Abstract
We demonstrate here that Mn 2+-doped Prussian blue nanoparticles of ca. 55 nm loaded with doxorubicin may be used as efficient therapeutic agents for combined photothermal and chemo-therapy of cancer cells with a synergic effect under two photon irradiation. Photothermal therapy (PTT) is a promising strategy for the therapeutic treatment of tumours, which consists in "burning" cancer cells by laser irradiation at low energy wavelengths in the presence of an NIR photo-adsorbing agent. 1,2 In comparison to conventional cancer treatments, it offers several advantages, such as high specicity, deep penetration, lower tumour recurrence, minimal invasiveness and low toxicity to normal tissues. 3,4 Due to the fact that the treatment efficiency highly depends on the outstanding capacity of the PTT agent to convert light into heat, numerous materials have recently been reported , such as organic dyes 5,6 or various inorganic nano-objects, including metallic nanostructures (Au nanorods or nanoshells, Ag, Pd), carbon based materials (nanotubes, spheres, graphene oxide), transition metal dichalcogenide nanoparticles, metal oxide nano-objects or up-conversion nanocrystals. 7-16 Among these, Prussian blue (PB) nano-objects have been developed as interesting PTT agents since they benet from many advantages, such as: (i) a controlled size ranging from a few to hundreds of nanometers, (ii) easy surface functionali-zation, (iii) excellent absorption properties in the NIR spectral domain due to an Fe 2+ to Fe 3+ intervalence charge transfer band ranging from 650 to 900 nm, (iv) high stability under irradiation , and (v) the fact that bulk PB is validated by the FDA under the brand name Radiogardase® as an antidote for human beings exposed to radioactive Cs +. 17 It has been shown in vitro that PB nanoparticles upon single photon excitation (SPE) (at 808 nm) can convert the laser irradiation into thermal energy contributing to an important temperature increase. 18,19 Their efficiency depends on the nanoparticles' concentration, their chemical composition, the laser power, the mode of irradiation and the irradiation time. Moreover, it has been demonstrated that nano-sized PB presents a higher efficiency in comparison with Au nanorods and a better photothermal stability than organic dyes used as conventional photothermal agents. 19,20 PTT effect of PB nanoparticles has also been demonstrated in vivo through their intra-tumoral injection that causes signicant tumour necrosis 24 h aer NIR irradiation in comparison with non-treated mice. 18 Nevertheless, the complete eradication of cancer cells using solely PTT treatment is rather difficult due to the suboptimal laser energy in deep tissues related to light scattering and absorption effects, a limited light penetration and the insufficient tumour target specicity of PTT agents. Some of these drawbacks may be circumvented using two photon excitation (TPE), which permits to increase the penetration depth and laser focalization allowing selective and efficient destruction of the targeted cancer cells with less damage to healthy tissues. 21-23 In this line of thought, we reported recently Mn 2+-doped PB nanoparticles of ca. 70 nm as efficient multifunctional PTT agents permitting to eradicate 97% of cancer cells 24 h aer irradiation under TPE during 10 min, which may also be followed by Magnetic Resonance Imaging (MRI). 24 However, the comparison between the efficiency of the single and two-photon excitations on the same nano-objects has never been investigated.