Mononuclear phagocytes as a target, not a barrier, for drug delivery

    Mononuclear phagocytes as a target, not a barrier, for drug delivery Seok-Beom Yong, Yoonsung Song, Hyung Jin Kim, Qurrat Ul Ain, Yong-Hee Kim PII: DOI: Reference:

S0168-3659(17)30022-6 doi:10.1016/j.jconrel.2017.01.024 COREL 8623

To appear in:

Journal of Controlled Release

Received date: Revised date: Accepted date:

19 November 2016 6 January 2017 16 January 2017

Please cite this article as: Seok-Beom Yong, Yoonsung Song, Hyung Jin Kim, Qurrat Ul Ain, Yong-Hee Kim, Mononuclear phagocytes as a target, not a barrier, for drug delivery, Journal of Controlled Release (2017), doi:10.1016/j.jconrel.2017.01.024

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Review

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Mononuclear phagocytes as a target, not a barrier, for drug delivery

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Seok-Beom Yong, Yoonsung Song, Hyung Jin Kim, Qurrat Ul Ain, and Yong-Hee Kim*

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Department of Bioengineering, Institute for Bioengineering and Biopharmaceutical Research, BK 21 Plus Future Biopharmaceutical Human Resources Training and Research Team,

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Hanyang University, 133-791 Seoul, Republic of Korea

Seoul

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*Correspondence to: Yong-Hee Kim, Department of Bioengineering, Hanyang University,

Tel.:+82 2 2220 2345

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E-mail address: [email protected]

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Abstract

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Mononuclear phagocytes have been generally recognized as a barrier to drug delivery. Recently, a new understanding of mononuclear phagocytes (MPS) ontogeny has surfaced and

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their functions in disease have been unveiled, demonstrating the need for re-evaluation of perspectives on mononuclear phagocytes in drug delivery. In this review, we described

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mononuclear phagocyte biology and focus on their accumulation mechanisms in disease sites with explanations of monocyte heterogeneity. In the ‘MPS as a barrier’ section, we

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summarized recent studies on mechanisms to avoid phagocytosis based on two different

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biological principles: protein adsorption and self-recognition. In the ‘MPS as a target’ section,

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more detailed descriptions were given on mononuclear phagocyte-targeted drug delivery systems and their applications to various diseases. Collectively, we emphasize in this review that mononuclear phagocytes are potent targets for future drug delivery systems.

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Mononuclear phagocyte-targeted delivery systems should be created with an understanding of mononuclear phagocyte ontogeny and pathology. Each specific subset of phagocytes should be targeted differently by location and function for improved disease-drug delivery while avoiding RES clearance such as Kupffer cells and splenic macrophages.

Key words: Mononuclear phagocyte drug delivery, Phagocyte avoidance, Phagocyte-targeted delivery

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Contents

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1. Introduction 1.1. Mononuclear phagocyte biology

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1.2. Mononuclear phagocytes in disease

1.2.1. Mechanisms of phagocyte accumulation in disease

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1.2.2. Monocyte heterogeneity in disease 2. Phagocytes as a barrier in drug delivery

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2.1. Opsonization: protein adsorption in biological fluid

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2.1.1. Prevention of opsonization by Polyethylene glycol modification (PEGylation)

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2.2. CD47, ‘self’-recognizing receptor 2.2.1. CD47-derived ‘self’ peptide 2.2.2. Natural cell-derived membrane coating to mimic ‘self’

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3. Phagocytes as a target in drug delivery 3.1. Pathogen-derived drug delivery system 3.1.1. Bacterial ghosts 3.1.2. Yeast-derived glucan shells

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3.2. Targeting ligand-mediated delivery system

3.2.2. DC3 peptide for dendritic cell targeting 3.2.3. DEC205+ dendritic cell targeting

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3.2.1. RVG peptide for acetylcholine receptor (AchR) targeting

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3.2.4. CD163 (Hemoglobin scavenging receptor) targeting 3.2.5. Fc receptor targeting

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3.2.6. M2 peptide for M2 macrophage targeting

3.2.7. Mannose receptor targeting & the ‘eat me’ signaling peptide coating

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3.3.1. Lipid-like material

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3. 3. Other systems without targeting ligand

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3.3.2. Negatively charged nanoparticles 3.2.3. Thioketal nanoparticles 3.4. Cargo-attached phagocytes as a vector for drug delivery

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4. Conclusion & future perspectives Acknowledgements References

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1. Introduction

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1.1.Mononuclear phagocyte biology

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Mononuclear phagocytes, a subset of leukocytes, are involved in various biological functions such as homeostasis and the immune response. Mononuclear phagocytes are

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composed of monocytes, macrophages and dendritic cells, which are classified depending on their phenotypical and functional characteristics. Monocytes are circulating, not resident,

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cells with precursor and effector functions, while macrophages are tissue-resident

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professional phagocytic cells. Dendritic cells are antigen presenting cells with phagocytic

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functions in the adaptive immune response. Mononuclear phagocytes are distributed in every organ and tissue type, with specialized functions for interacting with each unique environment (Fig. 1). Kupffer cells in the liver are responsible for clearance of debris and

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foreign materials in the circulation [1, 2], and splenic red pulp macrophages remove senescent red blood cells [3]. Langerhans cells in the skin, alveolar macrophages in the lung, and microglial cells in the brain join the local inflammation reaction as immunological effector cells [4]. In the embryonic stage, yolk sac originated Myb independent macrophages give rise to tissue macrophages with self-renewal ability [5] before fetal liver hematopoiesis development, and generally hematopoietic stem cells in bone marrow give rise to mononuclear phagocytes after birth including circulating monocytes, which further

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differentiate into macrophages and dendritic cells in tissues [6]. In the steady state, mononuclear phagocytes in organs such as the intestines and liver are replenished and

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constitutively pooled by blood monocytes [7-9]; however, microglial cells in the brain [10]

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1.2. Mononuclear phagocytes in disease

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and Langerhans cells in the skin [6] are not.

In addition to their homeostatic functions in the healthy state, mononuclear

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phagocytes are involved in a broad spectrum of diseases, primarily by their accumulation and

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immunological effector functions [11]. Mononuclear phagocytes accumulate in disease areas

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and are differentiated and polarized by environmental cues; they increase the immune response by releasing cytokines or repairing damaged tissues. Macrophages can be generally categorized into M1 and M2 macrophages. M1 macrophages are classically activated and

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release inflammatory cytokines such as TNF-α, IL-6, and IL-1β, which increase inflammation. M1 polarization is related to most inflammatory diseases. M2 macrophages are alternatively activated macrophages that release IL-10 and suppress the immune-response. Tumor associated macrophages are representative of M2 polarization. In various inflammatory diseases, macrophages show multiple polarization states as in between M1-M2 spectra rather than M1 or M2 one-way polarization. Environmental cue-polarized macrophages release cytokines that function as immune-effector molecules and chemokines that attract the blood

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circulating immune cells to extravasate and enter the lesion [12]. Because many previous publications have already dealt with macrophage phenotypes and effector functions [13-15],

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here we focused on the origins and mechanisms of mononuclear phagocyte accumulation,

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specifically of macrophages, in disease areas.

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1.2.1. Mechanisms of phagocyte accumulation in disease

The mechanisms of phagocyte accumulation are broadly categorized by consistent

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monocyte migration and differentiation into inflammatory macrophages or by local

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proliferation. Swirski et al. demonstrated that splenic reservoir Ly6c high monocytes, rather

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than blood circulating monocytes and bone marrow derived cells, are the main migrating population for inflammation in cases of myocardial infarction [16]. On the other hand, in helminth infections, macrophage accumulation was reported to be induced by local

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proliferation of macrophages mediated by Th2 cytokine IL-4 and not from the consecutive supply from the monocytes [17]. In obese patients, chronic inflammatory diseases also highlight macrophage accumulation in adipose tissues as a major source for inflammatory cytokines [18, 19], and adipose tissue macrophage accumulation is thought to be dominated by migration of blood monocytes [20].On the other hand, a recent paper demonstrated that local proliferation of macrophages induced by MCP-1 also contributes to their accumulation in adipose tissue [21]. In atherosclerotic plaques, monocyte migration dominates phagocyte

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accumulation in early disease stages; however, local proliferation of macrophages is the main source for late disease stage lesion macrophage accumulation [22]. In brain inflammation

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using the experimental autoimmune encephalitis (EAE) model, inflammatory monocytes are the major and leading cells inducing EAE pathology that do not give rise to microglial cells

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in the healthy state [23, 24]. Macrophages that accumulate in tumor sites are termed tumor associated macrophages and raise cancer cells by immune suppression [25-30]. Franklin et al.

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demonstrated that tumor associated macrophages were pooled by inflammatory monocytes and that tissue resident macrophages are more closely related to the M2 phenotype than to

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tumor associated macrophages in terms of molecular characteristics [31].

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1.2.2. Monocyte heterogeneity in disease

Monocytes can be classified into classical or inflammatory monocytes and non-classical or

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patrolling monocytes based on their functions and surface proteins such as Ly6c, CD14, CD16, CCR2 and CCR5 [32]. Generally, CCR2+ inflammatory monocytes (CD14 high monocytes in human; Ly6c high monocytes in mouse) are thought to be the disease driving population by lesion accumulation giving rise to inflammatory macrophages; they differ from the non-classical monocytes, which function in tissue regeneration and immune surveillance by patrolling the vessel endothelium [33, 34]. CCR2+ inflammatory monocytes are the dominant migrating populations for described diseases; however, in a recent paper on

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rheumatoid arthritis, patrolling, non-classical monocytes (Ly6c low) were shown to be the disease driving population, and depletion of Ly6c high inflammatory monocytes did not

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affect the progression of rheumatoid arthritis [35]. In cases of tumor metastasis, Ly6c high CCR2+ inflammatory monocytes attracted by CCL2 support and trigger cancer cell

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metastasis [36], while Ly6c low patrolling monocytes suppress lung cancer metastasis [37]. Therefore, each subset of monocytes has different, not unified, generalized functions in

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disease pathologies.

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2. Phagocytes as a barrier in drug delivery

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Based on their biological functions, phagocytes have diverse roles in drug delivery. For a long time, phagocytes have been regarded as a hindrance to drug delivery. Most of the

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administered nanoparticles or drug delivery systems are sequestered and cleared by the reticuloendothelial system (RES) such as Kupffer cells in the liver and splenic macrophages. This primary hurdle has fueled the development of phagocyte avoidance systems. In this section, we introduce recent advances in the development of phagocyte avoidance technology.

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2.1. Opsonization: protein adsorption in biological fluid

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In a biological environment, systemically administered nanoparticles reach the blood stream and encounter diverse serum proteins. The serum proteins bind to the nanoparticle

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surface forming a protein ‘corona’, which affects the biological pathophysiology of the nanoparticles. Generally, adsorbed plasma proteins, opsonins, play a role as a bridge for

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Kupffer cell phagocytosis of nanoparticles [38]. Recently, protein coronas formed on silver nanoparticles and polystyrene nanoparticles were analyzed, and their dynamics and

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complexity over time were revealed [39]. Based on the knowledge of protein adsorption-

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mediated phagocytic uptake, various methods to reduce protein adsorption on nanoparticular

to diseases sites.

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drug delivery systems have been developed to prolong circulation and enhance drug delivery

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2.1.1. Prevention of opsonization by Polyethylene glycol modification (PEGylation)

Polyethylene glycol modification (PEGylation) has been applied to produce commercial drug delivery blockbusters. Compared to uncoated nanoparticles, PEGylated nanoparticles were shown to block serum protein binding on the surface and maintain prolonged circulation. The addition of hydrophilic PEG shell increased the biocompatibility of nanoparticles in the blood, conferring a stealth effect [40-43]. PEGylation not only reduces

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protein adsorption onto nanoparticles, but also controls protein corona composition depending on the density and size of the PEG used. High-density PEGylation inhibited serum

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dependent phagocytic or endocytic nanoparticle uptake in the presence of serum [44]. Recently, Schöttler et al. [45] demonstrated that the prevention of protein adsorption is not

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the direct reason for the PEG-mediated stealth effect. Rather, PEGylated nanoparticles mediate adsorption of specific serum lipoprotein, clusterin (apolipoprotein J) which have

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been reported to present various functions such as complement prevention. PEGylated nanoparticles exhibited low level of non-specific macrophage uptake when exposed to

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plasma proteins. Phagocytic uptake of polystyrene beads, modified with PEG or poly(ethyl

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ethylene phosphate) (PEEP), was inhibited in the presence of clusterin on the bead surface.

2.2. CD47, ‘self’-recognizing receptor

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Besides the prevention of protein adsorption, ‘self’ recognition has been spotlighted as an alternative strategy for drug delivery. The immune system distinguishes foreign invaders from 'self' because foreign particles are absent of 'markers of self', which are normally present on host cells. CD47, one of these 'markers of self', was been found of the red blood cell (RBC) surfaces [46] and most cells [47-50]. CD47 on normal cells prevented RES uptake by ‘don’t-eat-me’ signaling to induce inhibitory signaling of SIRP-α on macrophages [51]. Inconsistent with its primary function of identifying ‘self’, CD47 is

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overexpressed in many types of cancer cells for immune suppression and has been shown to

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be a target for cancer therapy [52-54].

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2.2.1. CD47-derived ‘self’ peptide

Minimal ‘self’ peptides, 21 amino acid residues which were designed from human

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CD47, showed appropriate binding and signaling of phagocytosis-inhibition. The minimal ‘self’ peptides-coated nanoparticles prolonged circulation time with reduced splenic

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accumulation in vivo compared to PEG-modified nanoparticles and whole human CD47-

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coated nanoparticles by inhibition of SIRP-α signaling-mediated phagocytosis, resulting in

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enhanced drug delivery to tumors [55].

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2.2.2. Natural cell-derived membrane coating to mimic ‘self’

Since CD47 is expressed on the surface of most cells, nanoparticles coated with cellderived membranes have shown ‘self’ mimicking phagocyte avoidance. Red blood cell (RBC) biomimetic particles were developed and RBC-derived membrane-coated PLGA particles have shown to retain membrane proteins of original RBC, including CD47 with the correct orientation, which resulted in prolonged circulation time with higher blood retention compared to PEG-modified nanoparticles or plain nanoparticles [56-58]. Functionalized

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silicon nanoparticles with the leukocyte membrane retained functional leukocyte surface proteins and showed reduced uptake by phagocytic cells of mouse and human origin in vitro,

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and delayed clearance by Kupffer cell in vivo. Additionally, leukocyte membranefunctionalized nanoparticles penetrated the endothelium and homed to the inflamed tissue by

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the natural characteristics of the leukocytes [59]. Platelet membrane bio-interfaced nanoparticles with functional CD47 also showed reduced phagocytic uptake with result of

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increased adhesion to the damaged tissues of rat. Based on natural platelet function, platelet nanoparticles bound to pathogens and suppressed their growth [60].

Instead of purifying

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and coating with cell membranes, Molinaro et al. [61] purified whole membrane proteins and

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reconstituted them in a form of artificial lipid layer. In addition to 'self’ marker-based

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phagocyte avoidance, cell membrane-derived biomimetic nanoparticles showed similar

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characteristics of originated cells.

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in biological fluid Prevention

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Polyethylene glycol (PEG)

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Mechanism Opsonization: protein adsorption

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Table 1. Summary of phagocyte avoidance systems

protein

Reference

adsorption, [39-42]

clusterin-mediated stealth effect ethyl

ethylene

phosphate Prevention

(PEEP)

of

protein

adsorption, [45]

clusterin-mediated stealth effect

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CD47, ‘self’-recognizing receptor

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CD47-derived ‘self’ peptide

Leukocyte

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Red blood cell mimetic nanoparticle membrane

nanoparticle

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reconstitution

leukocyte membrane-derived protein

Self-recognition

[55]

Self-recognition

[56-58]

coated Self-recognition, inflammatory tissue [59] homing effect

Platelet bio-interfaced nanoparticle

Liposome

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Poly

Self-recognition, pathogen suppressing [60] effect

with Self-recognition, inflammatory tissue [61] homing effect

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3.1. Pathogen-derived drug delivery system

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3. Phagocytes as a target in drug delivery

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The accumulation of mononuclear phagocytes in disease areas along with the main effector functions of mononuclear phagocytes inspired the idea that phagocytes could be a

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target for drug delivery. Phagocytes targeted drug delivery can reduce phagocyte mediated inflammation and diseases 1. By reducing inflammatory cytokines directly in MPS and 2.

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Inflammatory cell infiltration inhibition. Recognition of pathogens is mediated by pattern-

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recognition receptors on phagocytes and signaling for intracellular uptake [62, 63].

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Considering the pathogen-uptake characteristic of phagocytes, diverse pathogen-derived

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delivery systems were reported for phagocytic drug delivery.

3.1.1. Bacterial ghosts

E. coli-derived hollow bacterial ghosts containing EGFP plasmids were uptaken and expressed in mouse macrophage cells [64, 65]. Bacterial ghost-mediated vaccination induced adaptive immune responses against the target antigens in vivo, which was proposed as a strategy for cancer therapy [66].

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3.1.2. Yeast-derived glucan shells

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When β-1,3-D-glucan shells obtained from bakers’ yeast and loaded with siRNAs for TNF-α and Map4k4 were orally administered, phagocyte uptake was observed in gut

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associated lymphatic tissue (GALT) by recognizing dectin-1 (CLEC7A), resulting in suppressed inflammatory responses and improved survival rates in a mouse sepsis model [67,

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68]. In a type 2 diabetic obese mouse model, β1,3-D-glucan shells-mediated antiinflammatory siRNA delivery reduced inflammation in adipose tissue and improved overall

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metabolism and insulin sensitivity [68]. Further study with siRNA for lipoprotein lipase (LPL)

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also demonstrated the efficiency of a yeast-derived system for phagocyte-targeted gene

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delivery [69]. Antigens were delivered to dendritic cells using yeast-derived micro-particles and this system demonstrated a potential for cancer-immunotherapy [70]. Collectively, natural pathogen-derived systems have a strong potential for use in phagocyte-targeted drug

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delivery. However, there exists a risk of triggering an immune response due to pattern recognition receptor signaling such as induction of TNF-α or other cytokines [63, 71-73].

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3.2. Targeting ligand-mediated delivery system

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3.2.1. RVG peptide for acetylcholine receptor (AchR) targeting

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RVG peptide derived from rabies-virus glycoprotein was reported to mediate internalization into macrophages and dendritic cells via binding to the acetylcholine receptor.

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Oligo-arginine (9R)-conjugated RVG peptide delivered siRNA silencing TNF-α to mouse macrophages and demonstrated reduced neuro-and systemic- inflammation in vivo [74]. In

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mice transplanted with human immune cells, RVG-9R complexed with siRNA silencing

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HMGB1 was internalized into human macrophages and dendritic cells, resulting in improved

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survival rates in a humanized sepsis model [75]. However, since the RVG peptide was initially developed for brain-targeted siRNA delivery [76], unexpected adverse effects in the

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brain cannot be excluded.

3.2.2. DC3 peptide for dendritic cell targeting

DC3 represents 12-mer peptide screened on human dendritic cell by phage display. DC3 peptide solely binds to dendritic cells, not to other cells and doesn’t change the dendritic cell phenotype. For the purpose of immunization via dendritic cell, DC3-mediated antigen delivery to dendritic cells induced a targeted antigen-specific immune response [77]. DC3

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was also conjugated with oligo-arginine forming DC3-9R and DC3-9R-mediated siRNA delivery suppressed dengue virus replication in human dendritic cells and humanized mice

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with reduced TNF-α production [78].

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3.2.3. DEC205+ dendritic cell targeting

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High expression of DEC205, one of the C type lectins, on CD8α+ dendritic cells [79] inspired the dendritic cell-targeted drug delivery system. Anti-DEC205 single chain antibody-

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mediated tumor antigen delivery induced MHC class II-antigen presentation and a tumor

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antigen specific immune response [80]. The DEC205-targeted liposome delivered siRNAs to

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dendritic cells for immune-costimulatory factors such as CD40, CD80 and CD86 and reduced dendritic cell mediated immune signaling [81].

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3.2.4. CD163 (Hemoglobin scavenging receptor) targeting

Macrophage-specific expression of hemoglobin scavenging receptor, CD163, enabled targeted drug delivery [82]. Anti-CD163 antibody conjugated to dexamethasone showed an anti-inflammatory effect in a rat model [83], and CD163 antibody decoration of liposomes improved monocyte liposome uptake and intracellular cytotoxic drug delivery compared with plain liposomes [84].

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3.2.5. Fc receptor targeting

Fc receptor-mediated drug delivery is an alternate stream of phagocyte-targeting. IgG

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decoration on liposomes improved Fc receptor-mediated macrophage uptake of nanoparticles and antigen delivery to DCs [85]. A recent paper demonstrated improved drug efficacy

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against Staphylococcus aureus, which can resist from antibiotics by protective niche for S. aureus in the host cells. Anti-S. aureus monoclonal antibody-conjugated antibiotics

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demonstrated intracellular killing of bacteria after Fc receptor-mediated uptake. [86]. Among

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human Fc receptors, Fc gamma receptor I (FcgRI) is monocyte-lineage restricted and has

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demonstrated macrophage and monocyte targeted drug delivery. Anti-FcgRI antibody conjugation of oligo-arginine improved human macrophage gene delivery (unpublished data).

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3.2.6. M2 peptide for M2 macrophage targeting

Following phage display, the M2 macrophage targeting peptide (M2pep, YEQDPWGVKWWY) was recently screened on IL-4 polarized macrophages and demonstrated a higher binding ability to the M2 phenotype than to the M1 phenotype both in vitro and in vivo. Tumor-associated macrophages (TAMs) have been known to express antiinflammatory M2-like characteristics. The apoptotic KLAK peptide, after conjugation with

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the M2pep, induced apoptosis of TAMs in cancer cell bearing mice [87, 88]. M2pep-coated gold nanoparticles delivered siRNA silencing VEGF to TAMs with tumor suppression effects

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[89].

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3.2.7. Mannose receptor targeting & the ‘eat me’ signaling peptide coating

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Mannose receptors are highly expressed on surfaces of macrophages and dendritic cells. Nanoparticles coated with mannose for targeting the mannose receptor have been

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applied for antigen delivery [90] and chemical drug delivery [91]. Mannose receptors are also

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highly expressed on TAMs. Anti-mannose receptor nanobodies targeted TAMs were reported

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[92]. Mannose receptor-mediated gene delivery to alveolar macrophages and dendritic cells was reported [93, 94]. Tuftsin (TKPR) is one of the 'eat-me' signaling peptide. Tuftsinmodified alginate nanoparticles also demonstrated efficient macrophage gene delivery for

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anti-inflammation [95].

3.3. Other systems without targeting ligand

The above described studies mainly focused on ligand-mediated receptor targeting. Non-targeting systems such as, lipid-like materials and charge-based systems have also demonstrated efficient phagocyte drug delivery.

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3.3.1. Lipid-like material

Based on epoxide chemistry, Leuschner et al. [96] synthesized lipidoid libraries and

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showed that lipidoid nanoparticle such as C12-200 had the highest hepatocyte gene silencing ability in vivo with a low dose of siRNA. Lipidoid nanoparticles encapsulated with siRNAs

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were delivered and silenced monocyte chemokine receptors in blood, spleen and bone marrow, resulting in reduced chemotactic accumulation of inflammatory monocytes in

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various disease models such as myocardial infarction, islet transplantation, atherosclerosis

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and tumor [97]. Recently, lipidoid nanoparticle C12-200-mediated delivery of interferon

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regulatory factor (IRF5) siRNA in a myocardial infarction mouse model demonstrated M2 macrophage polarization in infarcted lesions in addition to improved infarct lesion healing [98]. Additionally, lipid like material showed myeloid cells-gene silencing in a non-human

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primate study [99].

3.3.2. Negatively charged nanoparticles

Generally, it is considered that nanoparticles with negative surface charge have difficulty in entering the cellular membrane because of charge-charge repulsion. However, surface carboxylated-PLGA microparticles showed MARCO-mediated monocyte uptake and

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triggered alteration of monocyte behavior for splenic accumulation, induced apoptosis and, consequently, inhibited monocyte migration in inflammatory regions with therapeutic effects

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[100]. Ratio-optimized negatively charged liposomes also demonstrated splenic accumulation of dendritic cells with targeted RNA delivery and induced immunization against the RNA-

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translated antigen. These results demonstrate that a subset of phagocytes can be targeted by charge modification solely without ligand modifications. Positively charged amino acids such

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as lysine-rich domains of MARCO were suggested as binding and internalization receptor

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3.3.3. Thioketal nanoparticles

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[101].

Wilson et al. [102] developed a thioketal nanoparticular (TKN) system utilizing ROS-induced degradation mechanism after uptake by phagocytes in the inflammatory

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environment. Orally delivered TKN encapsulating siRNA for TNF-α alleviated colitis severity in a dextran sodium sulfate (DSS)-induced mouse colitis model [102].

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3.4. Cargo-attached phagocytes as a vector for drug delivery

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In addition to being considered as direct targets for drug delivery, phagocytes have been used as vectors for drug delivery to diseased areas. Fundamentally, cargo-attached phagocytes are

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different from the phagocyte-targeting systems, but they are more closely related in sense of guiding them to disease region and phagocyte-mediated disease cure.Doshi et al. [103] phagocytosis-resistant

backpacks

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developed

with

multimeric

polymer

layers

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demonstrated controlled release of the model protein from the phagocyte attached backpack.

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Phagocytosis-resistant backpacks were not taken up by monocytes in vitro and delivered

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drugs to inflamed lung and skin more efficiently than healthy state after intravenous injection

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[104]. With the tumor-homing effect of monocytes, Wen-chia et al. developed a doxorubicin containing-echogenic polymer bubble and loaded them with mouse macrophages; that

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cellular vehicle localized to the tumor region and demonstrated anti-cancer effects [105].

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Table 2. Summary of phagocyte-targeted drug delivery systems Target cell drug

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Pathogen-derived

Cargo

delivery system Macrophage, cell Phagocytes

in

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Yeast-derived glucan shells

dendritic Antigen, siRNA

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Bacterial ghosts

associated

gut Antigen, siRNA

Reference

[64-66]

[67-70]

lymphatic

ligand-mediated

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Targeting

peptide

targeting

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delivery system RVG

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tissue

for

AchR Macrophage,

dendritic siRNA

[74-76]

cell Dendritic cell

Antigen, siRNA

[77, 78]

DEC205+ DC targeting

CD8α+ dendritic cell

Antigen, siRNA

[79-81]

Chemical drug

[82-84]

Antigen,

[85, 86]

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DC3 peptide for DC targeting

CD163

(Hemoglobin Monocyte, macrophage

scavenging receptor) targeting Fc receptor targeting

Monocyte, macrophage,

dendritic chemical drug

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for

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peptide

M2 Tumor

macrophage targeting

associated Apoptotic

macrophage

Mannose receptor targeting & Macrophage,

dendritic Antigen, siRNA, [90-95]

the ‘eat me’ signaling peptide cell

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imaging

coating systems

without

targeting ligand

charged Monocyte,

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Negatively

Monocyte, macrophage

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Lipid-like material (C12-200)

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nanoparticles

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Thioketal nanoparticles

agent,

toxin

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Other

[87-89]

peptide, siRNA

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M2

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cell

siRNA

[96-99]

splenic Antigen encoding [100, 101]

dendritic cell

RNA

Macrophage

siRNA

[102]

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4. Conclusion & future perspectives

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Textbook knowledges on mononuclear phagocyte homeostasis and ontogeny are changing [6] and mechanisms of their accumulation in disease lesions are resurfacing. Due to

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the unclarified functions and phenotypes of MPS in vivo, Guilliams called for re-unification of MPS nomenclature [106]. Certain subsets of monocytes have potential for use as drug

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delivery targets. Inflammatory monocytes are potent drug delivery targets for various diseases due to their disease site accumulating nature. A recent paper demonstrated that the

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tumor targeting effects of RGD-modified carbon-nanotubes were partially mediated and

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enhanced by inflammatory monocytes (~25% of total tumor accumulated carbon nanotubes)

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[107], which suggests inflammatory monocyte-mediated or targeted drug delivery for tumor therapy. Different from inflammatory monocytes, patrolling monocytes show specialized functions in the disease pathology of rheumatoid arthritis [35] and cancer metastasis [37],

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potentiating patrolling monocyte-targeted systems for understanding of disease pathology and for therapeutic purposes. The blood brain barrier is a major hurdle for brain drug delivery, and brain inflammation attracts inflammatory monocytes, which allows monocyte-mediated drug delivery systems for brain diseases such as Alzheimer’s disease [108]. Recently, many papers reported that mononuclear phagocytes are heterogeneous even in the same tissue. In tumor region, tumor associated macrophages (TAM) are divided into subtypes depending on their microenvironment [109]. Furthermore, tumor associated dendritic cells (TADC) also

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showed heterogeneity with different antigen uptake ability and T cell activation [110]. These

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studies indicate necessity of ‘subtype’-specific targeting systems for efficient therapy. Despite

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disease accumulating and phagocytic characteristics, MPS-internalized cargo does not ensure drug delivery efficiency. DEC205-mediated CpG-siRNA uptake in human monocytes showed

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a high uptake rate with no-target gene silencing effect [111], therefore, the MPS endosomal pathway should be overcome for efficient cargo delivery. Avoiding Kupffer cell clearance in

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the liver is another important challenge. A recent paper on the protein corona showed coronadirected liver hepato-stellate cell gene delivery, while avoiding Kupffer cell uptake [112],

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suggesting corona-mediated inhibition of Kupffer cell clearance. In conclusion, mononuclear

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phagocytes are attractive targets for development of future drug delivery systems;

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mononuclear phagocyte-targeted delivery systems should be created with an understanding of mononuclear phagocyte ontogeny and pathology. Consequently, each specific subset of phagocytes should be targeted differently by location and function for improved disease-drug

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delivery while avoiding RES clearance such as Kupffer cells and splenic macrophages.

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Acknowledgements

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This work was partially supported by grants from the National Research Foundation of Korea (2014049587, 2015003019), the Brain Korea 21 plus program (22A20130011095), and the

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Korean Health Technology R&D project through the Ministry of Health & Welfare (HI13C-

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1938-010014).

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Fig 1. Mononuclear phagocyte distribution in the body

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Fig 2. Mononuclear phagocyte accumulation into disease region

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Fig. 3. Nanotechnologies for phagocyte avoidance

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Fig. 4. Phagocyte-targeted drug delivery systems

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Graphical abstract