 210nm. Each sample was injected three times and the resultswere averaged to obtain the value of the concentration.3. Results and discussionFig. 2 shows a typical TEM bright field image of the cis-platin-loaded, MUA-modified Au–Au2S nanoparticles. Thedrug-loaded spherical particles were about 40–50 nm indiameter, and a compact core of Au–Au2S nanoparticles(dark contrast) was surrounded by a coating (light contrast).The coating presumably consisted of MUA and cis-platin.Fig. 3 shows the FTIR spectra of Au–Au2S, MUA-modifiedAu–Au2S, and cis-platin-loaded Au–Au2S nanoparticles,respectively. Pure Au–Au2S nanoparticles did not have thecharacteristic stretching vibration band of organic groups,whereas most of the IR bands of MUA were observed forMUA-modified Au–Au2S nanoparticles. The strongestbands at 2920 and 1700 cm 1 were assigned to asymmetricFig. 1. Chemical structures of cis-platin and MUA.Fig. 2. TEM image of cis-platin-loaded MUA-modified Au–Au2Snanoparticles. Core: Au–Au2S; shell: MUA-cisplatin.L. Ren, G.M. Chow / Materials Science and Engineering C 23 (2003) 113–116114and symmetric stretching vibrations mCH of the methylenegroups and stretching vibration mCMO of the carboxylic acidgroups of MUA, respectively, indicating that MUA wasadsorbed on the Au–Au2S nanoparticles. The FTIR spectrafor the cis-platin-loaded, MUA-functionalized Au–Au2Snanoparticles showed the appearance of new bands (indi-cated by closed circles) at 3280, 3200, 1614, and 1530cm 1, which were readily identified as the amine group.This indicates that a substantial amount of cis-platin wasbound to Au–Au2S nanoparticles through the MUA layer. Itis suggested that MUA was adsorbed to Au–Au2S nano-particles via its –SH end group. The –COOH end group ofMUA may be ionized to –COO group, which maysubsequently provide attachment sites for the protonatedNH3 (NH4+) group of cis-platin. This resulted in the adsorp-tion of cis-platin to Au–Au2S nanoparticles via the MUAlayer.Fig. 4 shows the UV–Vis spectra of Au–Au2S, MUA-modified Au–Au2S, and cis-platin-loaded, MUA-modifiedAu–Au2S nanocolloids. All UV–Vis spectra consisted oftwo absorption bands. The band I at 520 nm is assigned tothe surface-plasmon resonance of the Au nanoparticles,whereas the band II at 790 nm is due to Au-coated Au2Snanoparticles [6,7]. Fig. 4 also shows that the band II forboth of MUA-modified Au–Au2S and cis-platin-loadedAu–Au2S nanocolloids shifted to longer wavelength,which may due to the coating of MUA and cis-platin onAu–Au2S nanoparticles. Note that Au–Au2S nanocolloidswere stable against aggregation even after 3 months whencoated with MUA at pH 6, whereas the uncoated Au–Au2S nanocolloids or MUA-coated Au–Au2S nanocolloidsin acidic conditions (pHV 5) aggregated in 1 week (datanot shown). The long-term stability of Au–Au2S nano-particles against aggregation is important for future appli-cations.Fig. 5 shows the effects of solution pH on adsorptionpercentage of cis-platin to the MUA-modified Au–Au2Snanoparticles. The maximum cis-platin adsorption value(f 80%) was obtained at pH 6.0–7.0. However, below orabove this pH, a smaller amount of cis-platin was absorbed.At pHV 2.5 orz 8.5, the cis-platin was almost not adsorbedonto the MUA-modified Au–Au2S nanoparticles. This pH-dependent behavior can be interpreted as follows: when thepH was decreased, the COO groups of the MUA layerbecame protonated; when the pH was increased, the NH3group of cis-platin was not protonated to NH4+. As a result,ionic bond between COO groups of MUA layer and NH4+groups of cis-platin could not readily form in either acidic orbasic solutions.The release of cis-platin from MUA-modified Au–Au2Snanoparticles over the observed period (V 1 h) under NIRFig. 3. FTIR spectra of Au–Au2S nanoparticles, MUA-modified Au–Au2Snanoparticles, and cis-platin-loaded, MUA-modified Au–Au2S nano-particles. .: amine group.Fig. 4. UV–vis spectra of (a) Au–Au2S nanocolloids, (b) MUA-modifiedAu–Au2S nanocolloids, and (c) cis-platin-loaded Au–Au2S nanocolloids.Fig. 5. Adsorption percentage of cis-platin onto the MUA-modified Au–Au2S nanoparticles as a function of solution pH.L. Ren, G.M. Chow / Materials Science and Engineering C 23 (2003) 113–116 115light irradiation and by heating (40 jC) without NIRirradiation is shown in Fig. 6. The NIR irradiation wasperformed at room temperature. The temperature of thesolution during irradiation was not monitored. About 90%of cis-platin was released at the initial period (V 1 min)under NIR irradiation, and then the rate of release decreasedwith increasing time. For heating without NIR irradiation,the release of cis-platin started after heating at 40 jC for 10min, and only 40% of cis-platin was released from Au–Au2S nanoparticles during the period of 1 h. This shows thatmore cis-platin was released under NIR irradiation com-pared to heating without laser irradiation. The controlexperiments without laser irradiation or heating showed thatonly a little amount (1.2%) of cis-platin was released. It isthus suggested that the release of cis-platin from Au–Au2Snanocolloids is sensitive to both of heating and NIRirradiation. However, such dissociative reaction is morereadily initiated by the absorption of NIR light comparedto heating without laser irradiation. The cis-platin-loadedAu–Au2S nanocolloids may absorb the NIR photons, andthis absorption with high energy may lead to photochemicalinteraction, thermal interaction, photoablation, plasmainduced ablation, and photodisruption among nanocolloids[14,15]. These interactions may also occur to cause thecleavage of the ionic bond between COO and NH4+, andmay finally release cis-platin from Au–Au2S nanoparticles.However, the mechanism of the interactions between NIRlight and NIR sensitive Au–Au2S nanocolloids is presentlyunclear, and detailed work is in progress. The thermaleffects in NIR irradiation also need to be understood. Basedon the results shown in Fig. 5, it is suggested that theadsorption of cis-platin on Au–Au2S nanoparticles is stablein physiological conditions where pH is about 7.2–7.4,however, when NIR light is applied in therapy, cis-platinwill be released from the nanoparticles so that the cancerouscells will be killed. Hence, our preliminary study of drugrelease under NIR irradiation shows that cis-platin-loadedAu–Au2S nanocolloids can be a potential drug deliverysystem for cancer treatment.4. SummaryWe have reported a preliminary study of preparing a drugcarrier system in which MUA was used as a linker betweendrug and NIR sensitive Au–Au2S nanoparticles. The degreeof adsorption of cis-platin onto Au–Au2S nanoparticles wascontrolled by the solution pH value, and cis-platin wasreleased from nanoparticles under NIR irradiation at agreater rate than thermal activation without laser irradiation.The potential of this drug delivery system for cancer therapywarrants further investigation.AcknowledgementsThis work was supported by the Singapore-MIT alliance(SMA). L. Ren was supported by the SMA postdoctoralfellowship. We thank Dr. G. Chen in NTU for his help onusing Nd:YAG laser. We also thank Dr. C.-L. Ho and Dr. S.-C. Li of the department of pharmacy of NUS for their adviceand discussion.References[1] H. Calvert, I. Judson, W.J.F. Van der Vijgh, Cancer Surveys: Pharma-cokinetics and Cancer Chemotherapy, Cold Spring Harbor LaboratoryPress, New York, 1993.[2] K. Park, Controlled Drug Delivery: Challenges and Strategies, Amer-ican Chemical Society, Washington, DC, 1997.[3] L. Domellof, Drug Delivery in Cancer Treatment: II. Symptom Con-trol, Cytokines, Chemotherapy, Springer-Verlag, New York, 1989.[4] R. Raghavachari, Near-Infrared Applications in Biotechnology, Mar-cel Dekker, New York, 2001.[5] S. Sershen, S.L. Westcott, N.J. Halas, J.L. West, J. Biomed. Mater.Res. 51 (2000) 293.[6] H.S. Zhou, I. Honma, J.W. Haus, H. Sasabe, H. Komiyama, J. Lumin.70 (1996) 21.[7] R.D. Averitt, D. Sarkar, N.J. Halas, Phys. Rev. Lett. 78 (1997) 4217.[8] B. Merchant, Biologicals 26 (1998) 49.[9] J.L. West, N.J. Halas, Curr. Opin. Biotechnol. 11 (2000) 215.[10] F. Kratz, M.T. Schutte, Cancer J. 11 (1998) 176.[11] S.M. Moghimi, A.C. Hunter, Crit. Rev. Ther. Drug Carr. Syst. 18(2001) 527.[12] B. Lippert, Cisplatin: Chemistry and Biochemistry of a Leading Anti-cancer Drug, Wiley, New York, 1999.[13] H. Schmidbaur, Gold: Progress in Chemistry, Biochemistry, and Tech-nology, Wiley, Chichester, 1999.[14] M.H. Niemz, Laser-Tissue Interactions: Fundamentals and Applica-tions, Springer-Verlag, Germany, 1996.[15] I.W. Boyd, R.B. Jackman, Photochemical Processing of ElectronicMaterials, Academic Press, London, 1992.Fig. 6. Release of cis-platin from Au–Au2S nanoparticles under Nd:YAGlaser (room temperature) and heating (40 jC, without laser irradiation).L. Ren, G.M. Chow / Materials Science and Engineering C 23 (2003) 113–116116

Synthesis of nir-sensitive Au-Au2S nanocolloids for drug delivery

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Synthesis of nir-sensitive Au-Au2S nanocolloids for drug delivery

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