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. 2018 Jan 1;8(4):955-971.
doi: 10.7150/thno.22325. eCollection 2018.

All-in-One Theranostic Nanoplatform Based on Hollow MoSx for Photothermally-maneuvered Oxygen Self-enriched Photodynamic Therapy

Jinping Wang  1 , Li Liu  1 , Qing You  1 , Yilin Song  1 , Qi Sun  1 , Yidan Wang  1 , Yu Cheng  1 , Fengping Tan  1 , Nan Li  1
Affiliations

All-in-One Theranostic Nanoplatform Based on Hollow MoSx for Photothermally-maneuvered Oxygen Self-enriched Photodynamic Therapy

Jinping Wang et al. Theranostics. .

Abstract

Photodynamic therapy (PDT) kills cancer cells by converting tumor-dissolved oxygen into reactive singlet oxygen (1O2) using a photosensitizer under laser irradiation. However, pre-existing hypoxia in tumors and oxygen consumption during PDT can result in an inadequate oxygen supply, which in turn hampers PDT efficacy. Herein, an O2 self-sufficient nanotheranostic platform based on hollow MoSx nanoparticles (HMoSx) with oxygen-saturated perfluorohexane (O2@PFH) and surface-modified human serum albumin (HSA)/chloride aluminium phthalocyanine (AlPc) (O2@PFH@HMoSx-HSA/AlPc), has been designed for the imaging and oxygen self-enriched photodynamic therapy (Oxy-PDT) of cancer.

Methods: The in vitro anti-cancer activity and intracellular 1O2 generation performance of the nanoparticles were examined using 4T1 cells. We also evaluated the multimodal imaging capabilities and anti-tumor efficiency of the prepared nanoparticles in vivo using a 4T1 tumor-bearing nude mouse model.

Results: This nanoplatform could achieve the distinct in vivo fluorescence (FL)/photoacoustic (PA)/X-ray computed tomography (CT) triple-model imaging-guided photothermally-maneuvered Oxy-PDT. Interestingly, the fluorescence and Oxy-PDT properties of O2@PFH@HMoSx-HSA/AlPc were considerably quenched; however, photothermal activation by 670 nm laser irradiation induced a significant increase in temperature, which empowered the Oxy-PDT effect of the nanoparticles. In this study, O2@PFH@HMoSx-HSA/AlPc demonstrated a great potential to image and treat tumors both in vitro and in vivo, showing complete tumor-inhibition over 16 days after treatment in the 4T1 tumor model.

Conclusion: O2@PFH@HMoSx-HSA/AlPc is promising to be used as novel multifunctional theranostic nanoagent for triple-modal imaging as well as single wavelength NIR laser triggered PTT/Oxy-PDT synergistic therapy.

Keywords: Hollow structure; Oxygen self-enriched photodynamic therapy.; Photothermally maneuvered; Theranostic nanoagent; Triple-modal imaging.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Scheme 1
Scheme 1
Schematic illustration of O2@PFH@HMoSx-HSA/AlPc theranostic nanoagents for in vivo FL/PA/CT imaging and NIR laser triggered PTT/Oxy-PDT synergistic therapy of tumors.
Figure 1
Figure 1
(A) A scheme showing the synthesis and surface modification of HMoSx. (B) TEM images of the as-prepared HMoSx nanoparticles. (C) N2 adsorption/desorption isotherm and corresponding pore-size distribution curves (inset) of HMoSx nanoparticles. (D) Temperature elevation curves of aqueous solutions containing HMoSx-HSA with different concentrations under the irradiation of a 670 nm laser (1 W/cm2). (E) Photothermal images of HMoSx-HSA dispersion at different concentrations over a period of 6 min following exposure to NIR laser (670 nm, 1 W/cm2). (F-H) XPS spectrum of the as-prepared HMoSx nanoparticles: (F) survey spectra, and high-resolution of (G) Mo 3d and (H) S 2p.
Figure 2
Figure 2
(A) Schematic illustration of the AlPc and O2 release mechanism from O2@PFH@HMoSx-HSA/AlPc by sequential PTT/Oxy-PDT treatment. (B) HRTEM image of HMoSx-HSA/AlPc nanoparticles. The element maps shown the distribution of S (yellow), Mo (green), and Al (red). (C) UV-vis-NIR spectra and photographs (inset) of HMoSx-HSA/AlPc obtained at various AlPc loading concentrations after removal of excess free AlPc molecules. (D) UV-vis-NIR spectra and (E) Fluorescence spectra of free AlPc, HMoSx-HSA and HMoSx-HSA/AlPc in the aqueous solution. (F) In vitro release profiles of HMoSx-HSA/AlPc in the absence or presence of 670 nm laser irradiation. (G) O2 concentration change in different samples as indicated with or without NIR laser irradiation. (H) UV-vis-NIR spectra of mixture of O2@PFH@HMoSx-HSA/AlPc and DPBF exposure to 670 nm laser irradiation (1 W/cm2) for each time interval. (I) Singlet oxygen generation from different formulations in the presence of 670 nm laser.
Figure 3
Figure 3
(A) Cell viability assay of 4T1 cells treated with different samples with or without NIR laser in hypoxic and normoxic environments. (B) Cell viability assay of O2@PFH@HMoSx-HSA/AlPc plus NIR treated 4T1 cells in hypoxic and normoxic environments. (C) Cell viability assay of HMoSx-HSA/AlPc plus NIR treated cells in hypoxic and normoxic environments (D) Live-dead staining images of 4T1 cells treated with PBS, O2@PFH@HMoSx-HSA/AlPc, HMoSx-HSA+NIR, HMoSx-HSA/AlPc+NIR, or O2@PFH@HMoSx-HSA/AlPc+NIR, respectively, under a hypoxic condition. Scale bar: 500 μm. (E) Flow cytometry analysis of 4T1 cells after treatment with different samples under a hypoxic condition. Positive PI and Annexin V-Alexa Fluor 488 cells were defined as late apoptotic/necrotic cells.
Figure 4
Figure 4
ROS and hypoxia generation following incubation of the cells with nanoparticles and laser irradiation. Confocal images of the cells stained with ROS and hypoxia probes. Cell nuclei were stained by DAPI, scale bar: 20 μm.
Figure 5
Figure 5
(A) Fluorescence images of Balb/c nude mice at different time points after administration of free AlPc and HMoSx-HSA/AlPc; the bottom panel shows the ex vivo images examined at 24 h post-injection. (B) Photoacoustic intensity linearly fit to the concentration of HMoSx-HSA/AlPc aqueous solutions; inset: the corresponding PA images. (C) CT signal intensity linearly fit to the concentration of HMoSx-HSA/AlPc aqueous solutions; inset: the corresponding CT images. (D) Ultrasound (US) images and PA images of 4T1 tumor-bearing mice after being intravenously injected with HMoSx-HSA/AlPc at different time points. (E) In vivo CT images of tumors in mice before and after intratumor injection with HMoSx-HSA/AlPc. (F) The biodistribution of HMoSx-HSA/AlPc measured at 4, 8, 12 and 24 h post i.v. injection.
Figure 6
Figure 6
(A) Photothermal images of 4T1 tumor-bearing mice exposed to the NIR laser (670 nm, 1 W cm-2, 5 min) after intravenous injection with PBS and HMoSx-HSA/AlPc nanoparticles, respectively. (B) Photos of tumors collected from each group of the 4T1 tumor-bearing mice after various treatments. (C) Growth of 4T1 tumors in different groups of mice after treatment. The relative tumor volumes were normalized to their initial sizes. *P < 0.05, **P < 0.01. (D) Representative photos of mice 16 days after various treatments. (E) H&E-stained tumor slices collected from mice after treatment with different samples.
Figure 7
Figure 7
(A) Representative immunofluorescence images of tumor slices stained by the hypoxia-probe. The nuclei and hypoxic areas were stained with DAPI (blue), and anti-pimonidazole antibody (green), respectively. Scale bar: 200 μm. (B) Quantification of tumor hypoxia for different groups shown in (a). P values: *P < 0.05, **P < 0.01.
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