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Posted: Jul 11th, 2007
Carbon nanotubes as effective cancer killers
(Nanowerk Spotlight) Curing cancer is on of the many promises of nanotechnology. Although scientists have been making amazing progress in this area, there are still significant challenges that need to be overcome before highly selective, targeted anti-cancer therapy becomes available for everyday clinical use. A nanotechnology-based system to eradicate cancer needs four elements: 1) Molecular imaging at the cellular level so that even the slightest overexpressions can be monitored; 2) effective molecular targeting after identifying specific surface or nucleic acid markers; 3) a technique to kill the cells, that are identified as cancerous based on molecular imaging, simultaneously by photodynamic therapy or drug delivery and 4) a post molecular imaging technique to monitor the therapeutic efficacy. One of the problems today is that these four techniques are used separately or ineffectively, resulting in an overall poor therapeutic outcome. In what could amount to a quantum leap in cancer nanotechnology, researchers have now integrated these techniques simultaneously in vitro and shown that this results in higher therapeutic efficacies for destroying cancer cells. Their demonstration of multi-component molecular targeting of surface receptors and subsequent photo-thermal destruction of cancer cells using single-walled carbon nanotubes (SWCNTs) could lead to a new class of molecular delivery and cancer therapeutic systems.
While scientists usually develop and refine their techniques for individual components of the above-mentioned four elements, cancer nanotechnology can only become a clinical practice if these ideas are combined into a coherent therapy with the single goal of eradicating cancer. A group of U.S. researchers have precisely shown that in a new paper ("Integrated molecular targeting of IGF1R and HER2 surface receptors and destruction of breast cancer cells using single wall carbon nanotubes") where they describe targeting more than one class of receptor, show molecular imaging using simple microscopy techniques, improve selectivity by making carbon nanotubes go inside the cells for drug delivery, and finally show cell death using photodynamic therapy.
"We have shown that carbon nanotubes can be made to go inside cells, using receptor specific antibodies, to a much greater degree than was previously thought possible" Dr. Balaji Panchapakesan explains to Nanowerk. "Secondly, by targeting several classes of receptors simultaneously, we could improve the selectivity of killing cancer cells. Finally, we showed that molecular imaging using multicomponent targeting can be achieved using simple optical microscopy techniques and therefore is easier to implement in a clinical setting. While there are thousands of papers in cancer nanotechnology, none of these papers have attempted to integrate imaging, drug delivery and therapy simultaneously."
Panchapakesan, an Assistant Professor in Electrical and Computer Engineering at the University of Delaware, together with collaborators from the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia, functionalized SWCNT with HER2 and IGF1R specific antibodies and showed that they display selective attachment to breast cancer cells compared to SWCNT functionalized with non-specific antibodies. Photo-thermal treatment with laser resulted in the death of all cancer cells that had antibody/SWCNT hybrids attached (while more than 80% of the cells with SWCNT/non-specific antibody hybrids remained alive).
The researchers used SWCNT with an average size of 1.4 nm in diameter and 500 to 1000 nm in length. "One of the most intriguing observations that we made is how the SWCNT become internalized into the cells" says Panchapakesan. "Optical and confocal images obtained after the incubation of SWCNT–antibody conjugates with the cells demonstrated that the SWCNT were readily internalized into the cells over large areas."
(a) MCF7 cancer cells treated without nanotube–non-specific antibody complexes survived the NIR dosing at 800 mW cm-2 for 3 min. Trypan blue was used to investigate membrane permeability and while the background looks blue, the cells appear white and reflective due to the impermeability of the Trypan blue. (b) MCF7 cancer cells treated with nanotube–anti-IGF1-HER2 antibody complex showing that all the cells died after NIR dosing at 800 mW cm-2 for 3 min. The cells appear blue in color indicating cell death. Nanotubes start to precipitate as the samples started to dry around the cells. The diameters of both cell clusters (indicated by white arrows) have been divided into 20 µm grids. The percentage of dead cells in each grid has been estimated and plotted in the insets. (Reprinted with permission from IOP Publishing)
Panchapakesan says it is reasonable to think that the cells may be acting as a suction pump for internalization of SWCNT. When antibodies attach to their corresponding receptors in cancer cells, stresses are generated due to the release of free energy and this may create pressure differences across the membrane pores, thereby allowing the internalization of the SWCNT.
Antibodies incubated with the cells acted as biological transport carriers to realize the endocytosis of SWCNT. Shining near-infrared laser light heated the nanotubes inside the cells. The localized photo-thermal effect produced heat to destroy the cells completely.
"Light causes interesting properties in nanotubes such as photo-conductivity due to exciton generation, light induced elastic deformation of nanotubes, electrostatic charge separation and explosions such as SWCNT nanobombs" says Panchapakesan. "These effects are highly important for biomedical applications. For example, the explosions can not only be used for cancer therapeutics but also to generate acoustic waves at the nanoscale for the next generation of high efficiency ultrasound imaging applications. Stresses generated due to light on the surface of the SWCNT can also be used as a nanoscale delivery mechanism for proteins from the surface of the SWCNT into the cells."
The researchers are now working to see if they can integrate all these techniques – targeting, imaging and therapy – in vivo. "If yes" says Panchapakesan, "then we have a clear winner and we can improve clinical outcome by more than 70-80%, which is a quantum leap over the chemo and radiation therapy that is being used today."
The challenge of course is that they don't know whether these techniques will work in vivo as well as they did in the test tube. It certainly will take a fair amount of testing. But Panchapakesan is confident that this is the way to do it. "Unless, we integrate imaging, drug delivery and therapy all in one package, clinical outcome might still be poor" he says. "My vision is to package all these things into one 'Magic Pill' which you can take to get rid of cancer."