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 recently been investigated by researchers.
Gold NanoRods (AuNR)
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, an 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.
When AuNRs are exposed to NIR light, the oscillating electromagnetic field of the light causes the free electrons of the AuNR to collectively coherently oscillate. Changing the size and shape of AuNRs changes the wavelength that gets absorbed. A desired wavelength would be between 700-1000 nm because biological tissue is optically transparent at these wavelengths. While all AuNP properties are sensitive to change in their shape and size, Au nanorods properties are extremely sensitive to any change in any of their dimensions regarding their length and width or their aspect ratio. When light is shone on a metal NP, the NP forms a dipole oscillation along the direction of the electric field. When the oscillation reaches its maximum, this frequency is called the surface plasmon resonance (SPR). AuNR have two SPR spectrum bands: one in the NIR region caused by its longitudinal oscillation which tends to be stronger with a longer wavelength and one in the visible region caused by the transverse electronic oscillation which tends to be weaker with a shorter wavelength. The SPR characteristics account for the increase in light absorption for the particle. As the AuNR aspect ratio increases, the absorption wavelength is redshifted and light scattering efficiency is increased. The electrons excited by the NIR lose energy quickly after absorption via electron-electron collisions, and as these electrons relax back down, the energy is released as a phonon that then heats the environment of the AuNP which in cancer treatments would be the cancerous cells. This process is observed when a laser has a continuous wave onto the AuNP. Pulsed laser light beams generally results in the AuNP melting or ablation of the particle. Continuous wave lasers take minutes rather than a single pulse time for a pulsed laser, continues wave lasers are able to heat larger areas at once.
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, an 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. Another category of gold nanoshells are gold layer on liposomes, as soft template. In this case, drug can also be encapsulated inside and/or in bilayer and the release can be triggered by laser light. Gold is often used because it is a good absorber of light energy, it is tunable, non-biodegradable, and has imaging properties.
thermo Nano-Architectures (tNAs)
The failure of clinical translation of nanoparticles-mediated PTT is mainly ascribed to body persistence concerns. Indeed, the optical response of anisotropic nanomaterials can be tuned in the NIR region by increasing their size to up to 150 nm. On the other hand, body excretion of non-biodegradable noble metals nanomaterials above 10 nm occurs through the hepatobiliary route in a slow and inefficient manner. A common approach to avoid metal persistence is to reduce the nanoparticles size below the threshold for renal clearance, i.e. ultrasmall nanoparticles (USNPs), meanwhile the maximum light-to-heat transduction is for < 5 nm nanoparticles. On the other hand, the surface plasmon of excretable gold USNPs is in the UV/visible region (far from the first biological windows), severely limiting their potential application in PTT.
Recently, a straightforward approach has been presented in which body excretion of metals is combined with NIR-triggered PTT by employing ultrasmall-in-nano architectures composed by metal USNPs embedded in biodegradable silica nanocapsules. tNAs are the first reported NIR-absorbing plasmonic ultrasmall-in-nano platforms that jointly combine: i) photothermal conversion efficacy suitable for hyperthermia, ii) multiple photothermal sequences and iii) renal excretion of the building blocks after the therapeutic action. Nowadays, tNAs therapeutic effect has been assessed on valuable 3D models of human pancreatic adenocarcinoma.
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.
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