A chloroquine-induced macrophage-preconditioning strategy for improved nanodelivery

Joy Wolfram,Mauro Ferrari,Elvin Blanco,Zheng Li,Haoran Liu,Guodong Zhang,Haifa Shen,Sara Nizzero,Feng Li

doi:10.1038/s41598-017-14221-2

Joy Wolfram, Mauro Ferrari + Show 7 more

Open Access

https://doi.org/10.1038/s41598-017-14221-2

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Abstract

Site-specific localization is critical for improving the therapeutic efficacy and safety of drugs. Nanoparticles have emerged as promising tools for localized drug delivery. However, over 90% of systemically injected nanocarriers typically accumulate in the liver and spleen due to resident macrophages that form the mononuclear phagocyte system. In this study, the clinically approved antimalarial agent chloroquine was shown to reduce nanoparticle uptake in macrophages by suppressing endocytosis. Pretreatment of mice with a clinically relevant dose of chloroquine substantially decreased the accumulation of liposomes and silicon particles in the mononuclear phagocyte system and improved tumoritropic and organotropic delivery. The novel use of chloroquine as a macrophage-preconditioning agent presents a straightforward approach for addressing a major barrier in nanomedicine. Moreover, this priming strategy has broad applicability for improving the biodistribution and performance of particulate delivery systems. Ultimately, this study defines a paradigm for the combined use of macrophage-modulating agents with nanotherapeutics for improved site-specific delivery.

Highlights

The circulatory system is frequently exploited for drug delivery purposes, as it is often challenging to reach diseased cells through local interventions
This study demonstrates the novel use of chloroquine as an mononuclear phagocyte system (MPS)-preconditioning agent for improved site-specific delivery of particulate delivery systems
Chloroquine treatment lead to a reduction in nanoparticle endocytosis by macrophages, while uptake levels in cancer cells remained unchanged in response to the drug

Summary

Introduction

The circulatory system is frequently exploited for drug delivery purposes, as it is often challenging to reach diseased cells through local interventions. Up to 99% of the dose deposits in the liver and spleen, which contain resident macrophages that form the mononuclear phagocyte system (MPS)[9,10,11]. Less emphasis has been placed on modulating the microenvironment in the liver and spleen to reduce nanoparticle uptake[14]. Predominant pathways of nanoparticle uptake in the macrophage cell lines (pie chart). To explore the potential of MPS preconditioning strategies for improved drug delivery Such strategies should focus on transient deactivation of macrophages, as complete elimination of these cells has been shown to be toxic and even fatal in animal studies[15]

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