Nano-shuttles in the blood: a weapon against cancer

The nano-shuttles against tumors created at the Italian Institute of Technology in Genoa (IIT) are Italian, under the guidance of Paolo Decuzzi, director of the Precision Nanomedicine Laboratory. They have been called “smart drugs” that travel in the blood by affecting diseased tissues and sparing healthy ones. But the immune system is ready to intercept any “foreign” particle in the body … how to do it then? IIT researchers have built special nano-shuttles that manage to “trick” the immune system by taking the drug to its destination. Or, if necessary, the cells of the immune system that engulf enemies, intentionally letting themselves be captured by the macrophages, enhancing their action against tumors.

Technologies increasingly … nano
Our weapons against cancer are increasingly sophisticated and small! But how exactly?

Fig.1 The numbers are expressed in nanometers. Nanotechnologies operate on scales typically between 1 and 100 nanometers
We are in the order of nanometers, or one millionth of a millimeter. It is a measure so out of our daily life that we hardly imagine it. Yet these nanoparticles are particularly effective “shuttles” to convey therapeutic molecules against cancer, cardiovascular, inflammatory or neurological diseases. By means of blood circulation, they are able to reach any vascular district and easily orient themselves towards tissues that express an anomaly, for example by exploiting the increased permeability of blood vessels in the inflamed regions or the expression of certain receptors.

Escape from the immune system
The road to reach the target is long and winding. Immune cells patrol blood vessels to ensure the health of our body. It matters little that the nano-shuttles contain essential drugs for our health: when they enter the circulation they are covered with heterogeneous molecules called “opsonins” that identify them as “foreign bodies” and signal their presence to the immune cells. Macrophages, which represent the first line of defense against external threats, “eat” them by surrounding them with their membrane in a process called “phagocytosis”. Of all the inoculated nano-particles, only a tiny fraction really manages to reach the diseased tissues; the rest end up in the jaws of macrophages.

Fig.2 Macrophages incorporate foreign substances into their membrane, forming vesicles called phagosomes, which then merge with lysosomes for “digestion”
But all is not lost! The researchers know strategies for escaping the immune system, for example by decorating the surface of the particles with natural or synthetic polymers that prevent the adsorption of opsonins and repel the phagocyte membrane. But the solution is only temporary: the polymers can deteriorate and the nanoparticle remains uncovered.

Softer nano-shuttles
To evade the immune system, the researchers learned to play with the shape of the particles and also with their consistency! Decuzzi’s team has created softer nano-shuttles (with a greater ability to deform) with a consistency that mimics that of blood cells. But why would softer particles be able to escape macrophages?

Phagocytosis is a complex process, which involves a structural reorganization of the macrophage membrane. The membrane protrudes, folds, wraps itself; in doing this, it applies a set of mechanical forces on the particle itself to facilitate its internalization. The resulting force applied is greater if the body is rigid, but our nano-shuttles are soft and manage to … slip away! They can therefore oppose phagocytosis and become confused between the circulating cells by traveling undisturbed to their destination.

The opportunities for immunotherapy
The researchers have done more. They discovered how to modulate the consistency of nano-shuttles and consequently their interaction with macrophages. They then created a second type of more rigid nano-shuttle, of bone consistency, which is actually recognized by the immune cells. But it’s not a problem because its target is macrophages!

Rigid nano-shuttles work like special “Trojan horses”: they can be used to introduce immunomodulatory drugs directly into macrophages, enhancing their action against cancer cells. Using these two types of particles together we can attack the immune system from two fronts by combining traditional chemotherapy with the latest immunotherapy, the one that uses the immune system to fight cancer.

Nanotechnology is a field of great interest; they allow us to scrutinize the world on unthinkable scales until recently. We are learning to guide them to the target with increasing precision by overcoming obstacles and even using them to boost the immune system. The technique is currently being tested on animals, but if it works it would be a hope against particularly difficult tumors such as those of the ovary, lung and pancreas, glioblastoma and some forms of breast cancer.