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Abstract
Background
Gold nanorods (AuNRs), due to the optical and electronic properties namely the surface plasma resonance, have been developed to achieve the light-mediated photothermal therapy (PTT) for cancer. However, PTT alone may suffer from inefficient tumor killing. Recently, the combination of PTT and chemotherapy has been utilized to achieve synergistic anticancer effects.
Methods
In this study, AuNRs capped with hexadecyltrimethylammonium bromide (CTAB), poly(acrylic acid) (PAA), and PEGylated anisamide (a ligand known to target the sigma receptor) have been developed to produce a range of negatively charged anisamide-targeted PEGylated AuNRs (namely Au-CTAB-PAA-PEG-AA) for the combination of PTT and chemotherapy (termed as chemo-photothermal therapy [CPTT]). Epirubicin (EPI, an anthracycline drug) was efficiently loaded onto the surface of Au800-CTAB-PAA-PEG-AA via the electrostatic interaction forming Au800-CTAB-PAA-PEG-AA.EPI complex.
Results
The resultant complex demonstrated pH-dependent drug release, facilitated nucleus trafficking of EPI, and induced antiproliferative effects in human prostate cancer PC-3 cells. When Au800-CTAB-PAA-PEG-AA.EPI complex was further stimulated with desired laser irradiation, the synergistic outcome was evident in PC-3 xenograft mice.
Conclusion
These results demonstrate a promising strategy for clinical application of CPTT in cancer.
Supplementary materials
Synthesis of AuNR-CTAB with longitudinal wavelengths of ~700, 725, and 765 nm
Synthesis of gold nanorods (AuNRs) with longitudinal wavelength (~700 nm): About 75 mL of 0.2 M hexadecyl-trimethylammonium bromide (CTAB) solution was added to 0.485 mL of 12.36 mM AgNO3 solution at 25°C, which was followed by the addition of 75 mL of 0.001 M HAuCl4. Afterward, 1.8 mL of 0.0788 M C6H8O6 was added, and the solution color changed from dark yellow to colorless. Subsequently, 0.108 mL of the seed solution was added to the growth solution at 27°C–30°C. The solution color changed to dark blue within 5–15 minutes. The growth medium was kept undisturbed at 27°C–30°C for 22 hours. The obtained AuNR-CTAB (~700 nm) complex was washed three times with deionized water by centrifugation (12,500 rpm, 5 minutes) prior to the following experiments.
Synthesis of AuNRs with longitudinal wavelength (~725 nm): About 75 mL of 0.2 M CTAB solution was added to 2.184 mL of 12.36 mM AgNO3 solution at 25°C, which was followed by the addition of 75 mL of 0.001 M HAuCl4. Afterward, 1.8 mL of 0.0788 M C6H8O6 was added, and the solution color changed from dark yellow to colorless. Subsequently, 0.108 mL of the seed solution was added to the growth solution at 27°C–30°C. The solution color changed to dark blue within 10–20 minutes. The growth medium was kept undisturbed at 27°C–30°C for 22 hours. The obtained AuNR-CTAB (~725 nm) was washed three times with deionized water by centrifugation (12,500 rpm, 5 minutes) prior to the following experiments.
Synthesis of AuNRs with longitudinal wavelength (~765 nm): About 75 mL of 0.2 M CTAB solution was added to 3 mL of 4 mM AgNO3 solution at 25°C, which was followed by the addition of 75 mL of 0.001 M HAuCl4. Afterward, 1.05 mL of 0.0788 M C6H8O6 was added, and the solution color changed from dark yellow to colorless. Subsequently, 0.108 mL of the seed solution was added to the growth solution at 27°C–30°C. The solution color changed to deep red within 15–30 minutes. The growth medium was kept undisturbed at 27°C–30°C for 22 hours. The obtained AuNR-CTAB (~765 nm) was washed three times with deionized water by centrifugation (12,500 rpm, 5 minutes) prior to the following experiments.
Figure S1 TEM images of Au700-CTAB, Au725-CTAB, and Au765-CTAB (scale bar =50 nm).
Abbreviations: TEM, transmission electron microscopy; Au, gold; CTAB, hexadecyltrimethylammonium bromide.
Figure S2 1H NMR spectrum of anisic-NHS.
Abbreviations: NMR, nuclear magnetic resonance; NHS, N-hydroxysuccinimide.
Figure S3 1H NMR spectrum of SH-PEG5000-AA.
Abbreviations: NMR, nuclear magnetic resonance; PEG, polyethylene glycol; AA, anisamide.
Figure S4 Stability of Au800-CTAB-PAA-PEG-AA.EPI complex (MR =5) incubated in the saline at 4°C (left tube in the image) and 37°C (right tube in the image) for 4, 24, and 48 hours. In addition, the size distribution results obtained from dynamic light scattering demonstrated that no aggregation occurred following the incubation.
Abbreviations: Au, gold; CTAB, hexadecyltrimethylammonium bromide; PAA, poly(acrylic acid); AA, anisamide; PEG, polyethylene glycol; EPI, epirubicin; MR, mass ratio; PDI, polydispersity index.
Figure S5 (A) Kinetic changes of surface temperature after the laser irradiation (808 nm, 2.5 W/cm2) of PBS, EPI, Au800-CTAB-PAA-PEG-AA (AuNR-AA), and AuNR-AA. EPI complex for 4.5 minutes. (B) Thermographic images of PBS, EPI, AuNR-AA, and AuNR-AA.EPI complex after the laser stimulation (808 nm, 2.5 W/cm2) for 4.5 minutes.
Abbreviations: Au, gold; CTAB, hexadecyltrimethylammonium bromide; PAA, poly(acrylic acid); AA, anisamide; PEG, polyethylene glycol; EPI, epirubicin.
Figure S6 The expression of caspase 3, cleaved caspase 3, caspase 9, cleaved caspase 9, Bax, and Bcl-2 was determined using Western blotting (n=3) relative to β-actin. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001 relative to the untreated group; &P<0.05 relative to the AuNR-AA.EPI group.
Abbreviations: AuNR, gold nanorod; AA, anisamide; EPI, epirubicin.
Acknowledgments
This work was supported by the Outstanding Youth Foundation from the Department of Science and Technology, Jilin Province, China (20170520046JH), the Start-Up Research Grant Program from Jilin University (451170301168, 451160102052, 419080500667), and the Fundamental Research Funds for the Central Universities, China. Jin Pei, Kamil Rahme and Jianfeng Guo are co-corresponding authors.
Disclosure
The authors report no conflicts of interest in this work.