ABSTRACT: Liposomes are the most extensively used 14 nanocarriers in cancer therapy. Despite the advantages 15 these vehicles provide over free drugs, there are still 16 limitations with regards to the efficiency of liposomes delivery 17 to tumors and off-target accumulation. A better under-18 standing of nanodrugs extravasation mechanisms in different 19 tumor types and normal vessels is needed to improve their 20 antitumor activity. We used intravital microscopy to track for 21 fluorescent liposomes behavior in xenograft tumor models 22 (murine breast cancer 4T1 and melanoma B16, human 23 prostate cancer 22Rv1) and normal skin and identified two 24 distinct extravasation patterns. Microleakage, a local peri-25 vascular nanoparticle deposition, was found both in 26 malignant and healthy tissues. This type of liposomes leakage does not provide access to tumor cells and is presumably 27 responsible for drug deposition in normal tissues. In contrast, macroleakage penetrated deep into tissues and localized 28 predominantly on the tumor−host interface. Although neutrophils did not uptake liposomes, their extravasation appeared 29 to initiate both micro- and macroleakages. Based on neutrophils and liposomes extravasation dynamics, we hypothesized
30 that microleakage and macroleakage are subsequent steps of the extravasation process corresponding to liposomes 31 transport through endothelial and subendothelial barriers. Of note, extravasation spots were detected more often in the 32 proximity of neutrophils, and across studied tumor types, neutrophils counts correlated with leakage frequencies. 33 Reduced liposomes accumulation in 4T1 tumors upon Ly6G depletion further corroborated neutrophils role in 34 nanoparticles delivery. Elucidating liposomes extravasation routes has a potential to help improve existing strategies and 35 develop effective nanodrugs for cancer therapy.
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Supporting Information
Victor A. Naumenko, Kseniya Yu. Vlasova, Anastasiia S. Garanina, Pavel A. Melnikov, Daria M. Potashnikova,∥ Daniil A. Vishnevskiy, Stepan S. Vodopyanov, Vladimir P. Chekhonin, Maxim A. Abakumov and Alexander G. Majouga
National University of Science and Technology (MISIS), Moscow 119049, Russia
School of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119991, Russia
Department of Medical Nanobiotechnology, N. I. Pirogov Russian National Research Medical University, Moscow 117997, Russia
School of Biology, Department of Cell Biology and Histology, M. V. Lomonosov Moscow State University, Moscow 119234, Russia
Mendeleev University of Chemical Technology of Russia, Moscow 125047, Russia