Moyens de livrer le médicament.

(Mar. 10, 2010) — After making a diagnosis of cancer, clinicians have a number of treatment options. Most of these involve coordinating multiple attacks on the tumor using an arsenal of cancer-killing therapies. Chemotherapy, where toxic drugs are used to specifically kill cancer cells, is a very powerful weapon in this arsenal. It is extremely effective in treating some cancers, such as testicular cancer and Hodgkin's Disease, but works poorly in other cancer types.

Après avoir fait un diagnostique de cancer, les médecins ont un certain nombre d'options devant eux. Généralment le plan d'attaque comporte des attaques multiples sur les tumeurs en utilisant des thérapies pour tuer le cancer. La chimio ou des médicaments toxiques est une arme puissante et efficace dans certains cancers comme le cancer des testicules et la maldie de Hodgking mais fonctionne assez peu dans les autres types de cancers.

Although the reasons for these different responses are complex, one of the known limitations for solid tumors is that sometimes killer drugs injected into the bloodstream are not delivered efficiently to the tumor tissue, and even if they do reach their target, are not retained long enough to administer their lethal hit.


Les raisons pour comprendre la différence de réactions sont complexes. L'une d'elles est que parfois les médicaments ne sont pas livrer efficacement aux tissus cancéreux et même si ils le sont, les médicaments ne restent pas assez longtemps pour jouer leur rôle pour tuer le cancer.


Professor Lisa Coussens and her coworkers, based at the University of California San Francisco Medical Center, have now discovered a way of enhancing drug delivery to tumors: using the cancer's own architecture to bring about its downfall. Solid tumors need a good blood supply in order to grow, and the blood vessels nourishing the tumors are frequently disorganized and leaky, allowing drugs to leach into the tumor. However, this useful property is counteracted by high tissue pressure within the tumor itself, which creates a barrier for drug uptake. Coussens' team have found a way of tipping the balance in favor of the blood vessels. Using a mouse model of cancer, they show that blocking the action of a signaling molecule called ALK5 makes tumor blood vessels even leakier for a short period of time, and this window of leakiness can be used to "open up" the tumor for more efficient delivery of drugs.

Le professeur Linda Coussens a découvert un nouveau moyen d'Améliorer la livraison du médicament : utiliser l'architecture propre au cancer pour en arriver à sa perte. Les tumeurs solides nécessitent un bon réseau d'apport sanguin pour croitre, et les vaisseaux sanguins qui nourrisent la tumeur sont souvent faibles et plein de trous permettant aux médicament de s'infiltrer dans la tumeur. cependant cette propriété utile est contrecarrée par la haute pression dans la tumeur elle-même ce qui constitue une barrière pour le médicament pour infiltrer la tumeur. En utilisant une souris, elle a montré que de bloquer l'action d'une molécule appelée ALK5 rend les vaisseaux de la tumeur encore plus faibles et poreux pour une petite période de temps et cette fenêtre de faiblesse peut être utilisé pour que les médicaments soient plus efficaces.

Coussens' discovery has exciting implications.

La découverte de Coussens a d'excitantes implications.

(Dec. 9, 2009) — Researchers at Burnham Institute for Medical Research at University of California, Santa Barbara have identified a peptide (a chain of amino acids) that specifically recognizes and penetrates cancerous tumors but not normal tissues. The peptide was also shown to deliver diagnostic particles and medicines into the tumor. This new peptide, called iRGD, could dramatically enhance both cancer detection and treatment.

Les chercheurs ont trouvé un peptide (une chaine d'acide aminés) qui reconnait et pénètre les tumeurs cancéreuses mais pas les tissus normaux. Ce peptide a aussi livrer des particules pour le diagnostic et des médecines dans la tumeurs. Il est appelé iRGD et pourrait améliorer significativement la détection et le traitement du cancer.

The work is being published December 8 in the journal Cancer Cell.

Led by Erkki Ruoslahti, M.D., Ph.D., distinguished Burnham professor at UCSB, this research was built on Dr. Ruoslahti's previous discovery of "vascular zip codes," which showed that blood vessels in different tissues (including diseased tissues) have different signatures. These signatures can be detected and used to dock drugs onto vessels inside the diseased tissue. In addition to homing in on tumor vessels, the new iRGD peptide penetrates them to bind inside the tumor. Previous peptides have been shown to recognize and bind to tumors, but were unable to go beyond the tumor blood vessels.

Cette recherche est une suite des découvertes du docteur Ruoslahti sur les "codes postaux vasculaires" qui ont montré que les vaisseaux sanguins dans différents tissus ont différentes signatures. Ces signatures peuvent être détectées et utilisées pour arimer les médicaments dans les vaisseaux de ces tissus. Des peptides avaient déja été utilisés pour reconnaitre et se lier aux tumeurs mais n'avaient pas été capable d'aller plus loin que les vaisseaux sanguins de la tumeur.

"This peptide has extraordinary tumor-penetrating properties, and I hope that it will make possible substantial improvements in cancer treatment," says Dr. Ruoslahti. "In our animal studies, the iRGD peptide has increased the efficacy of a number of anti-cancer drugs without increasing their side effects. If these animal experiments translate into human cancers, we would be able to treat cancer more effectively than before, while greatly reducing the side effects the patient would suffer."

"Cette peptide a des propriétés extraordinaires de pénétration et j'espère qu'elle fera qu'il sera possible de faire des améliorations aux traitements du cancer" a dit le docteur Ruoslahti. "Dans notre étude sur des animaux, les iRGD ont augmenté l'efficacité de beaucoup de médicaments anti-cancer sans en augmenter les effets secondaires. Si ces résultats d'expériences sur des animaux se confirment dans les expériences sur des humains, nous serons capables de traiter le cancer plus efficacement que jamais tout en réduisant les effets secondaires."

The novel iRGD peptide, identified by using phage display for a peptide that binds to the blood vessels of pancreatic and bone tumors, was tested to determine its ability to penetrate tumors. Researchers injected fluorescent-labeled iRGD into tumor-bearing mice and found that the peptide accumulated in a variety of tumors, including prostate, breast, pancreatic, brain and other types. In addition, the peptide only targeted the tumors and did not accumulate in normal tissue.

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Iron oxide nanoworms, which can be visualized by magnetic resonance imaging, were coupled to the peptide and shown to penetrate the tumors, whereas uncoupled nanoworms could not. This demonstrates that iRGD can deliver diagnostics to tumors. The anti-cancer drug Abraxane was also shown to target, penetrate and spread more within tumor tissue when coupled to iRGD than with other formulations.

(June 26, 2009) — It is now possible to engineer tiny containers the size of a virus to deliver drugs and other materials with almost 100 percent efficiency to targeted cells in the bloodstream.

C'est maintenant possible de faire des contenants de médicaments de la taille d'un virusqui ciblent les cellules cancéreuses avec 100% d'efficacité.

According to a new Cornell study, the technique could one day be used to deliver vaccines, drugs or genetic material to treat cancer and blood and immunological disorders. The research is published in the journal Gene Therapy.


"This study greatly extends the range of therapies," said Michael King, Cornell associate professor of biomedical engineering, who co-authored the study with lead author Zhong Huang, a former Cornell research associate who is now an assistant professor at the Shenzhen University School of Medicine in China. "We can introduce just about any drug or genetic material that can be encapsulated, and it is delivered to any circulating cells that are specifically targeted," King added.

The technique involves filling the tiny lipid containers, or nanoscale capsules, with a molecular cargo and coating the capsules with adhesive proteins called selectins that specifically bind to target cells. A shunt coated with the capsules is then inserted between a vein and an artery. Much as burrs attach to clothing in a field, the selectin-coated capsules adhere to targeted cells in the bloodstream.

La technique consiste à remplir les petits contenants de lipides, de capsules ou de l'échelle nanométrique, avec une cargaison moléculaire et le revêtement de la capsule avec de la colle que des protéines appelées sélectines lient spécifiquement aux cellules cibles. Un shunt enduit avec les capsules est ensuite inséré entre une veine et une artère. Comme la mousse sur un vêtement, la sélectine adhére aux les cellules dans le sang.


After rolling along the shunt wall, the cells break free from the wall with the capsules still attached and ingest their contents.

Après avoir suivi le mur, les cellules se libèrent avec les capsules et ingèrent leus contenus.

The technique mimics a natural immune response that occurs during inflammation, which stimulates cells on blood vessel walls to express selectins, which quickly form adhesive bonds with passing white blood cells. The white blood cells then stick to the selectins and roll along the vessel wall before leaving the bloodstream to fight disease or infection.

Selectin proteins may be used to specifically target nucleated (cells with a nucleus) cells in the bloodstream.

The study shows that since only the targeted cells ingest the contents of the nanocapsules, the technique could greatly reduce the adverse side effects caused by some drugs.

In a previous paper, King showed how metastasizing cancer cells circulating in the blood stream can stick to selectin-coated devices containing a second protein that programs cancer cells to self-destruct.

Said King, "We've found a way to disable the function of cancer cells without compromising the immune system," which is a problem with many other therapies directed against metastasis.

The current study demonstrates that genetic material can be delivered to targeted cells to turn off specific genes and interfere with processes that lead to disease. The researchers filled nanocapsules with a small-interfering RNA (siRNA) and targeted them to specific circulating cells. When the targeted cells ingested the capsules, the siRNA turned off a gene that produces an enzyme that contributes to the degradation of cartilage in arthritis.

In a similar manner, the method could be used to target the delivery of chemotherapy drugs, vaccine antigens to white blood cells, specific molecules that mitigate auto-immune disorders and more, King said.

MIT engineers have outfitted cells with tiny "backpacks" that could allow them to deliver chemotherapy agents, diagnose tumors or become building blocks for tissue engineering.

Les ingénieurs du MIT ont inventé des cellules avec de microscopiques packsacs qui pourraient permettre de livrer les agents de chimiothérapie, de diagnostiquer les maladies ou de devenir des blocs de constructions pour des tissus humains.

Michael Rubner, director of MIT's Center for Materials Science and Engineering and senior author of a paper on the work that appeared online in Nano Letters on Nov. 5, said he believes this is the first time anyone has attached such a synthetic patch to a cell.

C'est la première fois qu'une telle chose est inventée.

The polymer backpacks allow researchers to use cells to ferry tiny cargoes and manipulate their movements using magnetic fields. Since each patch covers only a small portion of the cell surface, it does not interfere with the cell's normal functions or prevent it from interacting with the external environment.

Les packsacs de polymer permettent aux chercheurs d'utiliser les cellules pour transporter de petites charges et manipuler leurs mouvements en utlisants des champs magnétiques. Parce que le packsac ne couvre qu'une petite partie de la cellule, cela ne l'empêche pas ses principales fonctions et interactions.

"The goal is to perturb the cell as little as possible," said Robert Cohen, the St. Laurent Professor of Chemical Engineering at MIT and an author of the paper.

Le but est de perturber la cellule le moins possible.

The researchers worked with B and T cells, two types of immune cells that can home to various tissues in the body, including tumors, infection sites, and lymphoid tissues — a trait that could be exploited to achieve targeted drug or vaccine delivery.

Les chercheurs ont travaillé avec des cellules de type B et T, deux types de cellules qui peuvent se nicher dans différents tissus humains, incluant les tumeurs, les sites d'infection, et les tissus lymphoïdes, ce qui pourrait être utiliser pour faire des médicaments ciblés ou livrer des vaccins.

"The idea is that we use cells as vectors to carry materials to tumors, infection sites or other tissue sites," said Darrell Irvine, an author of the paper and associate professor of materials science and engineering and biological engineering.
Cellular backpacks carrying chemotherapy agents could target tumor cells, while cells equipped with patches carrying imaging agents could help identify tumors by binding to protein markers expressed by cancer cells.

Another possible application is in tissue engineering. Patches could be designed that allow researchers to align cells in a certain pattern, eliminating the need for a tissue scaffold.

The polymer patch system consists of three layers, each with a different function, stacked onto a surface. The bottom layer tethers the polymer to the surface, the middle layer contains the payload, and the top layer serves as a "hook" that catches and binds cells.

Once the layers are set up, cells enter the system and flow across the surface, getting stuck on the polymer hooks. The patch is then detached from the surface by simply lowering the temperature, and the cells float away, with backpacks attached.
"The rest of the cell is untouched and able to interact with the environment," said Albert Swiston, lead author of the paper and a graduate student in materials science and engineering.

The researchers found that T cells with backpacks were able to perform their normal functions, including migrating across a surface, just as they would without anything attached.

By loading the backpacks with magnetic nanoparticles, the researchers can control the cells' movement with a magnetic field.
Because the polymer synthesis and assembly takes place before the patches are attached to cells, there is plenty of opportunity to tweak the process to improve the polymers' effectiveness and ensure they won't be toxic to cells, the researchers say.