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. 2014 Mar;31(3):554-65.
doi: 10.1007/s11095-013-1180-7.

Near-infrared light-sensitive liposomes for the enhanced photothermal tumor treatment by the combination with chemotherapy

Jian You, Peizun Zhang, Fuqiang Hu, Yongzhong Du, Hong Yuan, Jiang Zhu, Zuhua Wang, Jialin Zhou, Chun Li

Near-infrared light-sensitive liposomes for the enhanced photothermal tumor treatment by the combination with chemotherapy

Jian You et al. Pharm Res. 2014 Mar.

Abstract

Purpose: To develop a near-infrared (NIR) light-sensitive liposome, which contains hollow gold nanospheres (HAuNS) and doxorubicin (DOX), and evaluate their potential utility for enhancing antitumor activity and controlling drug release.

Methods: The liposomes (DOX&HAuNS-TSL) were designed based on a thermal sensitive liposome (TSL) formulation, and hydrophobically modified HAuNS were attached onto the membrane of the liposomes. The behavior of DOX release from the liposomes was investigated by the dialysis, diffusion in agarose gel and cellular uptake of the drug. The biodistribution of DOX&HAuNS-TSL was assessed by i.v. injection in tumor-bearing nude mice. Antitumor efficacy was evaluated both histologically using excised tissue and intuitively by measuring the tumor size and weight.

Results: Rapid and repetitive DOX release from the liposomes (DOX&HAuNS-TSL), could be readily achieved upon NIR laser irradiation. The treatment of tumor cells with DOX&HAuNS-TSL followed by NIR laser irradiation showed significantly greater cytotoxicity than the treatment with DOX&HAuNS-TSL alone, DOX-TSL alone (chemotherapy alone) and HAuNS-TSL plus NIR laser irradiation (Photothermal ablation, PTA, alone). In vivo antitumor study indicated that the combination of simultaneous photothermal and chemotherapeutic effect mediated by DOX&HAuNS-TSL plus NIR laser presented a significantly higher antitumor efficacy than the PTA alone mediated by HAuNS-TSL plus NIR laser irradiation.

Conclusions: Our study could be as the valuable reference and direction for the clinical application of PTA in tumor therapy.

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Figures

Figure 1
Figure 1
(A) Hypothetical structure of DOX&HAuNS-TSL and the triggered drug release under NIR laser irradiation. (B) The absorption spectra of HAuNS and OMPHAuNS, which showed that the plasma resonance peaks for both HAuNS and OMP-HAuNS were in the NIR region (~800 nm). (C) DSC peak maximums and the phase transition temperature (Tm) of blank TSL and DOX&HAuNS-TSL. (D) TME image of HAuNS (a), blank TSL (b) and DOX/HAuNS-TSL (c). The samples were stained by phosphotungstic acid before the observation. The liposomes presented to be white spheres, and OMP-HAuNS (the write arrow) was mainly attached on the surface (e.g. membrane) of the liposomes.
Figure 2
Figure 2
(A) NIR-light-triggered release of DOX from DOX&HAuNS-TSL by NIR laser over a period of 5 min at the output power of 3W (triangle) or 6W (diamond) and DOX-TSL by NIR laser over a period of 5 min at the output power of 3W (cross). DOX release from DOX-TSL (solid diamond) and DOX&HAuNS-TSL (traverse) without NIR laser irradiation was as controls. Red arrows indicate the beginning time points of NIR laser irradiation. (B) The triggered-release of DOX from DOX&HAuNS-TSL mediated by NIR laser irradiation (3W for 20 min), which was observed by in vivo imaging system. Yellow circle indicated the location of the hole in the agarose gel, where the sample was put. Red fluorescent signal out of the yellow circle represented the released DOX molecule from the micelles. (C) Cell uptake of DOX&HAuNS-TSL and DOX-TSL followed by NIR laser irradiation. The released DOX from DOX&HAuNS-TSL was located in BEL-7402 cell nuclei.
Figure 3
Figure 3
(A) BEL-7402 cell viability as a function of HAuNS or DOX concentration. (A) Cells were treated with DOX&HAuNS-TSL plus NIR laser (diamond), DOX&HAuNS-TSL alone (cross), DOX-TSL alone (solid triangle) and free DOX (solid square). (B) Cells were treated with DOX-TSL with (square) or without (solid triangle) NIR laser irradiation. (C) Cells were treated with DOX&HAuNS-TSL plus NIR laser (diamond) or HAuNS-TSL plus NIR laser (triangle). (D) Cells were treated with DOX&HAuNS-TSL plus NIR laser (diamond) or DOX-TSL plus NIR laser (square).
Figure 4
Figure 4
(A) The in vivo imaging of the mice, bearing BEL-7402, at different time after iv injection of DiR marked DOX&HAuNS-TSL. (B) The fluorescent imaging of various tissues at 6, 24, and 48h after the iv injection of the liposomes. (C) The accumulation of DOX&HAuNS-TSL in various tissues was calculated as %ID/g (the percentage of the injected dose per gram of tissue). The fluorescent intensity, responding the amount of the liposomes, was read by the imaging system. Inset: The accumulation of DOX&HAuNS-TSL in tumors at 6, 24, and 48 h.
Figure 5
Figure 5
Antitumor activity of various treatments against BEL-7402 tumors. (A) tumor growth curves for mice treated with saline plus NIR laser (n=6), HAuNS-TSL plus NIR laser (n=6), DOX-TSL alone (n=6), and DOX&HAuNS-TSL plus NIR laser (n=6). All mice were injected for total three times, and all tumors in mice, except the group of DOX-TSL, were irradiated by NIR laser (2.0 W/cm2 for 5 minutes) for total three times at 24h after each injection. (B) Photographs of tumors and (C) average tumor weights in different treatment groups. Tumors were removed on day 22 for all groups except the saline plus laser group, in which tumors were removed on day 12. (D) Representative photographs of tumors in DOX&HAuNS-TSL plus NIR laser and HAuNS-TSL plus NIR laser before and after the treatment.
Figure 6
Figure 6
Representative photomicrographs of hematoxylin and eosin (H&E)–stained slides from scar tissue (A, left) and residual tumor (A, right) from the mice treated with DOX&HAuNS-TSL plus NIR laser. Representative photomicrographs of H&E– stained slides from residual tumor (B, left) and scar tissue (B, right) from the mice treated with HAuNS-TSL plus NIR laser. (C) Representative photomicrographs of H&E–stained slides of the tumor in saline group.
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