The scientific team of the NUST MISIS Laboratory of Biomedical Nanomaterials has conducted an intravital (on the living tissue) study of the mechanism of targeted drug delivery to malignant tumors using liposomes. It turned out that the immune cells of the body neutrophils increase the efficiency of drug delivery to the tumor by 30%. The results have been published in the international scientific journal ACS Nano.
Liposomes — artificially created fat vesicles — penetrate into the tumor due to the so-called enhanced permeability and retention (EPR) effect.
The EPR effect appears due to the excessive proliferation of blood vessels caused by the abnormal need of the tumor for oxygen and nutrition. With the pathological growth, huge pores up to 200 nm in diameter appear in the walls of blood vessels. Also, the growth of the tumor causes compression of the lymphatic vessels and prevents the normal outflow of intercellular fluid. Thus, liposomes penetrate into the tumor and cannot exit due to impaired lymphatic drainage.
It is believed that due to the EPR effect, liposomes can only penetrate into the tumor, but not into the healthy tissues. But is that so? And what happens inside the vessel?
Scientists at the NUST MISIS Laboratory of Biomedical Nanomaterials observed the delivery of the drug to the tissues of healthy mice and to various types of malignant tumors: breast cancer, prostate cancer, and melanoma. The observations were carried out using an intravital microscope, which allows you to study processes directly in a living organism.
“The first conclusion we received as a result of the study is that there are two types of penetration of liposomes from blood vessels into tissues occurring in living tissues. A microleakage is a small isolated accumulation of liposomes around a vessel. This process is useless for the treatment of tumors, as it does not allow the drug to reach the tumor cells. Moreover, microleakages were found in healthy tissues, which explains the toxicity of liposome-based drugs used in a modern clinic,” says Viktor Naumenko, author of the work, researcher at the NUST MISIS Laboratory of Biomedical Nanomaterials.
The second, most interesting observation result is that neutrophil, a type of white blood cell and the body’s immune cell, promotes leakages into the tumor tissue. When the neutrophil leaves the vessel, along with it, through the “ajar door” in the vascular wall, liposomes manage to penetrate into the tumor. According to the results obtained by the scientific team, neutrophils increase the efficiency of liposomes penetration into the tumor by a third.
This discovery gives a clear pattern: neutrophils increase the vascular permeability of the tumor for targeted delivery of liposomal drugs and therefore increase the chance of cure. Moreover, this happens only in the case of a microleakage, which is a large diffuse “cloud” of liposomes that penetrates deep into the tumor, thereby ensuring targeted drug delivery.
“Distinguishing between two types of leakages is important for understanding the mechanism of how liposome-based drugs work. Our results indicate that microleakages not only do not contribute to the delivery of drugs to tumor cells but are also responsible for its unwanted accumulation in healthy tissues. The therapeutic effect is achieved due to macroleakages, and neutrophils can help strengthen it,” Viktor Naumenko emphasized.
The team is currently continuing laboratory studies to reduce the unwanted side effects of liposome therapy.