Chemokine-Releasing Nanoparticles for Manipulation of Lymph Node Microenvironment.

Taissia G Popova,Virginia Espina,Lance A Liotta,Ruben Magni,Allison Teunis,Alessandra Luchini,Serguei G Popov

doi:10.3390/nano5010298

Abstract

Chemokines (CKs) secreted by the host cells into surrounding tissue establish concentration gradients directing the migration of leukocytes. We propose an in vivo CK gradient remodeling approach based on sustained release of CKs by the crosslinked poly(N-isopropylacrylamide) hydrogel open meshwork nano-particles (NPs) containing internal crosslinked dye affinity baits for a reversible CK binding and release. The sustained release is based on a new principle of affinity off-rate tuning. The NPs with Cibacron Blue F3G-A and Reactive Blue-4 baits demonstrated a low-micromolar affinity binding to IL-8, MIP-2, and MCP-1 with a half-life of several hours at 37 °C. The capacity of NPs loaded with IL-8 and MIP-1α to increase neutrophil recruitment to lymph nodes (LNs) was tested in mice after footpad injection. Fluorescently-labeled NPs used as tracers indicated the delivery into the sub-capsular compartment of draining LNs. The animals administered the CK-loaded NPs demonstrated a widening of the sub-capsular space and a strong LN influx of leukocytes, while mice injected with control NPs without CKs or bolus doses of soluble CKs alone showed only a marginal neutrophil response. This technology provides a new means to therapeutically direct or restore immune cell traffic, and can also be employed for simultaneous therapy delivery.

Highlights

Lymphoid organs and tissues of the host play key roles in the protection of the host from infections and spread of tumors
The NPs we synthesized are based on poly(N-isopropylacrylamide) and methylenebisacrylamide as a cross-linker co-polymerized with allylamine or acrylic acid (AAc,) for incorporation of different chemical baits [19]
The average particle diameter in PBS at 25 °C for different batches was in the range of 600–700 nm with a standard deviation of size from 3 to 17 nm

Summary

Introduction

Lymphoid organs and tissues of the host play key roles in the protection of the host from infections and spread of tumors. CKs secreted by the host cells into the surrounding tissue establish soluble and/or immobilized concentration gradients directing the migration of leukocytes toward areas of high CK concentration. Macrophages, dendritic cells (DCs) and neutrophils (PMNs) use chemotaxis for delivery and presentation of antigens to secondary lymphoid organs. Many pathogens have evolved sophisticated means to thwart the host defense system, including the blockade of leukocyte chemotaxis toward the infection [3,4]. A promising approach is to locally engineer CK gradients with the goal of promoting the accumulation of key immune players, such as DCs and neutrophils, or eliciting cascades of immune responses to eliminate pathogens or tumors [5,6,7]

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