Neutrophil is a friend of the liposome
NUST MISIS scientists have discovered a new factor of effective drug delivery in tumors
The scientific team of the laboratory "Biological Nanomaterials" of NUST MISIS conducted an intravital (on living tissues) study of the mechanism of targeted drug delivery to malignant tumors using liposomes. It turned out that the immune cells of the neutrophil body increase the effectiveness of drug delivery to the tumor by 30%. The results of the work are published in the international scientific journal ACS Nano (Naumenko et al., Extravasating Neutrophils Open Vascular Barrier and Improve Liposomes Delivery to Tumors).
Liposomes – artificially created fat bubbles – penetrate the tumor due to the so-called effect of "enhanced permeability and retention" (enhanced permeability and retention, EPR).
The EPR effect occurs due to excessive vasodilation caused by the abnormal need of the tumor for oxygen and nutrition. With 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 penetrate only into the tumor, but not into healthy tissues. However, is this really the case? And what happens in the vessel?
Scientists of the laboratory "Biomedical Nanomaterials" of NUST MISIS The drug was observed to be delivered 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 us to study the processes directly in a living organism.
"The first conclusion that we received as a result of the study is that there are two types of liposome penetration from blood vessels into tissues in living tissues. A micro–leak is a small isolated accumulation of liposomes around a vessel. Such a process is useless for tumor therapy, as it does not allow the drug to reach tumor cells. Moreover, micro–leaks have been found in healthy tissues, which explains the toxicity of liposome-based drugs used in modern clinics," says Viktor Naumenko, the author of the work, a researcher at the Biomedical Nanomaterials laboratory of NUST MISIS.
The second, most interesting result of observation is that neutrophils, varieties of leukocytes, and immune cells of the body contribute to leaks into tumor tissue. When the neutrophil leaves the vessel, together with it, through the "slightly opening door" in the vascular wall, liposomes manage to penetrate into the tumor. According to the results obtained by the research team, neutrophils increase the efficiency of liposome penetration into the tumor by a third.
This discovery gives a clear pattern: neutrophils increase the permeability of tumor vessels for targeted delivery of liposomal drugs, and therefore increase the chances of a cure. Moreover, this happens only in the case of a macro leak, which is a large diffuse "cloud" of liposomes that penetrates deep into the tumor, thereby ensuring targeted drug delivery.
"Distinguishing between the two types of leaks is important for understanding the mechanism of how liposome-based drugs work. Our results indicate that micro-leaks not only do not contribute to the delivery of drugs to tumor cells, but are also responsible for its undesirable accumulation in healthy tissues. The therapeutic effect is achieved due to macro leaks, and neutrophils are able to help strengthen it," Viktor Naumenko stressed.
Currently, the team continues laboratory research in order to reduce the undesirable side effects of liposomal therapy.
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