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. 2015 Sep 24:5:14258.
doi: 10.1038/srep14258.

NIR-driven Smart Theranostic Nanomedicine for On-demand Drug Release and Synergistic Antitumour Therapy

Pengfei Zhao  1   2 , Mingbin Zheng  1   3 , Zhenyu Luo  1   2 , Ping Gong  1 , Guanhui Gao  1 , Zonghai Sheng  1 , Cuifang Zheng  1 , Yifan Ma  1 , Lintao Cai  1
Affiliations

NIR-driven Smart Theranostic Nanomedicine for On-demand Drug Release and Synergistic Antitumour Therapy

Pengfei Zhao et al. Sci Rep. .

Abstract

Smart nanoparticles (NPs) that respond to external and internal stimulations have been developing to achieve optimal drug release in tumour. However, applying these smart NPs to attain high antitumour performance is hampered by limited drug carriers and inefficient spatiotemporal control. Here we report a noninvasive NIR-driven, temperature-sensitive DI-TSL (DOX/ICG-loaded temperature sensitive liposomes) co-encapsulating doxorubicin (DOX) and indocyanine green (ICG). This theranostic system applies thermo-responsive lipid to controllably release drug, utilizes the fluorescence (FL) of DOX/ICG to real-time trace the distribution of NPs, and employs DOX/ICG to treat cancer by chemo/photothermal therapy. DI-TSL exhibits uniform size distribution, excellent FL/size stability, enhanced response to NIR-laser, and 3 times increased drug release through laser irradiation. After endocytosis by MCF-7 breast adenocarcinoma cells, DI-TSL in cellular endosomes can cause hyperthermia through laser irradiation, then endosomes are disrupted and DI-TSL 'opens' to release DOX simultaneously for increased cytotoxicity. Furthermore, DI-TSL shows laser-controlled release of DOX in tumour, enhanced ICG and DOX retention by 7 times and 4 times compared with free drugs. Thermo-sensitive DI-TSL manifests high efficiency to promote cell apoptosis, and completely eradicate tumour without side-effect. DI-TSL may provide a smart strategy to release drugs on demand for combinatorial cancer therapy.

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Figures

Figure 1
Figure 1. A scheme showing the mechanism of remote NIR-triggered DOX release and further cytotoxicity in tumour.
The DI-TSL are treated with remote NIR laser (808 nm, 0.5 W/cm2, 5 min) after the injection, and kill cancer cells in different ways: 1) Intracellular DI-TSL escape from cell endosomes by NIR laser induced endosomal disruption, and DOX release from ‘opened’ DI-TSL and enter the cytosol after cellular uptake. 2) Extracellular DI-TSL immediate released DOX through smash, burst, and swell, and DOX diffuses into the tumour along a high concentration gradient, attacking tumour cells.
Figure 2
Figure 2. Characterization of DI-TSL and NIR laser-driven DOX release.
(a) Size distribution, TEM images and schematic representation of DI-TSL (Scale bar = 50 nm). (b) Size distribution and TEM images of DI-TSL after laser irradiation (808 nm, 1 W/cm2, 5 min), and schemes showing smash, burst, and swell of DI-TSL (Scale bar = 100 nm). (c) Size stability of DI-TSL in ultrapure water, PBS, 10% plasma/Heparin in PBS, and FBS within 5 d. (d) ICG FL stability of free ICG in ultrapure water, and ICG FL stability of DI-TSL in ultrapure water, PBS, and FBS within 5 d. (e) Temperature rising profiles of PBS, free ICG, free DOX, ICG-TSL and DI-TSL under continuous laser irradiation. (f) DOX release curves of DI-TSL at 37 °C or 43 °C water bath (WB). (g) DOX release profiles of DI-TSL in 37 °C without or with laser irradiation (808 nm, 1 W/cm2, 5 min). The red arrows indicated the time point of laser irradiation. (h) Evaluation of DOX signals in DOX, DOX + laser, DI-TSL and DI-TSL + laser groups, and ICG signals in ICG, ICG + laser, DI-TSL and DI-TSL + laser groups (n = 3). **P < 0.01.
Figure 3
Figure 3. NIR laser-driven drug release of DI-TSL in MCF-7 cells.
(a) CLSM images of MCF-7 cells treated with ICG-TSL without (top) or with (bottom) NIR laser irradiation (808 nm, 1 W/cm2, 5 min). Nuclei were stained with Hoechst 33258 (blue), endo/lysosomes were stained with Lysotracker (green), and red was the FL of ICG in the ICG-TSL. (b) Flow cytometry histogram profile of DOX FL in MCF-7 cells treated with DOX, DOX + laser, DI-TSL, or DI-TSL + laser. (c) Mean FL intensity analysis for flow cytometry of MCF-7 cells after incubation with DOX, DOX + laser, DI-TSL, or DI-TSL + laser (n = 3). **P < 0.01. Scale bar = 20 μm.
Figure 4
Figure 4. NIR laser-driven drug release for increased cellular cytotoxicity.
(a) Cell viability of MCF-7 cells treated with ICG-TSL of various ICG concentrations and the same NIR laser irradiation (808 nm, 1 W/cm2, 5 min) (n = 3). (b) Cell viability of MCF-7 cells treated with free DOX or DI-TSL containing various DOX concentrations without and with NIR laser irradiation (808 nm, 1 W/cm2, 5 min). The DI-TSL or free DOX were immediately washed away after incubation in the experiments. (n = 3). **P < 0.01. (c) Flow cytometry analysis of MCF-7 cells after incubation with free DOX, DOX + laser, DI-TSL, or DI-TSL + laser. Double stained cells were considered as late apoptotic/necrotic cells.
Figure 5
Figure 5. In vivo FL imaging of DOX or ICG in nude mice bearing MCF-7 tumours after intratumoural injection of DOX + ICG, or DI-TSL.
(a) Time-lapse ICG FL in nude mice within 48 h after injection of DOX + ICG or DI-TSL (tumours were marked with white-dotted circles). (b) Quantified total FL intensities of ICG at different time points (n = 3). **P < 0.01. (c) Time-lapse DOX FL in vivo within 48 h after injection of DOX + ICG or DI-TSL (tumours were marked with white-dotted circles). (d) Quantified total FL intensities of DOX at different time points (n = 3).
Figure 6
Figure 6. NIR laser-induced temperature increase in MCF-7 tumour tissues, and in vivo imaging of nude mice bearing MCF-7 tumours showing laser-driven DOX release.
(a) Temperature increasing profiles of laser-irradiated (808 nm, 0.5 W/cm2, 5 min) tumour tissues 16 h after injection of PBS, DOX, ICG-TSL, or DI-TSL, and indicated infrared thermo-graphic maps of mice after 5 min irradiation. (b) Time-lapse FL images of DOX and ICG after intratumoural injection of DI-TSL + laser. The laser was treated 16 h after the injection (tumours were marked with white-dotted circles). (c) Semi-quantitative FL intensities of DOX and ICG around the tumour at the time points as indicated.
Figure 7
Figure 7. In vivo apoptosis imaging showing the accumulation and retention of apoptosis marker Annexin-Vivo 750 in tumours, and synergistic strategies of DI-TSL for tumour therapy.
(a) In vivo apoptosis images 24 h after Annexin-Vivo 750 injection for different treatment as indicated (tumours were marked with white-dotted circle), showing apoptotic tumour cells in the tumour induced by different treatments. (b) Quantitative FL intensities of Annexin-Vivo 750 around the tumour (n = 3). **P < 0.01, compared with DI-TSL + laser. (c) MCF-7 tumour growth profiles of nude mice in different groups after treatment (n = 5). **P < 0.01. (d) Weight profiles of MCF-7 bearing mice after treatment as indicated.
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