RESEARCH

Combined Nano-Therapies

To combat cancer with early detection and treatment, new strategies have emerged thanks to the development of nanomaterials exhibiting new properties stemming from the reduction of their size. One major mission of these nanomaterials is the promise to bring nano-physical therapies on target tissues, with precise temporal and spatial control of the therapeutic action, together with low side effects. These nano-physical therapies are mediated by nanoparticles cores that can be excited by a remote energy source (light, magnetism or radiation), and generate in turn a physical effect, such as heat, force, or field. In this context, we have been investigating the efficiency of magnetic hyperthermia, photothermia, and photodynamic therapy for cancer therapies, with the final aim to combine one with the other, for enhanced treatments at low nanoparticles doses.

We first chose to tackle the combined nano-therapies concept by using liposomes (produced by Christine Ménager’s team, PHENIX, UMR8234, UPMC) as carriers to convey both magnetic nanoparticles and photosensitizers (Figure 1, Di Corato et al. ACS nano 2015). The design method allowed liposomes to feature an unprecedented magnetic nanoparticle cargo amount. Additionally, lipid bilayer shell constituted a well-suited delivery environment for enclosing the hydrophobic photosensitizer by preventing aggregation. The double cargo translated into double functionality: the optimized hybrid liposomes generated cytotoxic singlet oxygen under 650-nm excitation and produced heat under alternate magnetic field stimulation, coupling photodynamic therapy to magnetic hyperthermia, respectively. By merging both therapeutic modalities, we obtained an extremely efficient tumor cell death in vitro, and a spectacular tumor regression in vivo. The multifunctional smart liposomal nano-platform presented here is thus not only novel for its dual loading, but also demonstrates for the first time the potential of combining synergistically magnetic hyperthermia with photodynamic therapy for unparalleled antitumoral efficacy.

Figure 1 : Combining magnetic hypethermia with photodynamic therapy using ultramagnetic photosensitive liposomes. Di Corato et al.
CNRS Press Release http://www2.cnrs.fr/presse/communique/3969.htm

Concerning thermal therapies, state-of-the-art modalities are the magnetic hyperthermia and the photothermal ones. Yet, for both, main limitations are the important doses of nanoparticles needed to achieve a therapeutic heating. Thus, the obvious question comes to mind: why not combine the two heat sources - magnetic and plasmonic - into a single nanohybrid structure to enhance heating efficiency? The team of Ali Abou-Hassan (PHENIX, UMR8234, UPMC) managed to produce the first biocompatible magneto-plasmonic nanohybrid with a magnetic core - nanoflower like - optimised for maximal magnetic heating efficiency, and variable gold shell whose thickness and morphology can be fine-tuned during the elaboration process, resulting in tunable plasmon resonances in the biological window (near infrared) and high photothermal efficiencies.

Figure 2 : Combining magnetic hypethermia with photothermia using magneto-plasmonic nanohybrids. Espinosa et al. Nanoscale 2015

Not only we provided a direct insight in the structure, chemistry and intrinsic plasmonic response of an individual, isolated nanostructure using advanced scanning transmission electron microscopy (collaboration Guillaume Radtke, IMPMC, UPMC; Matthieu Bugnet, Gianluigi Botton, McMaster University), but also, we demonstrated dual heating with simultaneous magnetic and laser excitation.

We extended this magneto-photo-thermal modality to iron oxide nanoparticles only (Figure 3, Espinosa et al.). Indeed, we demonstrated that photothermia with magnetic nanoparticles could be proposed as an alternate to magnetic hyperthermia. We explored the magneto-photo-thermal modality with iron oxide nanocubes (produced by the team of Teresa Pellegrino, IIT, Genova), from the characterization of thermal efficiency in solution to tumor eradication in vivo. In brief: i) In suspension, nanocube heat-generating capacity rose from 700-900 W/g with the magnetic modality alone up to 5000 W/g with combined magneto-photo stimulation; ii) intracellularly, the enhancement is even more striking (15-fold), as laser excitation restores the optimal efficiency of magnetic hyperthermia, which is otherwise inhibited by mechanical nano-frustration; iii) As a result, complete cell death in vitro and total tumor eradication in vivo could be achieved thanks to the synergistic heating action, at injected iron doses 4-8 times lower than those used for existing methods of magnetic hyperthermia.

While the ultimate target for nanoparticle-mediated photothermal therapy is the cancer cell, heating performance has rarely been evaluated in cancer cells in vitro, or in vivo in the tumor environment. In the attempt to bridge this gap, we provided magnetic hyperthermia measurements in the cellular environment (Di Corato et al. Biomaterials, 2014) and photothermal measurements of plasmonic nanoparticles (gold nanostars, produced by Luis Liz-Marzán’s team, CIC biomaGUNE) in environments of increasing biological complexity, from aqueous dispersion to solid tumors, via tumor cells in vitro (Figure 4, Espinosa et al. Adv HealthCare Mat, 2016).

Figure 3 : Magneto-Photo-Thermia with iron oxide nanocubes. Espinosa et al. ACS nano 2016.

Figure 4 : once gold nanostars nanoparticles are internalized by cancer cells and confined within endosomes, heating generation is no more modulated by size and wavelength parameters; Espinosa et al. Adv HealthCare Mat, 2016.

Team

References

  • Espinosa A, Di Corato R, Kolosnjaj-Tabi J, Flaud P, Pellegrino T, Wilhelm C. Duality of Iron Oxide Nanoparticles in Cancer Therapy: Amplification of Heating Efficiency by Magnetic Hyperthermia and Photothermal Bimodal Treatment. ACS Nano, 10, 2436-46 (2016)
  • Espinosa A, Silva AKA, Sánchez-Iglesias A, Grzelczak M, Péchoux C, Desboeufs K, Liz-Marzán LM, Wilhelm C. Cancer cell internalisation of gold nanostars impacts their photothermal efficiency in vitro and in vivo: towards a plasmonic thermal fingerprint in tumoral environment. Advanced HealthCare Materials, 5, 1040-48 (2016)
  • Di Corato R, Béalle G, Kolosnjaj-Tabi J, Espinosa A, Clément O, Silva AKA, Ménager C, Wilhelm C. Combining magnetic hyperthermia and photodynamic therapy for tumor ablation with photoresponsive magnetic liposomes.; ACS Nano, 9, 2904-16 (2015)
  • Espinosa A, Bugnet M, Radtke G, Neveu S, Botton GA, Wilhelm C, Abou-Hassan A. Can magneto-plasmonic nanohybrids efficiently combine photothermia with magnetic hyperthermia? Nanoscale, 7, 18872-77 (2015)
  • Di Corato R, Espinosa A, Lartigue L, Tharaud M, Chat S, Pellegrino T, Ménager C, Gazeau F, Wilhelm C. Magnetic hyperthermia efficiency in the cellular environment for different nanoparticle designs. Biomaterials 24, 6400–11 (2014)