Bacteria-like mesoporous silica-coated gold nanorods for positron emission tomography and photoacoustic imaging-guided chemo-photothermal combined therapy

Abstract

Mesoporous silica nanoshell (MSN) coating has been demonstrated as a versatile surface modification strategy for various kinds of inorganic functional nanoparticles, such as gold nanorods (GNRs), to achieve not only improved nanoparticle stability but also concomitant drug loading capability. However, limited drug loading capacity and low tumor accumulation rate in vivo are two major challenges for the biomedical applications of MSN-coated GNRs (GNR@MSN). In this study, by coating uniformly sized GNRs with MSN in an oil-water biphase reaction system, we have successfully synthesized a new bacteria-like GNR@MSN (i.e., bGNR@MSN) with a significantly enlarged pore size (4-8 nm) and surface area (470 m²/g). After PEGylation and highly efficient loading of doxorubicin (DOX, 40.9%, w/w), bGNR@MSN were used for positron emission tomography (PET, via facile and chelator-free ⁸⁹Zr-labeling) and photoacoustic imaging-guided chemo-photothermal cancer therapy in vivo. PET imaging showed that ⁸⁹Zr-labeled bGNR@MSN(DOX)-PEG can passively target to the 4T1 murine breast cancer-bearing mice with high efficiency (∼10 %ID/g), based on enhanced permeability and retention effect. Significantly enhanced chemo-photothermal combination therapy was also achieved due to excellent photothermal effect and near-infrared-light-triggered drug release by bGNR@MSN(DOX)-PEG at the tumor site. The promising results indicate great potential of bGNR@MSN-PEG nanoplatforms for future cancer diagnosis and therapy.

Keywords: Cancer; Chemo-photothermal therapy; Gold nanorods; Mesoporous silica nanoparticles; Positron emission tomography; Theranostics.

Figure 1

The scheme showing the synthetic strategy of bGNR@MSN(DOX)-PEG nanoplatforms and possible mechanism of NIR-triggered DOX release.

Figure 2

Morphology and structure of GNRs and bGNR@MSN. (a) TEM image of GNRs; (b) and (c) TEM images of bGNR@MSN with 12 h silica coating time. The red arrows indicate the size (~6.7 nm) of mesopores; (d) TEM image of bGNR@MSN with 24 h silica coating time.

Figure 3

(a) Nitrogen adsorption and desorption isotherms and pore size distributions (inset) of bGNR@MSN. (b) UV–vis absorption spectra and photographs (inset, from left to right) of GNRs, bGNR@MSN and bGNR@MSN(DOX). (c) Hydrodynamic size analysis of bGNR@MSN (black line) and bGNR@MSN-PEG (red line) by DLS. (d) Surface zeta potential of GNRs, bGNR@MSN, bGNR@MSN-NH₂, bGNR@MSN-PEG.

Figure 4

(a) Photothermal heating curves of GNRs with different concentrations with the 808 nm NIR laser irradiation at a power density of 0.25 W/cm². The MSNs (3mg/mL) and water were used as control groups. (b) The DOX loading efficiency (inset) and NIR-triggered DOX release under different pH conditions mediated by bGNR@MSN-PEG. (c) Cell viability of 4T1 cells under different in vitro treatment conditions: chemotherapy by DOX (grey) and bGNR@MSN(DOX) (blue); photothermal therapy by bGNR@MSN with NIR laser (0.5 W/cm² for 5min, green); chemo-photothermal therapy by bGNR@MSN(DOX) with NIR laser (0.5 W/cm² for 5min, red). (d) Optical microscopy images of trypan blue-stained cells after incubation with concentration of bGNR@MSN (i: 0 μg/mL; ii: 10 μg/mL; iii: 40 μg/mL; iv: 80 μg/mL) and exposure to the NIR laser (0.5 W/cm² for 5min). Scale bar: 50 μm.

Figure 5

(a) Autoradiographic images of TLC plates indicating chelator-free radiolabeling of ⁸⁹Zr-bGNR@MSN(DOX)-PEG at different time points. (b) Serial PET images of 4T1 tumor-bearing mice at different time points post-injection of ⁸⁹Zr-bGNR@MSN(DOX)-PEG. Tumors are indicated by yellow arrowheads. (c) Time-radioactivity curves of 4T1 tumor, blood, liver and muscle after intravenous injection of ⁸⁹Zr-bGNR@MSN(DOX)-PEG. (d) Biodistribution studies in 4T1 tumor bearing mice at 24 h post-injection of ⁸⁹Zr-bGNR@MSN(DOX)-PEG. All data represent 4 mice per group.

Figure 6

(a) In vivo PA imaging of 4T1 tumor-bearing mice at before and 24 h post-i.v. injection of bGNR@MSN(DOX)-PEG. (b) Quantitative ROI analysis results of photoacoustic signal within the yellow circles in PA images. (c) Photothermal images of 4T1 tumor-bearing mice under 808 nm NIR laser irradiation after 24 h of i.v. injection of PBS (150 μL) or bGNR@MSN(DOX)-PEG (150 μL, 2 mg/mL) taken by a thermal camera.

Figure 7

(a) 4T1 tumor growth profiles after different treatments (n=4). (b) Weight of dissected 4T1 tumors at Day 14 after different treatments (n=4, *P<0.05, **P<0.01, ***P<0.001). (c) Representative photographs of mice before various treatments (Day 1) and after the treatments (Day 2, Day 7, Day 14 and Day 21). The unit of the ruler is inch. (d) H&E staining of tumor sections 24 h after different treatments. Scale bar: 100 μm.