Selective cancer therapy using IR-laser-excited gold nanorods

Phototherapy (either chemical or thermal) has been used to treat cancers (tumors) employing various sensitizing dyes to absorb visible light from lasers and LEDs. The application of nanoparticles in medicine includes bioimaging and biosensing,^1,2 drug delivery,^3,4 cancer cell diagnostics, and therapeutics.^5–12 By changing the shape of nanoparticles from spheres to nanorods, the absorption or scattering wavelength changes from the visible to the near-IR (NIR) region and offers the advantages of larger absorption and scattering cross-sections and much deeper penetration in tissues.^7,11,13 Recent studies have shown that gold nanorods (GNRs) attached to antibodies⁶ and viral vectors⁹ could be used for selective and efficient photothermal therapy.

The theory behind these nanomedical applications is characterized by the selectivity and sensitivity of the associated surface plasmon resonance (SPR) in response to incident light, i.e., changes in transmission or reflection. The selectivity of SPR is given by its absorption peak, which is redshifted when the sizes of nanospheres increase or when aspect ratio (R) increases in the the case of nanorods. Figure 1 shows the resonant absorption wavelength of various lasers in the visible spectrum (for R=1) and NIR (for R>1).¹³

Figure 1. The resonant wavelength is redshifted from the visible (for spherical nanoparticles, with R=1) to near-IR (for nanorods, with R > 1). R: Aspect ratio. NIR: Near-IR.

NIR lasers for cancer therapy offer much deeper penetration depths than do visible lasers. However, they are limited to normal tissues. At resonant laser wavelengths, the absorption coefficients of cancer tissues with GNR components increase significantly to about 2.0–5.0cm⁻¹, depending on the concentration of GNRs. Consequently, penetration depth in cancer tissues is still limited to about 0.2–0.5cm. In addition, the distribution of the aspect ratios of GNRs and their concentrations inside tumors are difficult to control for perfect matching to the laser peak absorption. Overheating of the surface area of targeted tissues is another important issue in photothermal therapy. To overcome these intrinsic difficulties, I previously proposed novel techniques¹⁴ to improve the efficiency and selectivity of cancer therapy using NIR lasers and operated in so-called pulsed-train modes.¹⁵

Figure 2. Experimental setup for an IR-laser-excited gold (Au) nanorod solution. The temperature increase was measured by thermal probes. DAQ: Data acquisition.

Here I describe the effectiveness of NIR-laser-excited GNRs as active media for selectively killing cancer cells. The key parameters of the laser and GNR solution include the extinction coefficient, penetration depth, laser fluence, and irradiation time, which all define the temperature-increase profiles of the targeted area. The temperature change of the GNR solution due to laser heating is described by a heat-diffusion equation¹⁶

where z is the laser-propagation direction (or along the depth of the GNR solution), F is the laser fluence, K and k are, respectively, the thermal conductivity and diffusivity of the solution, ∂T is the partial temperature differential and ∂t the partial time differential, and e is the logarithmic base. B=[A(A+2S )]¹², where B is the extinction coefficient, and A and Sare the absorption and scattering coefficients.

Figure 2 shows the experimental setup using an NIR diode-laser system and temperature-feedback-controlled thermal probes (custom-made by New Vision Inc.¹⁷) with fiber that is coupled and connected to a handpiece. Using a focusing lens, the laser output from the fiber end is collimated and absorbed by the solution of GNRs mixed in distilled water. Various absorption coefficients are available either by diluting the GNR concentration or by using different NIR laser wavelengths (750–950nm). Two thermal couples (T-type, Omega) were inserted in the solution at positions of z=1.5 and 5.0mm to measure the temperature near the surface and inside the solution.

Together with colleagues, I designed Labview software to generate a pulsed-train laser with a controlled on-off switch to keep the GNR solution surface temperature at a preset value of ∼35°C without overheating. The volume temperature continues to increase and reaches a stable value close to the surface temperature. In contrast, in continuous-wave mode, surface overheating cannot be avoided when increasing the volume temperature. We measured the near-surface (at z=1.5mm) temperature increase of 10°C (from an initial temperature of 25–35°C) using diode lasers at 808 and 852nm for various laser fluences (F=0.5–4.0W/cm²).

Figure 3 shows the measured surface and volume temperature increase (dT) profiles of a GNR solution (with R=4.0) heated by diode lasers at 808nm (with A=2.9cm⁻¹) and 852nm (with A=2.0cm⁻¹) for a fixed AF=2.88W/cm³. We controlled dT to be about 10°C (with a bandwidth about 0.25°C) at near-surface (z=1.5mm) by on-off pulses such that the volume (z=5.0mm) temperature increased to ∼ 8°C, which cannot be achieved in continuous-wave-mode operation without overheating the solution surface. In addition, larger F shows a faster rise in dT and a higher volume dT (at z=5.0mm) inside the solution. These important features are consistent with our theoretical work, presented elsewhere.¹⁵

Figure 3. Measured temperature increase profile (dT) due to diode lasers for fixed AF=2.8W/cm³at 808nm (A=2.9cm⁻¹, dashed curve) and 852nm (A=2.0cm⁻¹, solid curve).

Figure 4 shows the effects for fixed F=2.0W/cm². As expected, a larger A achieves a higher surface dT. However, the results showing that (for a fixed F) a smaller A achieves a higher volume dT represent a contrary trend to that shown in Figure 3. These novel features are also predicted by our earlier work.¹⁵

Figure 4. Identical to Figure 3 but for fixed F=2.0Wcm².

In summary, optimal laser operation for the surface and volume heating of GNR solutions is achievable by a pulsed-train technique that uses an autocontrolled laser on-off switch to maintain the desired temperature for killing cancer cells. For fixed laser fluence, a GNR solution with a smaller extinction coefficient provides higher volume temperature but increases that of the surface more slowly. As next steps, we plan to apply the methods detailed here to cells and tumors in animals.