Tag Archives: tumors

Skin-based vaccination delivery courtesy of nanotechnology

A May 28, 2019 news item on Nanowerk announced research targeting Langerham cells and the immune system (Note: A link has been removed),

Researchers at the Max Planck Institute of Colloids and Interfaces in Potsdam developed targeted nanoparticles that are taken up by certain immune cells of the human skin (ACS Central Science, “A specific, glycomimetic Langerin ligand for human Langerhans cell targeting”). These so-called Langerhans cells coordinate the immune response and alert the body when pathogens or tumors occur.

This new nanoparticle technology platform enables targeted drug delivery of vaccines or pharmaceuticals to Langerhans cells, triggering a controlled immune response to naturally eradicate the pathogen or tumor.

Internalized nanoparticles (red) in a Langerhans cell (green membrane marker). Specific targeting of these skin immune cells may lead to novel approaches for skin vaccination [weniger] © Langerhans Zellforschung Labor an der Medizinischen Universität Innsbruck Courtesy: Max Planck Institute

A May 28,2019 Max Planck Institute (MPI) press release, which originated the news item, provides further explanations,

The skin is a particularly attractive place for the application of many drugs that affect the immune system, as the appropriate target cells lie directly beneath the skin. These Langerhans cells are able to elicit an immune reaction in the entire body of the patient after local application of an active substance.

Langerhans Cells – Experts of pathogen defense

To develop a targeted drug delivery system, which guides drugs directly to Langerhans cells, one can make use of their natural function: as professional, antigen-presenting cells they detect pathogens, internalize them and present components of these pathogens to effector cells of the immune system (T cells). For detection and uptake, Langerhans cells use receptors on their surface that search the environment for microbes. They especially recognize pathogens by the unique coating of sugar structures on their surface. Langerin, a protein of the C-type lectins family, is such a receptor on Langerhans cells that can detect viruses and bacteria. The specific expression of Langerin on Langerhans cells allows a targeted drug delivery encapsulated in nanoparticleswhile minimizing the side effects.

The research team of Dr. Christoph Rademacher at the Max Planck Institute of Colloids and Interfaces has now been able to exploit the knowledge of the underlying detection mechanisms with atomic resolution: “Based on our insight how immune cells recognize sugars, we developed a synthetic, sugar-like substance that enables nanoparticles to specifically bind to Langerhans cells”, says Dr. Christoph Rademacher. In collaboration with a scientific team from the Laboratory for Langerhans Cell Research of the Medical University of Innsbruck, nanoparticles have been developed that can be incorporated into Langerhans cells of the human skin through this interaction. The researchers thus lay the foundation for further developments, for example to deliver vaccines directly through the skin to the immune cells. “Imagine avoiding needles for vaccination in the future or directly activating the body’s immune system against infections and maybe even cancer”, adds Dr. Christoph Rademacher. Langerhans cells are responsible for activating the immune system systemically. Based on these findings, it may be possible in the future to develop novel vaccines against infections or immunotherapies for the treatment of cancer or autoimmune diseases.

The starting points for this work were the pioneering contributions from Ralph M. Steinman (Nobel Prize 2011) and other scientists who showed the potential of dendritic cells. Langerhans cells are one subset of these cells and are able to trigger an immune response. These findings were subsequently refined for use in cancer therapy. It has been shown that an immune response can be achieved via artificially introduced antigens. Later work confirmed these findings and also demonstrated that human Langerhans cells are also able to activate the immune system, which is particularly interesting for skin vaccination. Targeted delivery of immunomodulators to Langerhans cells would thus be desirable. However, this is often hindered or even prevented by the complex environment of the skin, especially by competing phagocytes in this tissue, such as macrophages. Consequently, pharmaceuticals not taken up by the Langerhans cells, but internalized into bystander cells may lead to unwanted side effects.

Recognition through synthetic sugars

Based on insights on the interaction between Langerin and its natural sugar ligands Christoph Rademacher and his team developed a synthetic ligand, which binds specifically to the receptor on Langerhans cells. For this purpose, synthetic sugars were produced in the laboratory and their interactions with the receptor were examined by nuclear magnetic resonance spectroscopy. With this method the researchers were able to determine which atoms of the ligand interact with which parts of the receptor. By using this structure-based approach they found out that a compound can be anchored and tested on these nanoparticles. These particles are liposomes, which have been used for many years in the clinic in the absence of such targeting ligands as a carrier for various drugs. The difference with existing systems is that the sugar-like ligand now allows specific binding to Langerhans cells. The investigations on these immune cells were carried out in collaboration with the research group of Assoz. Prof. Patrizia Stoitzner at the Langerhans Cell Research Laboratory of the Medical University of Innsbruck. Together they could show that the specific uptake of liposomes is possible even in the complex environment of human skin. The scientists used different methods such as flow cytometry and confocal microscopy for their findings.

These liposomal particles may now provide a common platform for researchers at the MPI of Colloids and Interfaces to work on the development of novel vaccines in the future.

Here’s a link to and a citation for the paper,

A Specific, Glycomimetic Langerin Ligand for Human Langerhans Cell Targeting by Eike-Christian Wamhoff, Jessica Schulze, Lydia Bellmann, Mareike Rentzsch, Gunnar Bachem, Felix F. Fuchsberger, Juliane Rademacher, Martin Hermann, Barbara Del Frari, Rob van Dalen, David Hartmann, Nina M. van Sorge, Oliver Seitz, Patrizia Stoitzner, Christoph Rademacher. ACS Cent. Sci.201955808-820 DOI: https://doi.org/10.1021/acscentsci.9b00093 Publication Date: May 10, 2019 Copyright © 2019 American Chemical Society

This paper appears to be open access.

“Nano-submarines” for a headache

How did those German scientists miss an opportunity to mention the 1966 movie “Fantastic Voyage” and Raquel Welch (the bombshell of her day)? For anyone not familiar with the movie it, featured a submarine that the scientists entered before being miniaturized and …

Raquel Welch, Stephen Boyd, and Arthur Kennedy in Fantastic Voyage (1966) [It looks like the scientists in thesubmarine are now gazing at some body part or other.]

I’m not sure what part of the body these actors are supposed to be dealing with but perhaps this plot description from the IMDB Fantastic Voyage entry will help a bit,

A scientist is nearly assassinated. In order to save him, a submarine is shrunken to microscopic size and injected into his blood stream with a small crew. Problems arise almost as soon as they enter the bloodstream.

Scientist Jan Benes, who knows the secret to keeping soldiers shrunken for an indefinite period, escapes from behind the Iron Curtain with the help of CIA agent Grant. While being transferred, their motorcade is attacked. Benes strikes his head, causing a blood clot to form in his brain. Grant is ordered to accompany a group of scientists as they are miniaturized. The crew has one hour to get in Benes’s brain, remove the clot and get out. Written by Brian Washington <Sargebri@att.net>

Perhaps they’ve left their submarine to get closer to the clot in the brain?

Now for the latest involving “nano-submarines,” or as these scientists prefer nanocarriers, from a July 19, 2018 news item on Nanowerk,

Scientists at the Mainz University Medical Center and the Max Planck Institute for Polymer Research (MPI-P) have developed a new method to enable miniature drug-filled nanocarriers to dock on to immune cells, which in turn attack tumors. In the future, this may lead to targeted treatment that can largely eliminate damage to healthy tissue.

A July 19, 2018 Johannes Gutenberg Universitaet Mainz press release, which originated the news item, explains further,

In modern medicine, patients receiving medication to treat tumors or for pain therapy are often given drugs that disperse throughout the entire body, even though the section of the organ to be treated may be only small and clearly demarcated. One solution would be to administer drugs that target specific cell types. Such nanocarriers are just what scientists are working to develop. These contain, in a manner of speaking, miniature submarines [emphasis mine] no larger than a thousandth of the diameter of a human hair. Invisible to the naked eye, these nanocarriers are loaded with a pharmacologically-active agent, allowing them to function as concentrated transport containers. The surface of these nanocarriers or drug capsules is specially coated to enable them, for example, to dock on to tissue interspersed with tumor cells. The coating is usually composed of antibodies that act much like address labels to seek out binding sites on the target cells, such as tumor cells or immune cells that attack tumors.

Professor Volker Mailänder and his team from the Department of Dermatology at the University Medical Center of Johannes Gutenberg University Mainz (JGU) have recently developed an ingenious new method of binding antibodies to such drug capsules. “Up to now, we have always had to use elaborate chemical methods to bind these antibodies to nanocapsules,” explained Mailänder. “We have now been able to show that all that you need to do is to combine antibodies and nanocapsules together in an acidified solution.”

In their paper in Nature Nanotechnology, the researchers emphasize that binding nanocapsules and antibodies in this way is almost twice as efficient as chemical bonding in the test tube, significantly improving the targeted transport of drugs. In conditions such as those found in the blood, they also found that chemically coupled antibodies almost completely lost their efficacy, while antibodies that are not chemically attached remained functional.

“The standard method of binding antibodies using complex chemical processes can degrade antibodies or even destroy them, or the nanocarrier in the blood can become rapidly covered with proteins,” explained Professor Katharina Landfester from the Max Planck Institute for Polymer Research. In contrast, the new method, which is based on the physical effect known as adsorption or adhesion, protects the antibodies. This makes the nanocarrier more stable and enables it to distribute the drugs more effectively in the body.

To develop their new method, the researchers combined antibodies and drug transporters in an acidic solution. This led – in contrast to binding at a neutral pH – to more efficient coating of the nanoparticle surface. As the researchers explain, this leaves less room on the nanocarrier for blood proteins that could prevent them from docking to a target cell.

Overall, the researchers are confident that the newly developed method will facilitate and improve the efficiency and applicability of therapy methods based on nanotechnology.

I love this video,

Here’s a link to and a citation for the paper,

Pre-adsorption of antibodies enables targeting of nanocarriers despite a biomolecular corona by Manuel Tonigold, Johanna Simon, Diego Estupiñán, Maria Kokkinopoulou, Jonas Reinholz, Ulrike Kintzel, Anke Kaltbeitzel, Patricia Renz, Matthias P. Domogalla, Kerstin Steinbrink, Ingo Lieberwirth, Daniel Crespy, Katharina Landfester & Volker Mailänder. Nature Nanotechnology (2018) DOI: https://doi.org/10.1038/s41565-018-0171-6 Published 18 June 2018

This paper is behind a paywall.