Another useful application of light absorption by gold nanoparticles is generation of heat for plasmonic photothermal therapy (PPTT). By changing the size, shape, or composition of the nanoparticles, the color of light that absorbs maximal energy can be tuned over the visible and NIR spectra. The NIR region from 650 nm to 900 nm is a desirable optical window in human tissue for deep penetration of light. Whereas gold spheres are tunable across the visible spectrum, the nanoshells and nanorods are both tunable across the NIR spectrum. The main determining factor of nanorod peak absorption is the aspect ratio of the particle: the relation of the length to width. By changing the aspect ratio (ratio of the short end to long end), gold nanorods are tunable over the near IR region from 650 nm to 1000 nm, where tissue penetration of human tissue by light is maximal. Although light penetration of human tissue is limited to a few millimeters in the visible region, microwatt laser NIR light can penetrate 10 cm into breast tissue and 4 cm into skull/brain or deep muscle tissue. Higher power US Food and Drug Administration class 3 lasers can penetrate through 7 cm of muscle and neonatal skull/brain [39
]. From a surgeon’s perspective, in practical use, light delivery and nanoparticle selection can be tailored to specific lesions. Light and nanoparticles can be delivered externally, within the tumor by intravascular canalization, direct needle-guided placement, or into a postoperative field for residual tumor cells.
Gold nanoshells, a first generation nanotechnology with a silica core surrounded by a gold shell, have been successfully tested in vitro [40
], in vivo in animal models [42
], and are currently initiating human trials for NIR photothermal therapy in refractory head and neck cancers [13
]. However, based on modeling of heating efficiencies of gold nanospheres, nanorods, nanoshells and molecular dyes, gold nanorods seem to be far superior agents [43
Selective targeting with PPTT of OSCC was demonstrated in vitro in the visible range with immunoconjugated gold nanospheres [5
]. Using a laser in the visible region at 442 nm, gold nanospheres were efficiently heated and killed the cells in two malignant OSCC cell lines at 19 W/cm2
(HOC 313 clone 8) and 25 W/cm2
(HSC 3) at much lower energy compared to the nonmalignant cell line (HaCat) at 57 W/cm2
]. However, visible light only penetrates human tissue on the order of a few millimeters and nanospheres would be limited to surface applications.
By changing the shape to a rod, or using a nanoshell, the peak absorption wavelength can be tuned to the NIR spectrum. Gold nanoshells targeted to breast cancer [41
] and gold nanorods targeted to OSCC in the NIR [4
] have been reported for combined imaging and photothermal therapy at 800 nm using a Ti:sapphire laser [4
]. Nanorods achieve tumoricidal effect with less energy than either nanoshells or nanospheres. Nanoshells caused cell death at 35 W/cm2
for 7 min exposure [41
], whereas immunotargeted gold nanorods achieved cell death with 3 min exposure at 10 W/cm2
in vitro .
Based on heating and modeling experiments, gold nanoparticles can generate temperatures of 70°C to 80°C in these cells using far lower laser powers than conventional dyes [44
]. Temperatures of 70°C to 80°C celsius are hot enough to denature proteins and disrupt protein, DNA, and RNA. Image analysis suggest cell death occurs because of blebbing formation of the cell wall and loss of membrane integrity [45
]. Cell injury is likely related to both necrosis and cell membrane rupture.
Comparison of gold nanospheres, nanorods, and nanoshells reveals the gold nanoparticles absorb light at 104
times better than the best molecular dyes. Gold nanorods absorb a similar amount of energy as gold nanoshells at one third the size because the entire nanorod is composed of gold [43
]. Furthermore, nanorods absorb the most energy per particle volume of all the particles. To compare particles across a range of sizes, a volumetric coefficient, expressed as a per micron absorption coefficient uabs
can be calculated. Examining the nanoshell configuration used in vivo for photothermal trials (inner core, 60 nm; outer core, 70 nm) [40
], the nanoshells have a uabs
of 35.62 with a peak absorption at 892 nm. At 11.4 nm, the nanorods uabs
1000.87 at 863 nm, roughly 30 times more than the nanoshells (Table ) [43
Comparison of absorption coefficient of nanorods and nanoshells
Both nanorods and nanoshells are tested in vivo with PPTT. Hirsch et al. [41
] found a maximal temperature rise of 37°C using 4 to 6 min of laser exposure in a murine model of transmissible venereal tumor with 10- to 25-fold less laser energy than needed for indocyanine green dye [41
]. In an OSCC murine model, PEGylated nanorods were successfully imaged in OSCC implanted murine tumors using an infrared light source and charge coupled device digital camera (Fig. ). Treatment with an 808 nm LED laser with a 6 mm beam achieved a 22°C temperature rise and a 25% (intravenous route) and 57% (direct injection into tumor) reduction of tumor compared with the sham treatment group after 13 days. Imaging revealed the direct injection group had 2.18 times greater absorption of light in the tumor than the intravenous injection group and 4.35 greater than the control group at 2 min (Fig. ).
Fig. 1 Near infrared absorption imaging with gold nanorods in mice treated with tumors (top). Extinction spectra (bottom) reveal that direct injection achieves nearly twice the absorption of intravascular injection of the nanorods. PBS—phosphate buffered (more ...)
The biodistribution of gold nanorods appears similar to other nanoparticles and can be delivered intravascularly to tumors. In vivo mice studies demonstrated PEG-nanorods accumulates about one third of the gold in the tumor [9
], making gold nanorods very attractive for PPTT applications in the head and neck.