Extravasating Neutrophils Open Vascular Barrier and Improve Liposomes Delivery to Tumors

Abstract

Liposomes are the most extensively used nanocarriers in cancer therapy. Despite the advantages these vehicles provide over free drugs, there are still limitations with regards to the efficiency of liposomes delivery to tumors and off-target accumulation. A better understanding of nanodrugs extravasation mechanisms in different tumor types and normal vessels is needed to improve their antitumor activity. We used intravital microscopy to track for fluorescent liposomes behavior in xenograft tumor models (murine breast cancer 4T1 and melanoma B16, human prostate cancer 22Rv1) and normal skin and identified two distinct extravasation patterns. Microleakage, a local perivascular nanoparticle deposition, was found both in malignant and healthy tissues. This type of liposomes leakage does not provide access to tumor cells and is presumably responsible for drug deposition in normal tissues. In contrast, macroleakage penetrated deep into tissues and localized predominantly on the tumor−host interface. Although neutrophils did not uptake liposomes, their extravasation appeared to initiate both micro-and macroleakages. Based on neutrophils and liposomes extravasation dynamics, we hypothesized that microleakage and macroleakage are subsequent steps of the extravasation process corresponding to liposomes transport through endothelial and subendothelial barriers. Of note, extravasation spots were detected more often in the proximity of neutrophils, and across studied tumor types, neutrophils counts correlated with leakage frequencies. Reduced liposomes accumulation in 4T1 tumors upon Ly6G depletion further corroborated neutrophils role in nanoparticles delivery. Elucidating liposomes extravasation routes has a potential to help improve existing strategies and develop effective nanodrugs for cancer therapy.

Recent Advances in Nanocarrier-Assisted Therapeutics Delivery Systems

“…Thus far, the majority of liposomal nanocarriers are intended for intravenous use [16]. While being the most extensively used nanocarriers in cancer therapy, wider applications of liposomal nanocarriers are still challenged by their capacity to reach the desired delivery efficiency and their inevitable off-target accumulations [17].…”

Macrophage imaging and subset analysis using single-cell RNA sequencing

“…Myeloid cells play central roles in shaping the vasculature, extracellular matrix, and overall EPR effect of tissues. For instance, perivascular TAM and neutrophils can produce growth factors including vascular endothelial growth factor (VEGF) to promote angiogenesis and metastasis in solid tumors [173], and this also can promote local bursts of vessel permeability and drug penetration into tissue [8,174].…”

The Neutrophil: Constant Defender and First Responder

“…Manipulating PMN responses could be the basis of an effective potential cancer immunotherapy approach, the goal of which would be to restore the pro-inflammatory function of PMNs and direct them toward tumor associated molecular patterns (127). A recent study has shown that pores in the endothelial barrier, formed by extravasating PMNs, improve the delivery of liposomes to tumors (128), and therefore could contribute to efficacy in new cancer therapy approaches that rely on delivery of drugs inside liposomes.…”