NIR-Mediated drug release and tumor theranostics using melanin-loaded liposomes


Abstract

Background: Heat generation in a drug delivery carrier by exposure to near-infrared (NIR) light with excellent tissue transmittance is an effective strategy for drug release and tumor therapy. Because liposomes have amphiphilic properties, they are useful as drug carriers. Liposomes are also very suitable for drug delivery strategies using heat generation by NIR laser because lipid bilayers are easily broken by heat. Thermally generated bubbles from liposomes not only induce drug release, but also enable ultrasound imaging.

Methods: Melanin, perfluorohexane (PFH), and 5-fluorouracil (5-FU)-loaded liposomes (melanin@PFH@5-FU-liposomes) that can generate heat and bubble by NIR laser irradiation were prepared by a thin film method. Conversion of light to heat and bubble generation of melanin@PFH@5-FU-liposomes were evaluated using an infrared (IR) thermal imaging camera and an ultrasound imaging system both in vitro and in vivo. To investigate tumor therapeutic effect, NIR laser of 808 nm was used to irradiate tumor site for 10 min after injecting melanin@PFH@5-FU-liposome into tail veins of CT26-bearing mice.

Results: Melanin@PFH@5-FU-liposomes showed a spherical shape with a size of 209.6 ± 4.3 nm. Upon NIR laser irradiation, melanin@PFH@5-FU-liposomes exhibited effective temperature increase both in vitro and in vivo. In this regard, temperature increase caused a phase transition of PFH to induce bubble generation dramatically, resulting in effective drug release behavior and ultrasound imaging. The temperature of the tumor site was increased to 52 t and contrast was greatly enhanced during ultrasound imaging due to the generation of bubble. More importantly, tumor growth was effectively inhibited by injection of melanin@PFH@5-FU-liposomes with laser irradiation.

Conclusions: Based on intrinsic photothermal properties of melanin and phase transition properties of PFH, melanin@PFH@5-FU-liposomes exhibited effective heat and bubble generation upon NIR laser irradiation. The elevated temperature induced bubble generation, resulting in contrast enhancement of ultrasound imaging. Melanin@PFH@5-FU-liposomes under NIR laser irradiation induced the death of cancer cells, thereby effectively inhibiting tumor growth. These results suggest that melanin@PFH@5-FU-liposomes can be utilized as a promising agent for photothermal tumor therapy and ultrasound imaging.

Keywords: Liposome; Melanin; Perfluorohexane; Photothermal cancer therapy; Ultrasound imaging.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Schematic illustration of (A) the preparation of melanin@PFH@5-FU-liposome and (B) when melanin@PFH@5-FU-liposome was irradiated with an 808 nm NIR laser at a power density of 1.5 W/cm2, the photothermal effect of melanin induced vaporization of PFH and accelerates 5-FU release
Fig. 2
Fig. 2
(A) Size distribution of melanin@5-FU-liposomes, (B) Mean diameter of PFH emulsions, (C) Size distribution and (D) TEM image of melanin@PFH@5-FU-liposomes
Fig. 3
Fig. 3
Photothermal conversion ability of melanin@PFH@5-FU-liposomes. (A) IR thermal imaging camera images and (B) temperature change curve of melanin@PFH@5-FU-liposomes for 10 min at 1.5 W/cm2 under NIR 808 nm laser irradiation
Fig. 4
Fig. 4
Evaluation of bubble generation ability. (A) Photograph, (B) ultrasound image, and (C) gray scale intensity of bubbles generated in melanin@PFH@5-FU-liposomes by 808 nm NIR laser. White arrows within the ultrasound image indicate bubble generation
Fig. 5
Fig. 5
NIR-triggered 5-FU release behavior from melanin@PFH@5-FU-liposomes. (A) Release profile of 5-FU from melanin@PFH@5-FU-liposomes with and without PFH and laser irradiation, (B) Release profile of 5-FU by repeated laser irradiation
Fig. 6
Fig. 6
In vitro cytotoxicity study. (A) Cell viability of HaCaT and CT26 cells treated with melanin@PFH@5-FU-liposomes at various amount and (B) Cell viability of CT26 cells treated with melanin@PFH@5-FU-liposomes for 10 min at 1.5 W/cm2 under NIR 808 nm laser irradiation
Fig. 7
Fig. 7
In vivo animal study for heat and bubble generation in tumor tissues. (A) IR thermal images and (B) ultrasound images of tumor tissues in CT26-bearing mice before and after laser irradiation at 1 h, 4 h, and 12 h after intravenous injection of melanin@PFH@5-FU-liposomes
Fig. 8
Fig. 8
In vivo photothermal tumor therapeutic effects of melanin@PFH@5-FU-liposomes. (A) Tumor growth and (B) body weight changes of CT26-bearing mice after injection of melanin@PFH@5-FU-liposomes without or with laser irradiation for a period of 16 days
Fig. 9
Fig. 9
In vivo photothermal tumor therapeutic effects. (A) Photographs of CT26-bearing mice and (B) photo images of H&E stained tumor tissues at 16 days post treatment of laser irradiation following injection of melanin@PFH@5-FU-liposomes
Fig. 10
Fig. 10
Photo images of H&E stained tissues (heart, kidney, liver, lung, and spleen) collected from mice of different groups
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