(Jan. 29, 2008) — Carbon nanotubes-cylinders so tiny that it takes 50,000 lying side by side to equal the width of a human hair-are packed with the potential to be highly accurate vehicles for administering medicines and other therapeutic agents to patients. But a dearth of data about what happens to the tubes after they discharge their medical payloads has been a major stumbling block to progress.

Des nanotubes de carbones si petits que cela en prends 50,000 cote-à-cote pour équivaloir à l'épaisseur d'un cheveu sont des véhicules potentiels pour administrer des médicaments.


Now, Stanford researchers, who spent months tracking the tiny tubes inside mice, have found some answers.


Studies in mice already had shown that most nanomaterials tend to accumulate in organs such as the liver and spleen, which was a concern because no one knew how long they could linger. But fears that the tiny tubes might be piling up in vital organs, like discarded refrigerators at the bottom of a rural ravine, can now be put to rest, said Hongjie Dai, the J. G. Jackson and C. J. Wood Professor of Chemistry at Stanford, whose research team has demonstrated that the nanotubes exit the organs.

Les études déja faites ont montré que la plupart du nanomatériel tend à s'accumuler dans les organes tels que le foie et les poumons ce qui pose un problème car personne ne sait combien de temps il peut résider là. Mais les peurs que le nanomatériel puisse s'Accumuler dans les organes vitaux sont dépassées d'après le docteur Hongjie Dai et d'autres qui ont démontré que le nanomatériel sort des organes.

Dai and his group found that the carbon nanotubes leave the body primarily through the feces, with some by way of the urine. ''That's nice to know,'' Dai said. ''This now proves that they do get out of the system.''
The full extent of the news, which is scheduled to be published the week of Jan. 28 in Proceedings of the National Academy of Sciences Online Early Edition (PNAS), is even better than that: The three-month-long study also allays worries that the nanotubes, by simply remaining in the organs for a long time, would prove toxic to the mouse.



''None of the mice died or showed any anomaly in the blood chemistry or in the main organs,'' said Dai, senior author on the PNAS paper. ''They appear very healthy, and they are gaining weight, just like normal mice. There's no obvious toxicity observed.'' The lack of toxicity of nanotubes in mice is consistent with a previous pilot study done by Sanjiv Gambhir, a professor of radiology at Stanford, and his research group in collaboration with Dai's group.

"Aucune des souris n'est morte ou n'a montré d'anormalité dans le sang ou dans les organes principaux."


''This is the first time anyone has done a systematic circulation and excretion study like this for nanotubes, and data on other nano particles is also scarce,'' Dai said. ''The excretion pathway may apply to other nano materials and may need to be looked at closely like this also.''
Previous research published by Dai's group has demonstrated the potential for using nanotubes in treating cancerous cells and targeting tumors in mice.



His group used Raman spectroscopy, a method of applying light from a laser beam that effectively ''illuminates'' the presence of the target molecules in the organs of the mice.


Being hit with light from the beam causes a detectable change in the state of a molecule's energy. Carbon nanotubes, composed entirely of carbon atoms that are mostly arranged in linked hexagonal rings, give off a strong signal in response to the beam. This allowed the researchers to pinpoint the position of the chosen molecules, as well as ascertain their abundance in the blood or organs.



Previous detection methods that relied on attaching fluorescent labels or spectroscopic tags to the nanotubes had yielded unreliable results. The attachments tended to either come loose from the tubes or decay over time spans ranging from a few days to only a few hours-far too short to reveal the ultimate fate of the nanotubes.


While knowing the carbon nanotubes will move through the digestive system at a healthy pace is critical to future practical applications, it is also crucial that the nanotubes not enter the digestive system too soon after being injected; they need to spend enough time in the circulatory system to find their way to their target location.


The key to fine-tuning the carbon nanotubes' speed of circulation turns on how the basic, bare-bones floor model is chemically accessorized.
''You can make the nanotubes circulate a very long time in the blood, if the chemistry is done right,'' Dai said. The researchers found that coating their carbon nanotubes with polyethylene glycol (PEG), a common ingredient in cosmetics, worked best.

They used a form of PEG with three little limbs sprouting off a central trunk. ''Those provide better shielding to the nanotube than just a single branch. Therefore, they interact less with the biological molecules around them,'' Dai said.

The team stuffed the PEG liberally into the linked hexagonal rings that compose the nanotubes, prompting Dai to describe the end result as resembling rolled-up chicken wire with feathers sticking out all over.
Though they may sound less than gorgeous visually, the feathery nanotubes turned in a beautiful performance in practical terms, Dai said. The coating of PEG made the nanotubes highly water soluble, which helped them to stay in the blood instead of being absorbed.

''They circulate in the blood for about 10 hours or so in mice, which seems to be a good length of time,'' Dai said.

The right chemical coating on nanotubes also can help ease them out of the mouse in a timely fashion, and the three-branched PEG was effective there, too.

Dai's earlier research demonstrated that nanotubes have promise for treating cancer with two different approaches. Once they have zeroed in on the target cells, shining light on the nanotubes causes them to generate heat, which can kill cancer cells. The other method is to rig the nanotubes to accumulate at targeted sites, where they can deliver medication from within the tubes.

Les recherches ont montré que les nanotubes promettent de traiter le cancer avec 2 différentes approches. Une fois qu'elles ont ciblé les celllules, une lumière réfléchissant sur le tube génère de la chaleur ce qui peut tuer les cellules cancéreuses. l'autre méthode est de diriger les nanotubes pour qu'ils s'accumulent sur un site ciblé ou ils peuvent liver la médication de l'intérieur du tube.
''[Carbon nanotubes] seem to be promising for biomedical applications and for potentially treating cancer, either using drugs or using the physical properties,'' Dai said. ''This is the reason we carried out the study of the fate of nanotubes in mice. I think this is really a very fundamental issue.''

(Jun. 16, 2008) — Researchers are testing a new way to kill cancer cells selectively by attaching cancer-seeking antibodies to tiny carbon tubes that heat up when exposed to near-infrared light.

Les chercheurs sont en train de tester un nouveau moyen de tuer les cellules cancéreuses en attachant des anticorps chercheurs à des microscopiques tubes de carbones qui ont la capacité de produire de la chaleur lorsqu'exposés à une source de rayonnement infra-rouge.

Biomedical scientists at UT Southwestern Medical Center and nanotechnology experts from UT Dallas describe their experiments in a study available online and in an upcoming print issue of Proceedings of the National Academy of Sciences.

Scientists are able to use biological molecules called monoclonal antibodies that bind to cancer cells. Monoclonal antibodies can work alone or can be attached to powerful anti-cancer drugs, radionuclides or toxins to deliver a deadly payload to cancer cells.

In this study, the researchers used monoclonal antibodies that targeted specific sites on lymphoma cells to coat tiny structures called carbon nanotubes. Carbon nanotubes are very small cylinders of graphite carbon that heat up when exposed to near-infrared light. This type of light, invisible to the human eye, is used in TV remote controls to switch channels and is detected by night-vision goggles. Near-infrared light can penetrate human tissue up to about 1½ inches.

Ce type de lumière invisible à l'oeil nu est utilisé par exemple dans les contrôles à distances pour les télés. La lumière peut pénétrer jusqu'à 1 pouce et demi dans le corps.

In cultures of cancerous lymphoma cells, the antibody-coated nanotubes attached to the cells' surfaces. When the targeted cells were then exposed to near-infrared light, the nanotubes heated up, generating enough heat to essentially "cook" the cells and kill them. Nanotubes coated with an unrelated antibody neither bound to nor killed the tumor cells.

Dans une culture de cellules lymphomatiques, les naotubes enduit d'anticorps se sont attachés à la surface des cellules. quand les mini-tubes furent exposées à la lumière, ils ont produit de la chaleur assez pour cuire les cellules cancéreuses et les tuer. Les cellules qui ne sont pas cancéreuses n'ont pas été affectées.

"Using near-infrared light for the induction of hyperthermia is particularly attractive because living tissues do not strongly absorb radiation in this range," said Dr. Ellen Vitetta, director of the Cancer Immunobiology Center at UT Southwestern and senior author of the study. "Once the carbon nanotubes have bound to the tumor cells, an external source of near-infrared light can be used to safely penetrate normal tissues and kill the tumor cells.

"Demonstrating this specific killing was the objective of this study. We have worked with targeted therapies for many years, and even when this degree of specificity can be demonstrated in a laboratory dish, there are many hurdles to translating these new therapies into clinical studies. We're just beginning to test this in mice, and although there is no guarantee it will work, we are optimistic."

Il y a encore beaucoup d'obstacles avant d'utiliser cette technologie sur des humains mais les chercheurs sont optimistes.

The use of carbon nanotubes to destroy cancer cells with heat is being explored by several research groups, but the new study is the first to show that both the antibody and the carbon nanotubes retained their physical properties and their functional abilities -- binding to and killing only the targeted cells. This was true even when the antibody-nanotube complex was placed in a setting designed to mimic conditions inside the human body.

Biomedical applications of nanoparticles are increasingly attracting the attention of basic and clinical scientists. There are, however, challenges to successfully developing nanomedical reagents. One is the potential that a new nanomaterial may damage healthy cells and organisms. This requires that the effects of nanomedical reagents on cells and organisms be thoroughly studied to determine whether the reagents are inherently toxic.

"There are rational approaches to detecting and minimizing the potential for nonspecific toxicity of the nanoparticles developed in our studies," said Dr. Rockford Draper, leader of the team from UT Dallas and a professor of molecular and cell biology.

Other researchers from UT Southwestern involved in the research were lead authors Pavitra Chakravarty, a graduate student in biomedical engineering, and Dr. Radu Marches, assistant professor in the Cancer Immunobiology Center. Authors from UT Dallas' Alan G. MacDiarmid NanoTech Institute were Dr. Inga Musselman, Dr. Paul Pantano and graduate student Pooja Bajaj. Two undergraduate students in UT Southwestern's Summer Undergraduate Research Fellowship program -- Austin Swafford from UT Dallas and Neil Zimmerman from the Massachusetts Institute of Technology -- also participated.

The research was supported by the Cancer Immunobiology Center at UT Southwestern, the Robert A. Welch Foundation, the Department of Defense and the Center for Applied Biology at UT Dallas.

Dr. Vitetta is a co-inventor on a patent describing the techniques outlined in the study.

voir aussi l'histoire d'un homme atteint du cancer à l'origine de cette thérapie

(Aug. 5, 2009) — By injecting man-made, microscopic tubes into tumors and heating them with a quick, 30-second zap of a laser, scientists have discovered a way to effectively kill kidney tumors in nearly 80 percent of mice. Researchers say that the finding suggests a potential future cancer treatment for humans.

En injectant des nanos tubes faits de la main de l'homme dans les tumeurs et en les chauffant 30 secondes avec l'aide d'un lazer, les scientifiques ont décoverts un moyen efficace de tuer les tumeurs dans presque 80% des soris. Ls chercheurs disent qu'il y a là un traitement potentiel pour le cancer dans le futur pourles humains.

The study appears in the August issue of PNAS (Proceedings of the National Academy of Sciences). It is the result of a collaborative effort between Wake Forest University School of Medicine, the Wake Forest University Center for Nanotechnology and Molecular Materials, Rice University and Virginia Tech.

L'étude est apparue en aoüt dans le numéro de PNAS.

"When dealing with cancer, survival is the endpoint that you are searching for," said Suzy Torti, Ph.D., lead investigator for the study and professor of biochemistry at Wake Forest University School of Medicine. "It's great if you can get the tumor to shrink, but the gold standard is to make the tumor shrink or disappear and not come back. It appears that we've found a way to do that."

"Quand il s'agit du cancer, la survie est ce qui nous intéresse. C'est bien de pouvoir faire rétrécir la tumeur mais le vrai but c'est de la faire disparaitre sans qu'elle ne puisse réapparaitre et c'est ce que nous avons trouver."

Nanotubes are long, thin, sub-microscopic tubes made of carbon. For the study, researchers used multi-walled nanotubes (MWCNTs), which contain several nanotubes nested within each other, prepared for the study by the Center for Nanotechnology and Molecular Materials. The tubes, when non-invasively exposed to laser-generated near-infrared radiation, respond by vibrating, creating heat. If enough heat is conducted, tumor cells near the tubes begin to shrink and die.

Les nanotubes sont des structures minces et élancées de taille sub-microscropiques faites de carbones. Pour l'étude, les chercheurs ont utilisés des nanotubes à parois multiples (MWCNTs) .Les microtubes une fois exposées à une lumière infra-rouge répondent en vibrant et en produisant assez de chaleur pour que les cellules cancéreuses près d'eux commencent à rétrécir et mourir.

Using a mouse model, researchers injected kidney tumors with different quantities of MWCNTs and exposed the area to a three-watt laser for 30 seconds.

Researchers found that the mice who received no treatment for their tumors died about 30 days into the study. Mice who received the nanotubes alone or laser treatment alone survived for a similar length of time. However, in the mice who received the MWCNTs followed by a 30-second laser treatment, researchers found that the higher the quantity of nanotubes injected, the longer the mice lived and the less tumor regrowth was seen. In fact, in the group that received the highest dose of MWCNTs, tumors completely disappeared in 80 percent of the mice. Many of those mice continued to live tumor-free through the completion of the study, which was about nine months later.

Un essai a été fait avec des souris auquelles ont a injectées le cancer du Celles qui ne recevaient aucun traitement mouraient dans l'espace de 30 jours, celles qui recevaient des nanotubes seuls ou le traitement au lazer seuls mouraient dans un laps de temps comparable. Toutefois parmi les souris qui recevaient les tubes à parois multiples suivi par 30 secondes de lazer, celles qui à qui ont injectaient la plus grande quantité de microtubes survivaient le plus longtemps et le moins les tumeurs réapparaissaient. En fait, dans le groupe qui a reçu la plus grande quantité de nanotubes, on a vu 80 les tumeurs disparaitre complètement pour 80% des souris. Plusieurs des souris ont survécu le temps de l'étude soit 9 mois.

"You can actually watch the tumors shrinking until, one day, they are gone," Torti said. "Not only did the mice survive, but they maintained their weight, didn't have any noticeable behavioral abnormalities and experienced no obvious problems with internal tissues. As far as we can tell, other than a transient burn on the skin that didn't seem to affect the animals and eventually went away, there were no real downsides – that's very encouraging."


"Vous pouvez voir les tumeurs rétrécir jusqu'au jour ou elles sont disparues complètement" dit Torti ""Non seulement les souris survivent mais elles maintiennent leur poids et n'ont pas de comportements anormaux et ne présentent aucun problème de tissus internes. Aussi loin que nous pouvons observer, il n'y a que des problèmes transitoires de brulures sur la peau qui n'afectent pas les animaux et disparaissent éventuellement. Il n'y a pas de véritables problèmes et c'est vraiment encourageant."

Current thermal ablation, or heat therapy, treatments for human tumors include radiofrequency ablation, which applies a single-point source of heat to the tumor rather than evenly heating the tumor throughout, like the MWCNTs were able to. In addition to the MWCNTs used in this study, other nanomaterials, such as single-walled carbon nanotubes and gold nanoshells, are also currently undergoing experimental investigation as cancer therapies at other institutions.

En plus des nanotubes à parois multiples, les expérimentateurs ont utlisé aussi des nanotubes de carbone à paroi simple et des nanostructures en or.

"MWCNTs are more effective at producing heat than other investigational nanomaterials," Torti said. "Because this is a heat therapy rather than a biological therapy, the treatment works on all tumor types if you get them hot enough. We are hopeful that we will be able to translate this into humans."

Les MWCNTs sont plus efficaces pour produire de la chaleur que les autres structures nanométriques et parce que c'est une thérapie mécanique plutot que biologique, le traitement marche sur tous les types de tumeurs si vou sles chauffer assez. Nous espérons pouvoir transférer la technologie sur l'humain.

Before the treatment can be tested in humans, however, studies need to be done to test the toxicity and safety, looking to see if the treatment causes any changes to organs over time, as well as the pharmacology of the treatment, looking at things such as what happens to the nanotubes, which are synthetic materials, over time.

Avant de pouvoir appliquer le traitement à l'humain, il faut regarder s'il ne causerait pas des changements à quelque organe que ce soit avec le temps.

The treatment would need to be tested in larger animals before being tested in human trials, as well. Conceptually, however, Torti said there is no barrier to applying the therapy into humans to treat tumors close to the surface of the skin, such as in the oral cavity and bladder wall.

Le traitement devra être tester sur des animaux de plus grande taille mais il n'y a pas de barrière à le tester sur des humians dans des tumeurs près de la peau comme la bouche ou la vessie.

"We're excited about this," Torti said. "This is the intersection between the physical and the medical sciences that represents the new frontier in modern medicine."

"Nous sommes excités de ça" dit Torti "C'est la nouvelle frontière dans la science moderne cette intersection entre le physique et les sciences médicales."

Les nanotubes de carbone sont expérimentés chez la souris depuis 2004. Ces cylindres microscopiques dont le diamètre ne dépasse pas quelques dizaines de nanomètres (ou milliardièmes de mètre) ont la capacité de pénétrer à l'intérieur de cellules cibles pour y déposer des médicaments. «Plusieurs équipes dans le monde ont réussi à faire régresser des tumeurs chez des souris cancéreuses et à prolonger leur survie. Mais il est trop tôt pour dire si et quand les nanotubes de carbone pourront être testés chez l'homme», affirme Al­­berto Bianco, du la­boratoire d'immunologie et de chimie thérapeutiques du CNRS à Strasbourg. Ce chercheur qui vient de passer en revue les principaux essais chez l'animal conduits dans le monde est aussi op­timiste que prudent (Nature Nanotechnology). Car de nombreux problèmes restent à régler.

Première difficulté : les nanotubes de carbone ne sont pas homogènes, ce qui complique l'évaluation des différents essais. Incorporés dans les pneus, les composants automobiles, les vélos, les raquettes de tennis, les écrans plats (à raison de plusieurs centaines de tonnes par an), ils ne sont pas conçus pour être utilisés en médecine. Les industriels militent pour que des normes soient mises en place. Mais, en attendant, c'est un peu le chaos.

C'est ainsi qu'avant de les injecter dans un organisme par voie sanguine, chaque laboratoire doit vérifier que les nanotubes sont exempts de catalyseurs ou d'éventuelles impuretés. Les chimistes doivent également les configurer pour qu'ils soient solubles dans l'organisme et qu'ils le restent pour éviter qu'ils ne s'agrègent.


Éventuelle toxicité

À la différence des liposomes qui peuvent transporter des médicaments à l'intérieur de leur membrane, les nanotubes les véhiculent à leur surface. «On sait mettre des molécules à l'intérieur d'un nanotube mais on ne sait pas encore fermer ni ouvrir la porte des nanotubes à volonté», reconnaît M. Bianco.

Le ciblage des na­notubes est assuré par des molécules placées elles aussi en surface. Mais à cette échelle, il est impossible de piloter quoi que ce soit. Les scientifiques en sont réduits à façonner la «clé» qui permettra au nanotube d'entrer dans la cellule tumorale. Une fois cette étape franchie, la molécule thérapeutique peut être délivrée selon plusieurs procédés très complexes, comme la présence d'un bras clivable entre le nanotube et la molécule elle-même.

Ces composés peuvent également transporter des vaccins, des antibiotiques voire des brins d'ARN capables de bloquer un gène défectueux. Par ailleurs, ils commencent à être utilisés en imagerie médicale. Mais le problème majeur reste leur éventuelle toxicité. «Des études montrent qu'ils ont parfois tendance à s'accumuler dans certains organes», note Alberto Bianco. Et la question de leurs effets à long terme se pose même s'ils sont éliminés par les voies biliaires ou l'urine.