New application of phthalocyanine molecules: from photodynamic therapy to photothermal therapy by means of structural regulation rather than formation of aggregates

Abstract

Phthalocyanine (Pc) molecules exhibit high extinction coefficients in near-infrared region, rendering them well-suited for phototherapies, but most of their applications are limited to the field of photodynamic therapy (PDT). Herein, for the first time, we illustrate that Pc molecules can be endowed with excellent photothermal properties by means of structural regulation rather than formation of aggregates. Three representative Pc derivatives show efficient activities of photothermal therapy (PTT) against human hepatocellular carcinoma cells. Among them, copper phthalocyanine (PcC1) exhibits a high in vivo PTT efficacy against mice bearing S180 tumors. The unique investigation in this article should light up a perspective of Pc's new applications for PTT, which enable to make up the inherent defects of PDT.

Fig. 1. (a) Chemical structures of PcA1 and PcA2. Only the major C_4h isomers are shown for tetra-substituted Pcs, which likely present the other isomers. (b) Electronic absorption and (c) fluorescence spectra (excited at 610 nm) of PcA1 and PcA2 (both at 4 μM) in DMF. Temperature variation profiles of (d) PcA1 and (e) PcA2 (both at 10 μM) in water with 0.1% CEL after being exposed to different laser irradiations (630 nm, 685 nm, and 730 nm, power densities are controlled at 1.0 W cm^–2).

Fig. 2. (a) Cytotoxic effect of PcA1 and PcA2 (both at 10 μM) on HepG2 cells in the presence and absence of laser irradiation (730 nm, 1.0 W cm^–2, 10 min). w/: with. w/o: without. Ctrl: control. (b) Temperature profiles of HepG2 cells induced by PcA1 and PcA2 under laser irradiation. Non-treated cells with laser were used as the control. (c) Cytotoxic effect of PcA1 and PcA2 on HepG2 cells after controlling the temperature of cells at less than 30 °C using an ice-bath during laser treatment. (d) ROS levels in HepG2 cells induced by PcA1 and PcA2. Scale bars = 50 μm.

Fig. 3. (a) Chemical structures of PcB1 and PcB2. (b) Cytotoxic effect of PcB1 on HepG2 cells with and without laser irradiation. PcB1/ice and Ctrl/ice mean controlling the temperature of cells at below 30 °C via an ice-bath during laser treatment. (c) ROS levels in HepG2 cells induced by PcB1 under laser irradiation. Scale bars = 75 μm. (d) Temperature variation profile of HepG2 cells incubated with PcB1 (5 μM) and exposed to the laser irradiation (730 nm, 1.0 W cm^–2). Non-treated cells exposed to the laser were used as the control.

Fig. 4. (a) Chemical structures of PcC1, PcC2, and PcC3. Only the major C_4h isomers were shown for tetra-substituted Pcs, which likely present the other isomers. (b) Temperature variation profile of PcC1 and PcC3 (both at 10 μM) in water with 10% CEL after being exposed to 685 nm laser irradiation (1.0 W cm^–2). (c) Electronic absorption of PcC1 and PcC3 (both at 4 μM) in water with 10% CEL. (d) Cytotoxic effect of PcC1 and PcC2 (both at 5 μM) on HepG2 cells with and without laser irradiation (630 nm, 1.0 W cm^–2, 5 min). (e) Temperature profile of HepG2 cells induced by PcC1 and PcC2 under laser irradiation. Non-treated cells with laser irradiation were used as the control. (f) ROS levels in HepG2 cells transfected with PcC1 and PcC2 under laser irradiation. Scale bars = 75 μm.

Fig. 5. Chemical structures of PcD1 and PcD2. Only the major C_4h isomers were shown for tetra-substituted Pcs, which likely present the other isomers.

Fig. 6. Temperature variation of different molecular dyes (all at 10 μM) in water with 0.1% CEL after being exposed to laser irradiation (685 nm, 1.0 W cm^–2) for 10 min. Ctrl is only water with 0.1% CEL.

Fig. 7. In vivo PTT effect. (a) Thermal images of mice bearing S180 tumors treated with PcC1 (200 μM, 50 μL) under continuous laser irradiation (685 nm, 0.2 W cm^–2) for 10 min. (b) Temperature profile of tumor sites after treatments. (c) Tumor growth curves of the three groups of mice after treatments.