"Active targeting of nanoparticles to tumours is the holy grail of therapeutic nanotechnology for cancer. We're getting closer to that goal", stated senior author Chun Li, Ph.D., professor in M. D. Anderson's Department of Experimental Diagnostic Imaging. When heated with lasers, the actively targeted hollow gold nanospheres did eight times more damage to melanoma tumours in mice than did the same nanospheres that gathered less directly in the tumours.
Lab and mouse model experiments demonstrated the first in vivo active targeting of gold nanostructures to tumours in conjunction with photothermal ablation - a minimally invasive treatment that uses heat generated through absorption of light to destroy target tissue. Tumours are burned with near-infrared light, which penetrates deeper into tissue than visible or ultraviolet light.
Photothermal ablation is used to treat some cancers by embedding optical fibers inside tumours to deliver near-infrared light. Its efficiency can be greatly improved when a light-absorbing material is applied to the tumour, Chun Li said. Photothermal ablation has been explored for melanoma, but because it also hits healthy tissue, dose duration and volume have been limited.
With hollow gold nanospheres inside melanoma cells, photothermal ablation destroyed tumours in mice with a laser light dose that was 12 percent of the dose required when the nanospheres aren't applied, Chin Li and colleagues reported. Such a low dose is more likely to spare surrounding tissue.
Injected, untargeted nanoparticles accumulate in tumours because they are so small that they fit through the larger pores of abnormal blood vessels that nourish cancer, Chun Li said. This "passive targeting" delivers a low dose of nanoparticles and concentrates them near the cell's vasculature.
The researchers packaged hollow, spherical gold nanospheres with a peptide - a small compound composed of amino acids - that binds to the melanocortin type 1 receptor, which is overly abundant in melanoma cells. They first treated melanoma cells in culture and later injected both targeted and untargeted nanospheres into mice with melanoma, then applied near-infrared light.
Fluorescent tagging of the targeted nanospheres showed that they were embedded in cultured melanoma cells, while hollow gold nanospheres without the targeting peptide were not. The targeted nanospheres were actively drawn into the cells through the cell membrane.
When the researchers beamed near-infrared light onto treated cultures, most cells with targeted nanospheres died, and almost all of those left were irreparably damaged. Only a small fraction of cells treated with untargeted nanospheres died. Cells treated only with near-infrared light or only with the nanospheres were undamaged.
In the mouse model, fluorescent tagging showed that the plain hollow gold nanospheres only accumulated near the tumour's blood vessels, while the targeted nanospheres were found throughout the tumour.
"There are many biological barriers to effective use of nanoparticles, with the liver and spleen being the most important", Chun Li stated. The body directs foreign particles and defective cells to those organs for destruction.
Most of the targeted nanospheres in the treated mice gathered in the tumour, with smaller amounts found in the liver and spleen. Most of the untargeted nanospheres gathered in the spleen, then in the liver and then the tumour, demonstrating the selectivity and importance of targeting.
In another group of mice, near-infrared light beamed into tumours with targeted nanospheres destroyed 66 percent of the tumours, but only destroyed 7,9 percent of tumours treated with untargeted nanospheres.
The researchers used F-18-labeled glucose to monitor tumour activity by observing how much glucose it metabolized. This action "lights up" the tumour for positron emission tomography (PET) imaging. Tumours treated with targeted shells largely went dark.
"Clinical implications of this approach are not limited to melanoma", Chun Li stated. "It's also a proof of principle that receptors common to other cancers can also be targeted by a peptide-guided hollow gold nanosphere. We've also shown that non-invasive PET can monitor early response to treatment."
The targeted nanospheres have a number of advantages, said Jin Zhang, Ph.D., professor in the University of California-Santa Cruz Department of Chemistry and developer of the hollow nanospheres. Their size - small even for nanoparticles at 40-50 nanometers in diameter - and spherical shape allow for greater uptake and cellular penetration. They have strong, but narrow and tunable ability to absorb light across the visible and near-infrared spectrum, making them unique from other metal nanoparticles.
The hollow spheres are pure gold, which has a long history of safe medical use with few side-effects, Chun Li said. This research was funded by grants from the National Cancer Institute Alliance for Nanotechnology in Cancer and the John S. Dunn Foundation to Chun Li, and a United States Department of Defense grant to Jin Zhang.
Co-authors with Jin Zhang and Chun Li are: first author Wei Lu, Ph.D., Chiyi Xiong, Ph.D. Guodong Zhang, Qian Huang and Rui Zhang, all of M. D. Anderson's Department of Experimental Diagnostic Imaging. Rui Zhang is a graduate student in The University of Texas Graduate School of Biomedical Sciences, which is jointly operated by M.D. Anderson and The University of Texas Health Science Center at Houston.
The University of Texas M.D. Anderson Cancer Center in Houston ranks as one of the world's most respected centres focused on cancer patient care, research, education and prevention. M.D. Anderson is one of only 41 Comprehensive Cancer Centers designated by the National Cancer Institute. For six of the past nine years, M.D. Anderson has ranked no. 1 in cancer care in "America's Best Hospitals", a survey published annually in U.S. News and World Report.