Photothermal therapy (PTT) refers to efforts to use electromagnetic radiation (most often in infrared wavelengths) for the treatment of various medical conditions, including cancer. This approach is an extension of photodynamic therapy, in which a photosensitizer is excited with specific band light. This activation brings the sensitizer to an excited state where it then releases vibrational energy (heat), which is what kills the targeted cells.
Unlike photodynamic therapy, photothermal therapy does not require oxygen to interact with the target cells or tissues. Current studies also show that photothermal therapy is able to use longer wavelength light, which is less energetic and therefore less harmful to other cells and tissues.
Most materials of interest currently being investigated for photothermal therapy are on the nanoscale. One of the key reasons behind this is the enhanced permeability and retention effect observed with particles in a certain size range (typically 20 - 300 nm). Molecules in this range have been observed to preferentially accumulate in tumor tissue. When a tumor forms, it requires new blood vessels in order to fuel its growth; these new blood vessels in/near tumors have different properties as compared to regular blood vessels, such as poor lymphatic drainage and a disorganized, leaky vasculature. These factors lead to a significantly higher concentration of certain particles in a tumor as compared to the rest of the body. Coupling this phenomenon with active targeting modalities (e.g., antibodies) has been recently been investigated by researchers.
One of the most promising directions in photothermal therapy is the use of gold nanoparticles. Initial efforts with gold nanoparticles, however, were not very effective in vivo because the spherical particles used had peak absorptions limited to 520 to 580 nm for particles ranging from 10 to 100 nm in diameter, respectively. These wavelengths were not effective in vivo because skin, tissues, and hemoglobin have a transmission window from 650 to 900 nm, with peak transmission at approximately 800 nm (known as the Near-Infrared Window). Development of gold nanorods was one solution for the disparity between the wavelengths required to excite spherical gold nanoparticles and the in vivo transmission window. The peak absorption of gold nanorods may be tuned from 550 nm up to 1 micrometre by altering its aspect ratio. Once tuned, the toxic byproducts of CTAB can be removed with non-cytotoxic polyethylene glycol (PEG). PEG not only keeps the nanorods from aggregating in serum once injected, but also increases bloodstream circulation times (leading to better adsorption of nanorods into the cancer tumor). This phenomenon is non-directional (enhanced permeability and retention effect) and has shown to improve tumor accumulation from an intravenous administration (systemic). Several studies report half life circulation times of greater than 15 hours. Once the nanorods have been cleared from the bloodstream, the tumor may be illuminated ex vivo with a diode laser. Nanorods located at distances up to approxmiately 10 times their diameter absorb roughly 80% of the incident light energy, creating sufficient heat to kill the local (cancer) cells.
Huang et al. investigated the feasibility of using gold nanorods for both cancer cell imaging as well as photothermal therapy. The authors conjugated antibodies (anti-EGFR monoclonal antibodies) to the surface of gold nanorods, allowing the gold nanorods to bind specifically to certain malignant cancer cells (HSC and HOC malignant cells). After incubating the cells with the gold nanorods, a 800 nm Ti:sapphire laser was used to irradiate the cells at varying powers. The authors reported successful destruction of the malignant cancer cells, while nonmalignant cells were unharmed.
Loo et al. investigated gold nanoshells, coating silica nanoparticles with a thin layer of gold. The authors conjugated antibodies (anti-HER2 or anti-IgG) to these nanoshells via PEG linkers. After incubation of SKBr3 cancer cells with the gold nanoshells, a 820 nm laser was used to irradiate the cells. Only the cells incubated with the gold nanoshells conjugated with the specific antibody (anti-HER2) were damaged by the laser.
Graphene and graphene oxide
Yang et al. demonstrated the viability of graphene for photothermal therapy in 2010 with in vivo mice models. An 808 nm laser at a power density of 2 W/cm2 was used to irradiate the tumor sites on mice for 5 minutes. As noted by the authors, the power densities of lasers used to heat gold nanorods range from 2 to 4 W/cm2. Thus, these nanoscale graphene sheets require a laser power on the lower end of the range used with gold nanoparticles to photothermally ablate tumors.
In 2012, Yang et al. incorporated the promising results regarding nanoscale reduced graphene oxide reported by Robinson et al. into another in vivo mice study. The therapeutic treatment used in this study involved the use of nanoscale reduced graphene oxide sheets, nearly identical to the ones used by Robinson et al. (but without any active targeting sequences attached). Nanoscale reduced graphene oxide sheets were successfully irradiated in order to completely destroy the targeted tumors. Most notably, the required power density of the 808 nm laser was reduced to 0.15 W/cm2, an order of magnitude lower than previously required power densities. This study demonstrates the higher efficacy of nanoscale reduced graphene oxide sheets as compared to both nanoscale graphene sheets and gold nanorods.
Some research has indicated problems with aggregation of the photosensitizers, local shock waves, hyperthermic effects, but otherwise little phototoxicity. Many potential side effects and complications, as well as other potential applications of photothermal therapy, are yet to be discovered.
- Maeda H, Wu J, Sawa T, Matsumura Y, Hori K, Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review, Journal of Controlled Release, 2000, 65 (1-2), 271-284
- Huang X, El-Sayed I, Qian W, El-Sayed M, Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods, Journal of the American Chemical Society, 2006, 128 (6), 2115-2120
- Loo C, Lowery A, Halas N, West J, Drezek R, Immunotargeted nanoshells for integrated cancer imaging and therapy, Nano Letters, 2005, 5 (4), 709-711
- Yang K, Zhang S, Zhang G, Sun X, Lee S-T, Liu Z, Graphene in mice: Ultrahigh in vivo tumor uptake and efficient photothermal therapy, Nano Letters, 2010, 10 (9), 3318- 3323
- Robinson J, Tabakman S, Liang Y, Wang H, Casalongue H S, Vinh D, Dai H, Ultrasmall reduced graphene oxide with high near-infrared absorbance for photothermal therapy, Journal of the American Chemical Society, 2011, 133 (17), 6825-6831
- Yang K, Wan J, Zhang S, Tian B, Zhang Y, Liu Z, The influence of surface chemistry and size of nanoscale graphene oxide on photothermal therapy of cancer using ultra-low laser power, Biomaterials, 2012, 33 (7), 2206-2214