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. 2017 Apr 10;7(7):1781-1794.
doi: 10.7150/thno.18437. eCollection 2017.

"VSports" Dual-Responsive Molecular Probe for Tumor Targeted Imaging and Photodynamic Therapy

Xiaoqing Meng  1   2 , Yueting Yang  1 , Lihua Zhou  1   3 , Li Zhang  1 , Yalin Lv  1 , Sanpeng Li  1   2 , Yayun Wu  1 , Mingbin Zheng  1   4   5 , Wenjun Li  1 , Guanhui Gao  1 , Guanjun Deng  1   2 , Tao Jiang  1 , Dapeng Ni  1   2 , Ping Gong  1   4   5 , Lintao Cai  1
Affiliations

Dual-Responsive Molecular Probe for Tumor Targeted Imaging and Photodynamic Therapy

Xiaoqing Meng et al. Theranostics. .

Abstract

The precision oncology significantly relies on the development of multifunctional agents to integrate tumor targeting, imaging and therapeutics VSports手机版. In this study, a first small-molecule theranostic probe, RhoSSCy is constructed by conjugating 5'-carboxyrhodamines (Rho) and heptamethine cyanine IR765 (Cy) using a reducible disulfide linker and pH tunable amino-group to realize thiols/pH dual sensing. In vitro experiments verify that RhoSSCy is highly sensitive for quantitative analysis and imaging intracellular pH gradient and biothiols. Furthermore, RhoSSCy shows superb tumor targeted dual-modal imaging via near-infrared fluorescence (NIRF) and photoacoustic (PA). Importantly, RhoSSCy also induces strongly reactive oxygen species for tumor photodynamic therapy (PDT) with robust antitumor activity both in vitro and in vivo. Such versatile small-molecule theranostic probe may be promising for tumor targeted imaging and precision therapy. .

Keywords: Dual-stimuli sensing; NIRF/PA imaging; Photodynamic therapy. ; Small-molecule theranostic probe; tumor targeting. V体育安卓版.

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Conflict of interest statement

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

Figures

Scheme 1
Scheme 1
Illustration of synthesis and functions of RhoSSCy. (A) Synthetic scheme of probe RhoSSCy. (B) Illustration of the theranostic strategy of RhoSSCy.
Figure 1
Figure 1
Optical properties of RhoSSCy. (A) UV-Vis absorption spectra of RhoSSCy in DMSO. (B) Fluorescence spectra of RhoSSCy in 20 mM PBS buffer (containing 1% DMF) upon excitation at 480 nm and 640 nm.
Scheme 2
Scheme 2
The proposed response mechanisms of RhoSSCy to thiols and pH.
Figure 2
Figure 2
Fluorescence responses of RhoSSCy to biothiols and pH in vitro. (A) Emission spectra of RhoSSCy under increasing GSH levels (0, 1, 2, 3, 4, 5, 10, 50 and 500 μM). (B) Fluorescence-based GSH titration curve (λex at 480 nm, λem at 580 nm). (C) The linear calibration plot of fluorescent intensity (λex at 480 nm, λem at 580 nm) and its corresponding GSH concentration. (D) Emission spectra of RhoSSCy under decreasing pH value. (E) Fluorescence-based pH titration curve (λex at 640 nm, λem at 765 nm). (F) The pH reversibility study of RhoSSCy between pH 5 and 10.
Figure 3
Figure 3
Fluorescence response of RhoSSCy to biothiols and pH in cells. (A) Fluorescent images of MCF-7 cells obtained in the presence and absence of GSH in buffer solution with different pH (6.0, 7.4 and 8.0). Bars, 25 μm. (B) Fluorescent intensity of the MCF-7 cells without GSH obtained from statistical analysis of the CLSM images in (A). (C) Fluorescent intensity of the MCF-7 cells with GSH obtained from statistical analysis of the CLSM images in (A). (D) Flow cytometry analysis of pH response of RhoSSCy to MCF-7 cells. (E) The linear calibration plot of fluorescent intensity and its corresponding pH value based on the flow cytometry analysis in (D).
Figure 4
Figure 4
Cellular targeting and uptake of RhoSSCy. (A) Fluorescence confocal microscope images of normal cells (293-T cells) and tumor cells (A549 cells and MCF-7 cells) treated with RhoSSCy. Bars, 50 μm. (B) The accumulation of RhoSSCy in normal cells and tumor cells by using flow cytometry analysis.
Figure 5
Figure 5
Tumor targeting NIRF imaging based on RhoSSCy. (A) NIRF imagings of tumor (white circle) in living mice at different time intervals after injection of RhoSSCy. (B) Semiquantitative fluorescent intensity (Fluo. Int.) of the tumor at indicated time-points. (C) Ex vivo NIRF imaging of dissected tumor tissue after tail vein injection of RhoSSCy. (D) Semiquantitative biodistribution of RhoSSCy in tumor determined by the averaged fluorescent intensity. (E) Ex vivo NIRF imaging of dissected tumor and organs come from mice in blank group (Control) and mice injected with RhoSSCy after 15 h postinjection. (F) Semiquantitative fluorescent intensity of dissected tumor and organs at indicated time-points. *P < 0.05, **P<0.01.
Figure 6
Figure 6
PA imaging based on RhoSSCy. (A) The linear relationship between PA intensity (P. A. Int.) and RhoSSCy concentration (Inset: PA images with different RhoSSCy concentrations). (B) The photo of nude mouse bearing MCF-7 tumor. White dash line indicated the position of PA imaging. (C) The corresponding ex vivo cryoslice of PA imaging, which come from the software of whole body MSOT system. (D) PA imaging of a tumor bearing nude mouse. Pink circle indicated the location of tumor. (E) Semiquantitative fluorescent intensity of the tumor at indicated time points.
Figure 7
Figure 7
Photodynamic therapy using RhoSSCy in vitro. (A) The linear relationship between fluorescent intensity of DCF, which correlated to the release of ROS, and RhoSSCy concentration. (B) Fluorescent images of MCF-7 cells under the different conditions. Viable cells were stained green with calcein-AM. Bars, 25 μm. (C) Cell survivals of MCF-7 after PDT treatment using RhoSSCy with different concentration.
Figure 8
Figure 8
In vivo PDT therapy using RhoSSCy. (A) The growth curve of MCF-7 xenograft tumors within 15 days in different groups (n = 6). *p < 0.05, **p < 0.01. (B) Survival rate of mice bearing MCF-7 tumors of disparate groups within 30 d after corresponding treatments. (C) Body weight change of mice under different conditions. (D) H&E stained images of sliced major organs and tumors collected from different groups.
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