Regulatory Mechanism of Localized Surface Plasmon Resonance

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Regulatory Mechanism of Localized Surface Plasmon Resonance Based on Gold Nanoparticles Coated Paclitaxel Nanoliposomes and Their Antitumor Efficacy Yuchu He, Mengxue Yang, Shuxian Zhao, Cong Cong, Xiaowei Li, Xin Cheng, Jingyue Yang, and Dawei Gao ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b03711 • Publication Date (Web): 09 Sep 2018 Downloaded from http://pubs.acs.org on September 10, 2018

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ACS Sustainable Chemistry & Engineering

Regulatory Mechanism of Localized Surface Plasmon Resonance Based on Gold Nanoparticles Coated Paclitaxel Nanoliposomes and Their Antitumor Efficacy

Yuchu He1,3, Mengxue Yang1, Shuxian Zhao1, Cong Cong1, Xiaowei Li1,3, Xin Cheng1, Jingyue Yang1, Dawei Gao1,2*

1

Applying Chemistry Key Lab of Hebei Province, Department of Bioengineer, Yanshan University, No.438 Hebei Street, Qinhuangdao, 066004, China.

2

State Key Laboratory of Metastable Materials Science and Technology, Yanshan University, Qinhuangdao 066004, P. R. China.

3

Hebei Province Asparagus Industry Technology Research Institute, Qinhuangdao, 066004, China.

*Corresponding author: Prof. Dawei Gao, Tel: (+86)13930338376. E-mail: [email protected]

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ABSTRACT: To functionalize the advanced controlled drug delivery systems, gold nanomaterials have been explored as photothermal therapy agents owing to their tunable and strong localized surface plasmon resonance (LSPR). As the major tissue chromophores are barely absorptive in the near-infrared (NIR) region (650-900 nm), it is becoming particularly important to regulate the LSPR absorption of gold nanomaterials to the NIR region to minimize the absorption. The main factors for the LSPR absorption of nanomaterials, which decides the photothermal effects, drug release and antitumor efficacy of gold based drug carriers, include morphology, size and dielectric constant of surrounding mediums. Herein, gold nanoparticles coated paclitaxel nanoliposomes (PTX-Lips@AuNPs) with various morphologies, sizes and dielectric constant of surrounding mediums were synthesized. We studied the regulatory mechanism of LSPR absorption and their antitumor efficacy. The results showed that the branched gold nanoshells coated paclitaxel nanoliposomes (PTX-Lips@BGNs) with big size (about 150 nm) in the medium of NaCl solution exhibit optimal antitumor efficacy among different parameters we have studied. Furthermore, the investigation of regulatory mechanism endows a synthetic theoretical basis of the nanomaterials in the future.

KEYWORDS: regulatory mechanism, localized surface plasmon resonance, gold based drug carriers, near-infrared, antitumor efficacy

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Introduction Nanomaterials are the convergence points between the large size biomolecules of life and the small size devices that human beings can make. Once made into nanoscale, the materials show different properties (e.g. small size effect1, quantum size effect2, quantum confinement effect3 and surface effect4 etc.) compared with macroscale, which change their performance (e.g. magnetism, light, electricity and heat) and application. Given these superior properties, nanomaterials have received widespread interest in the field of cancer therapy5–7 and theragnostic8–10. Thereinto, gold nanomaterials with various structures, for example, gold nanorods11,12, gold nanoparticles13,14 and gold nanocages15,16 etc. exhibit the property of photothermal conversion and prospect in photothermal therapy (PTT) because of their unique localized surface plasmon resonance (LSPR)17. Among them, gold nanoshell18 is widely favored owing to their facile and green synthesis. Meanwhile, the inorganic photosensitizer combined with various organic drug delivery nanosystems and multifunctional components are beneficial for reducing laser power and lessening the damage to normal tissue. So far, several gold-drug carriers have been prepared, such as gold nanorods-coated mesoporous silica nanorods19, gold nanostructures-coated human endogenous protein20 and polydopamine-coated gold nanorods21 etc. These drug carriers all exhibited high drug loading and drug delivery efficiency. Under the laser irradiation, the heat generated by gold nanomaterials leads to the accumulation of drug to complete the chemotherapy. It should also be mentioned that as the major tissue chromophores are barely absorptive in the near-infrared (NIR) region (650-900 nm), there is a pressing need to tune the LSPR absorption of gold nanomaterials to NIR region22. Gold nanoparticles have attracted tremendous efforts for cancer therapy23 and bioimaging24 on account of inherent attributes such as biocompatibility25, stability26, tunable optical properties6 and free of ROS-associated toxicities. However, the lack of LSPR absorption in the NIR region limits their application. Hence, over the past decade, some promising strategies under clinic investigation have focus on various 3



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kinds of NIR-sensitive gold nanomaterials prepared via using gold nanoparticles as seeds27–29. These gold nanomaterials have a remarkable red shift of LSPR absorption in the NIR region. The main factors for red shift include morphology and size of the nanoparticles and dielectric constant of the surrounding medium30. The photothermal effect of gold nanomaterials will be enhanced under the NIR laser irradiation, which improves the drug release of PTT-agent-combined drug delivery nanosystem and its antitumor

efficacy

accordingly.

Although

numerous

preparations

of

gold

nanomaterials have been illustrated, the regulatory mechanism of these nanomaterials is still not fully understood. We aim to illuminate the influential mechanism of morphology, size and dielectric constant of surrounding medium. Herein, we present a drug delivery system based on gold nanomaterials coated paclitaxel nanoliposomes with various morphologies (gold nanoparticles, gold nanoshells and branched gold nanoshells). Compared with other reported materials, the branched gold nanoshells coated paclitaxel nanoliposomes (PTX-Lips@BGNs) converted the light to heat while promoting the collapse of branched gold nanoshells and nanoliposomes. Subsequently, the PTX released from the nanoliposome sustainably to realize the photothermal-chemo synergistic therapy. Furthermore, the heat generated by the photothermal therapy could promote blood circulation and enhance the delivery of drugs. In addition, compared with other gold coated liposomes (gold nanoshells and gold nanoparticles), the maximum absorption peak of branched gold nanoshells is closer to the wavelength of laser, which showed enhanced photothermal effect under laser irradiation. Our synthesis is facile and green, which conform to the principles of green chemistry and sustainable development. At the same time, the drug delivery system can avoid immune system clearance and has a long cycle time with a sustained drug release in the body, which has a continuous effect in cancer therapy. Based on one type of those morphologies- PTX-Lips@BGNs, we also examined different sizes of the nanomaterials as well as surrounding mediums with different dielectric constant (H2O, C2H5OH and NaCl solution). The photothermal effect of gold nanomaterials drives the phase transformation of paclitaxel nanoliposomes to release drug under the 4


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NIR laser irradiation, which evolves synergistic cancer therapy by deep thermal ablation and chemotherapy (Scheme 1a). To the best of our knowledge, it is the first time to study the mechanism of red shift based on gold nanoparticles to form gold nanoshells and branched gold nanoshells, which regulates the LSPR absorption to or near to NIR region. This investigation provides a synthetic theoretical basis and explanations of nanomaterials to realize their sustainable effect.

Experimental Section Materials. Auric chloride (AuCl3) was purchased from Chengdu Xiya Reagent Co., Ltd (Chengdu, China). Sodium borohydride (NaBH4) and PEG-2000 were purchased from Tianjin Guangfu Fine Chemical Research Institute (Tianjin, China). HONH3Cl was purchased from Tianjin Fengchuan Chemical Technology Co., Ltd (Tianjin, China). Reduced L-Glutathione (GSH) was purchased from Sigma-Aldrich (Shanghai) Trading Co., Ltd. Paclitaxel was purchased from Shanghai yuanye Bio-Technology Co., Ltd (Shanghai, China). Soya lecithin (SPC, PC-98) was purchased from Shenyang Tianfeng Biological Pharmaceutical Co, Ltd (Shenyang, China). Cholesterol (Chol) was purchased from Tianjin Damao Chemical Instruments Supply Station (Tianjin, China). All the chemicals and solvents used in the study were analytical and chromatographic grade and deionized water was used throughout the experiments. Synthesis. Paclitaxel nanoliposomes (PTX-Lips): As a first step of PTX-Lips generation, paclitaxel (0.3mg mL-1), soya lecithin and cholesterol were mixed into ethanol as the lipid phase. Tween-80 and PEG-2000 were solubilized in phosphate-buffered saline as the aqueous phase. Then, the lipid phase was added dropwise into the aqueous phase under magnetic stirring for 2 hours. In this approach, PTX-Lips with nanoscale were prepared. Gold

nanoparticles coated paclitaxel nanoliposomes (PTX-Lips@AuNPs):

Reduced L-Glutathione (GSH) was added dropwise into the prepared PTX-Lips, and then the mixture solution was stirred gently for 2 hours. Gold seeds were synthesized by the chemical reduction of AuCl3 solution with NaBH4. Both the AuCl3 solution and 5



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the freshly prepared NaBH4 solution were put into an ice bath for 4 min and protected from light. Afterward, ice-cold NaBH4 solution (10 µL, 253 mM) was immediately added to the AuCl3 solution (1 mL, 0.5 mM). The mole ratio of AuCl3 to NaBH4 was 1:5. After vigorous stirring, Au seeds formed promptly and were transferred promptly to room temperature within 30 min. Finally, prepared gold seeds were put into the prepared PTX-Lips within volume ratio of 1:1. The resulting solution was gently mixed in a shaking incubator and then stored for 20 hours. The PTX-Lips@AuNPs were obtained. Gold nanoshells coated paclitaxel nanoliposomes (PTX-Lips@GNs): AuCl3 solution (500 µL, 2 mM) was added to the PTX-Lips@AuNPs, followed by the addition of NaBH4 solution (10 µL, 100 mM). The mole ratio of AuCl3 to NaBH4 was 1:1. After 4 hours of stirring at room temperature, 300 µL of 2 mM AuCl3 and 10 µL of NaBH4 (100 mM) solutions (the mole ratio of AuCl3 to NaBH4 was 3:5) were added to the resulting mixture and allowed to react for 4 hours under ambient conditions. The PTX-Lips@GNs were obtained. Branched gold nanoshells coated paclitaxel nanoliposomes (PTX-Lips@BGNs): AuCl3 solution (500 µL, 2 mM) was added to the PTX-Lips@AuNPs solution, followed by the addition of HONH3Cl solution (50 µL, 100 mM). The mole ratio of AuCl3 to HONH3Cl was 1:5. After 4 hours of stirring at room temperature, 300 µL of 2 mM AuCl3 and 30 µL of HONH3Cl (100 mM) solutions (the mole ratio of AuCl3 to HONH3Cl was 1:5) were added to the resulting mixture and allowed to react for 4 h under ambient conditions. The PTX-Lips@BGNs were prepared. Characterization. The morphologies and sizes of the synthesized PTX-Lips, PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs were characterized by transmission electron microscopy (TEM, HT7700, Japan) with a CCD camera operated at an accelerating voltage of 100 kV. The particle size distribution was determined by dynamic light scattering (DLS) on a Zetasizer Nano-ZS90 (Malvern Instruments, UK). The absorption spectra were obtained using a UV-vis spectrophotometer (Shimadzu UV2550, Japan). Photothermal conversion experiments. The photothermal effects of the prepared 6


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PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs were evaluated using NIR laser irradiation (MDL-N-808-10W-12120445, China). For this measurement, 0.5 mL of the prepared nanomaterials were added to tubes respectively. Then, the tubes were irradiated under 808-nm NIR laser (2 W/cm2, 10 min). The temperatures of the above solutions were recorded every 30 s by a digital thermometer. Drug release study in vitro. The paclitaxel release effects of PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs with laser irradiation were studied using the dialysis method. The experiment details were designed according to our previous study. Thereinto, at two-time points (the second hour and the sixth hour), the samples were irradiated by 808-nm light (2.0 W/cm2, 5 min), and then the samples were determined immediately. The drug contents were analyzed using UV-vis spectrophotometer. Cell culture. The HeLa cells (cervical cancer cell line) were purchased from Shanghai Tianjing Biological Technology Co. Ltd (Shanghai, China). The cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM) containing 10% fetal bovine serum and 1% penicillin/streptomycin at 37°C containing 5% CO2. Antitumor assay and photothermal therapy in vitro. The antitumor effects of prepared PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs with NIR light irradiation were evaluated by HeLa cells using the MTT assay. Briefly, the cells were seeded separately in 96-well plates (5.0×104 cells/well) and incubated for 24 hours. The paclitaxel concentrations were consistent (3.13, 6.25, 12.5, 25, 50 and 100 µg/mL). Additionally, the cells were treated with the PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs, followed by 808-nm laser irradiation (2 W/cm2, 5 min) and then incubation for another 20 hours. The cell inhibition rates were evaluated by MTT assay, and the inhibition rates of the samples were calculated according to the following equation: Cell viability (%) = OD sample/OD control × 100. OD sample and OD control represent the absorbance of the sample and PBS groups, respectively.

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Results and Discussion Characterization of PTX-Lips. The morphologies of PTX-Lips were analyzed by TEM, which demonstrated that PTX-Lips were spherical and equal size (Figure 1a). As measured by DLS, the PTX-Lips had a size distribution of 80 to 200 nm and the dispersibility was satisfactory (Figure 1b). Effect of morphology to LSPR. The morphologies of PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs were analyzed by TEM (Figure 2a-d, Supporting Information Figure S2a-d). The PTX-Lips were coated by gold seeds with different concentrations to form PTX-Lips@AuNPs with less or more gold seeds. As outlined in TEM images, gold seeds uniformly adhered to the surface of the PTX-Lips. When

the

gold

nanoparticles

finished

growing,

PTX-Lips@GNs

and

PTX-Lips@BGNs were obtained via reduction using NaBH4 or HONH3Cl. The surface of PTX-Lips@BGNs was more branched comparing to that of PTX-Lips@GNs. The UV-vis-NIR absorption spectrum confirmed the effect of morphology on LSPR absorption (Figure 2e). Less gold nanoparticles-based PTX-Lips showed the similar properties with gold nanoparticles (520 nm). As the gold nanoparticles gathering on the PTX-Lips, a slight red shift of LSPR absorption peak appeared, which centered at about 550 nm. In the wake of adding the AuCl3 and NaBH4 solution, gold nanoparticles were grown on the PTX-Lips sequentially to form PTX-Lips@GNs, which was found to exhibit a broad LSPR absorption peak centered at 580 nm. The surface of PTX-Lips@GNs became more branched when using HONH3Cl solution as reductant and with longer incubation time. So we call it PTX-Lips@BGNs instead, the LSPR absorption peak of which showed red shift to about 630 nm. As discussed above, the UV-vis-NIR absorption spectrum confirmed the effect of morphologies to LSPR absorption of these gold nanomaterials. The photothermal performance of these gold nanomaterials was examed as well. As shown in Figure 2f, the PTX-Lips@AuNPs (with less or more seeds) showed a less temperature rise with 808-nm laser irradiation compared with PTX-Lips@GNs and PTX-Lips@BGNs owing to the lack of LSPR absorption in NIR region. After 10 8


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mins’ irradiation with 808-nm laser at 2.0 W/cm2, the temperatures of PTX-Lips@GNs and PTX-Lips@BGNs solution increased from 27℃ to 57℃ and 68℃, respectively, which indicated that tuning the LSPR absorption to or near to NIR region enhanced the photothermal performance of these gold nanomaterials. As nanoliposomes, temperature rise leads to phase transformation, which releases the drug controllably31. The release profiles of paclitaxel from PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs were outlined in Figure 2g. The drug release depends on the temperature, which illustrates that PTX-Lips@BGNs showed higher level

of

drug

release.

Biocompatibility

of

PTX-Lips,

PTX-Lips@AuNPs,

PTX-Lips@GNs and PTX-Lips@BGNs was illustrated in Supporting Information (Figure S1). Cell viability of HeLa cells treated with PTX-Lips, PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs without laser irradiation at the same concentration of PTX (100 g/mL) was above 80%, which indicated good biocompatibility of the nanosystem. To investigate the antitumor efficacy, the possible cytotoxicity of PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs towards HeLa cells is probed (Figure 2h). The relative viability of the HeLa cells incubated with PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs (internal paclitaxel concentration is 3.13, 6.25, 12.5, 25, 50 and 100 µg/mL) for 24 hours was determined by the MTT assay. With the same nanostructure, the antitumor efficacy enhanced with the increase of paclitaxel. While with the same concentration of paclitaxel, PTX-Lips@BGNs showed much better effect of photothermal therapy. These results demonstrated the distinctive LSPR absorption and much better chemo-thermal antitumor efficacy of PTX-Lips@BGNs. The regulatory mechanism was investigated likewise. First, the PTX-Lips@AuNPs with less gold seeds showed the properties of gold nanoparticles alone, which were found to exhibit an LSPR absorption peak at about 520 nm. Next, a red shift to about 550 nm occurred with the increase of the concentration of gold nanoparticles. According to Rayleigh scattering formula32: I=

24π Nv n − n ( ) I (1) λ n + n 9



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(I: intensity of scattering light, I : intensity of incident light, N: the number of the scattering particles per unit volume, v: the volume of one particle, n and n : the refractive indices of the particle and the surrounding medium), the intensity of short wave scattering is stronger than long wave for nanoparticles (the decrease of leads to the increase of I). With the concentration of gold nanoparticles increased, the scattering times were increased as well. As a result, the red shift of LSPR absorption peak was occurred. Then, after further growing, the sizes of gold nanostructures became much bigger to form PTX-Lips@GNs and PTX-Lips@BGNs, whose LSPR absorption peaks centered at about 580 and 630 nm, respectively. Under the circumstance of primary reduction of NaBH4, gold nanoparticles were grown to form the smooth gold nanoshells, which no longer exhibit the optic properties of gold nanoparticles. Compared with the gold nanoparticles on the PTX-Lips, the size of PTX-Lips@GNs was remarkably larger, which led to the red shift from 550 nm to 580 nm (The mechanism of this kind of red shift was explained in the effect of size to LSPR). Finally, in the condition of two-time reduction of HONH3Cl, gold nanoparticles were grown to form the branched gold nanoshells. On the basis of the surface electron density theory of metal nanoparticles33: λ =

c mπ (ε + 2n ) (2) N e

(λ : absorption peak of nanoparticles, c: concentration of metal, m: effective mass of electron, N : free electron density on metal surface, e: electron charge, ε : high frequency dielectric constant of metal, n : refractive index of solvent), compared with the PTX-Lips@GNs, the superficial area of the PTX-Lips@BGNs was bigger due to its branched surface, which leaded to the smaller free electron density on the surface of gold nanoshells. Therefore, PTX-Lips@BGNs was found to exhibit red shift of LSPR absorption (580 nm to 630 nm) at the side of PTX-Lips@GNs. Effect of size to LSPR. So as to investigate the effect between size and LSPR absorption, PTX-Lips@BGNs with various sizes were analyzed by TEM and DLS (Figure 3a-e). Compared with the negative potential of PTX-Lips, PTX-Lips@BGNs showed a remarkable positive potential via the growing of gold seeds (Figure 3f). As 10


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a result, different sizes of PTX-Lips@BGNs (90, 110, 130 and 150 nm) were synthesized through disparate amount of AuCl3 and HONH3Cl solution respectively. Note that the establishment of different sizes was of no effect on their morphologies. With the increase of the size of PTX-Lips@BGNs, the UV-vis-NIR showed a slight red shift (Figure 3g) and the photothermal performance was enhanced accordingly (Figure 3h). On account of the different photothermal performance, the PTX-Lips@BGNs with higher temperature exhibited much better drug release (Figure 3i). To demonstrate the antitumor efficacy, the possible cytotoxicity of PTX-Lips@BGNs with various sizes towards HeLa cells was also probed. As shown in Figure 3j, the PTX-Lips@BGNs with about 150 nm showed much better antitumor efficacy than the groups of small sizes. These results confirmed that the PTX-Lips@BGNs showed red shift of LSPR absorption peak and enhanced antitumor efficacy with the increase of the size. Once made into nanoscale, the materials show different properties compared with macroscale. The PTX-Lips@BGNs with various sizes followed the quantum size effect. Kudo proposed a formula of relation between energy level spacing and particle diameter33, 34: 4 1 1 ∝ ∝ (3) 3! # $ (δ: energy level spacing, E& : Fermi level, N: electron number of one nanoparticle, V: δ=

volume, d: arrange particle size). The energy level spacing lessens with the increase of particle size. Hence, the transition energy of electron decreases, which leads to the shift to the long wave. As a result, the red shift of the size-increased PTX-Lips@BGNs occurred. From perspective of surface effect35, the specific surface area and relative number of atoms on the surface increase with decrease of size. Adjacent atoms around the surface atoms are missing, which causes insufficient coordination of the atoms due to the dangling bonds. Delocalized electrons reallocate between surface and interior, which leads to the increase of bond strength and chemical bond force constant. The surface atoms have higher activity. Therewith, compared with big size, nanoparticles with small size exhibit blue shift obviously. 11



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Effect of dielectric constant of surrounding medium to LSPR. Given that the dielectric constant of surrounding medium affects the LSPR absorption of nanomaterials, we investigated LSPR absorption and antitumor efficacy of PTX-Lips@BGNs in C2H5OH, H2O and NaCl solutions. As shown in Figure 4a-c, TEM images showed that there was no significant distinction, which indicated that the surrounding mediums do not affect the morphology and construction of PTX-Lips@BGNs. Compared with C2H5OH and H2O, the NaCl solution group exhibited a remarkable red-shift broad peak centered at about 750 nm (Figure 4d). The UV-vis-NIR absorption spectra illustrated the effects of dielectric constant of surrounding medium to regulate the LSPR absorption of PTX-Lips@BGNs to NIR region. Since the LSPR absorption peak was in the NIR region, NaCl solution group exhibited superior photothermal performance, drug release and antitumor efficacy under 808-nm laser irradiation (Figure 4e-g). To confirm the stability of PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs in cell medium and NaCl solution, DLS was analyzed in Supporting Information (Figure S3a and b), which indicated that the nanostructure is stable both in cell medium and NaCl solution. Furthermore, TEM image of PTX-Lips@BGNs in NaCl solution suggested no aggregation in NaCl solution compared with them in H2O. Thus, the red shift of LSPR absorption resulted from the effect of surrounding medium. According to the formula of relation between the LSPR frequency and dielectric constant of surrounding mediums36: ϵ = −

(()* ) )*

ϵ

(4)

The real part of the gold dielectric function ϵ is wavelength dependent. ϵ is the dielectric constant of surrounding medium.

((+, ) +,

is the function of the aspect ratio

(seem as constant). Since, the real part of gold dielectric constant (ϵ ) decrease with increase in wavelength, resonance wavelength increases with increase in -. . Therefore, NaCl solution group showed red shift of LSPR absorption peak compared with H2O and C2H5OH groups.

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Conclusions In the present study, we have rationally constructed and investigate three types of nanomaterials (PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs) and also explored the regulatory mechanism on LSPR absorption. With 808-nm laser irradiation, the nanomaterials whose LSPR absorptions were close to the NIR region exhibited outstanding photothermal performance. With the combination of PTT agents and drug delivery systems, good photothermal performance promoted the drug release. Therefore, the antitumor efficacy was enhanced as well. In addition, the red shift mechanism of the LSPR absorption was explained to some extent via the relevant theories of unique properties of nanomaterials. The influential factors of the red shift were morphology, size and dielectric constant of surrounding medium. The results indicated that branched surface, big size (about 150 nm) and medium of NaCl solution showed red shift of LSPR absorption (Scheme 1b) and much better antitumor efficacy of nanomaterial, which were interpreted via Rayleigh scattering formula, surface electron density theory, quantum size effect, surface effect and the relation between the LSPR frequency and dielectric constant of surrounding medium. Taken together, it is reasonable to believe that our investigation provides a synthetic theoretical basis of the gold based nanomaterials for future biomedicine.

Acknowledgments This work was supported by the National Natural Science Foundation (No. 21476190, 21776238), the Hebei province key basic research Foundation (No. 15961301D), Hebei education department key project (No. ZD2017084) and fund from Qinhuangdao science and technology research and development project (No. 201402B029).

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Scheme 1. (a) Schematic illustration of the synthesis route for the PTX-Lips, PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs and the NIR laser irradiation-induced chemo-photothermal therapy in tumor cells. (b) Regulation of LSPR absorption with various morphologies, sizes and dielectric constants of surrounding mediums.

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Figure 1. Characterization of PTX-Lips. (a) TEM image and (b) DLS size analysis of PTX-Lips.

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Figure 2. Effect of morphology to LSPR of gold based drug carries. (a)-(d) TEM images of less and more gold nanoparticles coated PTX-Lips, PTX-Lips@GNs and PTX-Lips@BGNs. (e) UV-vis-NIR absorption spectra and (f) photothermal profile with 808-nm laser of less and more gold nanoparticles coated PTX-Lips, PTX-Lips@GNs

and

PTX-Lips@BGNs

at

the

same

concentration.

(g)

light-responsive drug release and (h) cell viability of HeLa cells treated with PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs under 808-nm laser irradiation (*P < 0.05, **P < 0.01 compared with the PTX-Lips@AuNPs group).

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Figure 3. Effect of size to LSPR of gold based drug carries. (a)-(d) TEM images of PTX-Lips@BGNs with increscent sizes. (e) DLS size analysis, (g) UV-vis-NIR absorption spectra, (h) photothermal profile with 808 nm laser, (i) light-responsive drug release and (j) cell viability of HeLa cells treated with PTX-Lips@BGNs with increscent sizes and the same concentration under 808-nm laser irradiation (a, b, c, d are corresponding to size-increased PTX-Lips@BGNs in TEM images, *P < 0.05, **P < 0.01 compared with a group). (f) Zeta potential of PTX-Lips, PTX-Lips@AuNPs, PTX-Lips@GNs and PTX-Lips@BGNs.

20


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Figure 4. Effect of dielectric constant of surrounding medium to LSPR of gold based drug carries. (a)-(c) TEM images of PTX-Lips@BGNs in C2H5OH, H2O and NaCl solution. (d) UV-vis-NIR absorption spectra, (e) photothermal profiles with 808 nm laser, (f) light-responsive drug release and (g) cell viability of HeLa cells treated with PTX-Lips@BGNs in C2H5OH, H2O and NaCl solution at the same concentration under 808-nm laser irradiation (*P < 0.05, **P < 0.01 compared with the C2H5OH group).

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For Table of Contents Use Only:

This study is about the influential factors and regulatory mechanism of red shift for gold nanomaterials, which provides theoretical explanations for their wide applications.

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Regulatory Mechanism of Localized Surface Plasmon Resonance

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