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Exploiting or overcoming the dome trap for enhanced oral immunization and drug delivery
Accepted Manuscript Exploiting or overcoming the dome trap for enhanced oral immunization and drug delivery
Jianping Qi, Jie Zhuang, Yongjiu Lv, Yi Lu, Wei Wu PII: DOI: Reference:
S0168-3659(18)30081-6 doi:10.1016/j.jconrel.2018.02.021 COREL 9169
To appear in:
Journal of Controlled Release
Received date: Revised date: Accepted date:
11 December 2017 14 February 2018 14 February 2018
Please cite this article as: Jianping Qi, Jie Zhuang, Yongjiu Lv, Yi Lu, Wei Wu , Exploiting or overcoming the dome trap for enhanced oral immunization and drug delivery. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Corel(2017), doi:10.1016/j.jconrel.2018.02.021
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ACCEPTED MANUSCRIPT Exploiting or overcoming the dome trap for enhanced oral immunization and drug delivery
Key Laboratory of Smart Drug Delivery of MOE and PLA, School of Pharmacy,
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Jianping Qi1†, Jie Zhuang2†, Yongjiu Lv1 , Yi Lu1 , Wei Wu1,*
Institute of Nanotechnology and Health, School of Pharmacy, Shanghai University of
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Fudan University, Shanghai 201203, China
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Medicine & Health Sciences, Shanghai 201318, China
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These authors contributed equally to this article.
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†
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Corresponding author. Tel. & fax: +86 21 51980084. E-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract The microfold cells (M cells) residing in the outmost follicle-associated epithelia (FAE) of Peyer ’s patches capture foreign particles and hand over to sub-FAE lymphatics, where the particles are retained and disposed subsequently. A concept of “dome trap” is proposed to highlight the significance of this mechanism. For oral
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immunization, it is better to exploit the entrapment capacity to maximize immune response, whereas for drug delivery it is better to overcome the dome trap to transport
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drugs into the systemic circulation. By optimizing the size, shape, surface charges and
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surface properties of particles, either oral immunization or drug delivery can be potentially enhanced.
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Keywords: dome trap; oral; immunization; drug delivery; M cells; endocytosis;
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lymphatics
ACCEPTED MANUSCRIPT List of abbreviations DCs: dendritic cells FAE: follicle-associated epithelia GALT: gut-associated lymphatic tissues GC: germinal center GIT: gastrointestinal tract
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GMs: glucan microparticles GRAS: generally recognized as safe
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HPV: human papilloma virus IBD: inflammatory bowel disease
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IFR: intrafollicular region LAB: lactic acid bacteria
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LPS: lipopolysaccharide MPL: monophosphoryl lipid A
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PAMPs: pathogen-associated molecular patterns PEG: polyethylene glycol PLA: poly(lactic acid) PPs: Peyer’s patches
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PVA: poly(vinyl alcohol)
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PLGA: poly(lactic-co-glycolic acid)
SED: subepithelial dome region SLNs: solid lipid nanoparticles
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TL: tomato lectins
UEA-1: ulexeuropaeus 1 VLPs: Virus-like particles WGA: wheat germ agglutinin YCM: yeast cell derived microparticles
ACCEPTED MANUSCRIPT 1.
Introduction
Oral drug delivery is more promising than other routes because of ease of administration, multiple selectivity of dosage forms, safety issues and good patient compliance [1-3]. However, not all therapeutic drugs are absorbable via the gastrointestinal tract (GIT). The intestinal epithelia only admit a limited fraction of
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small molecules with properties favorable for absorption [4, 5]. Macromolecules and particles are not welcomed all the time. Paradoxically, researchers have long been
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intrigued with the challenge of delivering biomacromolecules (peptides, proteins,
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polysaccharides, nucleic acids, vaccines, etc.) via the oral route [6-8]. It is fortunate that the GIT "opens" a small window for us to achieve the goal; that is the
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long-recognized microfold cells (M cells) pathway [9-13]. Fig. 1 summarizes the general route and highlights the role of M cell pathway for the entry of various
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therapeutic drugs into the human body.
The M cells residing in the intestinal epithelia have long been recognized as
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scavengers to clear up pathogens entering the digestive tract [11]. On the other hand,
Fig. 1 The schematic diagram of general routes for the entry of various therapeutic drugs into the human body. Abbreviations: APC, antigen-presenting cells; GALT, gut-associated lymphoid tissue.
ACCEPTED MANUSCRIPT
the M-cell passage also opens a portal for the entry of therapeutic drugs into the systemic circulation [14, 15]. Now it is clear that M cells take up particulates and transport them very quickly to the subepithelial gut-associated lymphoid tissues (GALT) for further processing [16, 17]. By mimicking pathogens, antigens could be
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delivered to GALT in sufficient amount, where antigen-presenting cells (APC) are abundant, to elicit efficient oral immunization [18, 19]. Albeit beneficial from a
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perspective of oral immunization, the entrapment by GALT creates a barrier to
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systemic drug delivery [17].
Both oral immunization and oral delivery via M cells have a long history of
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almost thirty years [20-22]. In spite of years of efforts, the gross oral bioavailability of particles is limited to a maximum of 5-7% owing to the bottleneck of the M cell
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pathway [17, 23, 24]. On the contrary, oral immunization using particulate adjuvant is resurging recently [25], partly thanks for improved understanding of the underlying
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mechanisms. To better explain the situation, we proposed a concept of "dome trap" to highlight the significance of the lymphatic uptake and retention mechanisms. The
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current task is to either exploit the trapping capacity of the dome trap to optimize immune response or cross it for more efficient drug delivery. This paper will clearly outline the concept of “dome trap” and make updated
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reviews on recent approaches to optimize the efficacy of either oral immunization or drug delivery. The clarification of this concept is of scientific significance to point the way for future researches. 2. The concept of dome trap 2.1.Structure and physiology of the dome trap Small intestine serves as not only an important organ for the absorption of nutrients but also a physiological guard to fend off microorganisms. The lumen side of small intestine is lined with epithelial cell monolayers covered by gut mucus. There are different types of cells residing in the intestinal epithelia, each of which has specific
ACCEPTED MANUSCRIPT functions (Table 1). A majority of intestinal epithelial cells are absorptive cells that form the intestinal villi together with goblet cells [26]. Intestinal crypts are other important absorptive and digestive sites, which are consisted of absorptive, goblet and paneth cells. The villi and crypts in small intestine mainly take charge of digestion , absorption and protection from microorganisms and toxins [26]. There are some
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granular aggregation areas observed from intestinal subserosal side as well (Fig. 2A), which are called PPs [27]. PPs have the highest density in human ileum and are one of
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the largest organized lymphoid tissues that differ from both crypts and villi by its cellular phenotypes (Fig. 2B), functions, ultrastructural and biochemical properties
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[28, 29]. The outmost surfaces of PPs are covered by follicle-associated epithelia (FAE), which takes a dome shape, and characterized by the presence of little or no
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mucus due to very limited population of goblet cells in this area [30]. In addition, the
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digestive functions in the brush border of FAE are very low compared to villi or
Table 1 The function of different epithelial cells and sub-FAE immunocytes. Location
Function
Absorptive cells
Apical side of intestinal epithelium
Take charge of absorption of all kinds of nutrients
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Goblet cells
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Cell types
Apical side of intestinal epithelium
Secrete mucus to protect the intestinal epithelia
Apical side of intestinal epithelium
Secrete enzymes to combat xenobiotics
Apical side of Peyer’s patch
Capture foreign particles or pathogens and hand over to sub-FAE lymphatics
Dendritic cells
Sub-epithelial dome; some fuse with epithelium
Capture antigens or particles and present to T or B cells
Macrophages
Sub-epithelial dome
Engulf and process particles; eliminate microorganisms; present to T or B cells
B cells
Sub-epithelial dome
Stimulate immune response
T cells
Sub-epithelial dome
Stimulate immune response
M cells
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Peneth cells
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Fig. 2 The schematic diagram showing the location of PPs in small intestine (A); the diagram of FAE and adjacent normal epithelia (B); distribution of cells in PPs according to immunohistochemical data (C-F). Color staining to identify different cells and tissues: 4’, 6-diamidino-2-phenylindole: FO- follicle, FAE- follicleassociated epithelium, GC-germinal center, IFR-intrafollicular region, SED-subepithelial dome (C); anti-CD11c: dendritic cells (D); anti-CD4: T cells (E); anti-B220: B cells (F). Adapted with permission from ref. 32 and 35. crypts due to low levels of membrane-associated hydrolases [31]. The main structural
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characteristics of FAE are the presence of M cells and numerous intra-epithelial lymphocytes and macrophages [32]. The M cells are the main cell type in the PPs, which selectively transport foreign particulates to sub-FAE lymphoid tissues [33]. M cells differ significantly from the adjacent epithelial cells in both shape and function. The distinctive character of the apical surface of M cells is the presence of a thin mucus layer and very short microvilli [34], which allows for efficient uptake of particles. The basolateral membrane of M cells is usually invaginated to be a pocket filled with intra-epithelial lymphocytes and macrophages. These immunocytes constitute the lymphatic systems under FAE, which can be divided into five distinct regions including subepithelial dome region (SED), follicle (FO), germinal center
ACCEPTED MANUSCRIPT (GC) and two parts of intra- follicular region (IFR), respectively (Fig. 2C) [35]. Numerous dendritic cells (DCs) reside in SED and play an important role in oral immunization [36]. DCs distribute in not only SED but also other four parts under SED, for instance CD11c+ DCs in SED, CD8α+ DCs in T cell- rich IFRs and double-negative DCs in both SED and IFRs. B cells account for 75% of PP cells and
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reside primarily in the FO region. B cells in PPs could be at several differentiation and maturation stages due to the creation of molecular and cellular environment for class
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switching from IgM to IgA (e.g. IgM+ B220+ : 70%; IgM+IgA+B220 + : 1%; IgA+ B220+ : 3%; IgA+ B220- : 0.5%) [37]. T cells account for approximately 20% of PP cells and
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primarily reside in IFRs [36]. Altogether, the network of M cells and various types of immunocytes in both FAE and sub-FAE lymphatics (SED, FO, GC, IFR) form a
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physiological construct that we name as a "dome trap" (Fig. 3A), owing to not only
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the dome shape but also its capacity for entrapment of particles. Many researches confirm that PPs are able to take up a wide variety of particulates including pathogens and polymeric particles [38, 39]. However, the
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structure and function of PPs vary with species according to host-pathogen biology [37]. M cell numbers are generally thought to be regulated by bacterial challenge in
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the lumen, but there is also exception that abundant PP-like follicles are found in the small intestine of sterile neonatal ruminants and pigs [10]. In addition, the population
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of PP-like lymphoid follicles tends to reduce with age [40]. 2.2. Trafficking and trapping of particulates If take guards as a metaphor for M cells, the lymphatic tissues might be prisons for particles. The M cells recognize and imprison foreign particles and pathogens in the dome trap. Most particles are efficiently transported by M cells without much degradation because of the presence of relatively few lysosomes in M cell cytoplasm [21]. It is noticeable that entrance of particles into the body might be through the M
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Fig. 3 Diagram of the “dome trap” (A) that shows four possible pathways for transportation of particles in the “dome trap”: transport across M cells and subsequently capture by DC cells (1) or macrophage (4); particles across M cells migrate into lymph vessel without undergoing any uptake (2); particles across M cells are taken up by macrophages or DC cells and subsequently escape from these cells and enter lymph vessels (3). The accumulation of glucan particles within DC cells in SED following oral administration to mice (B1 and B2) and within macrophages in triple cells co-culture model (C). Adapted with permission from ref. 15 and 42, respectively.
cell pathway only because M cell-depletion completely blocks oral prion disease pathogenesis [41]. Particles internalized by M cells are immediately transported across the M cell cytoplasm, subsequently excreted as integral particles into the M cell pockets, and then migrate across the porous epithelial basal membrane to SED, where particles are identified and taken up by numerous residing lymphocytes and macrophages [17, 38]. Lymphocytes and macrophages identify and take up particles. Meanwhile, antigen processing occurs to initiate immune response if antigens or microorganisms are involved [42]. On the other hand, particles transported by M cells
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disseminated
into
the
mesenteric
lymph
and
further
distributed
to
reticulo-endothelial organs like liver and spleen via systemic circulation [17, 43]. Thus, the dome trap plays a significant role in the biological fate of particles. Direct evidence of dome entrapment was obtained by tracking the translocation of glucan microparticles (GMs) with particle sizes (2-4 m) large enough to render them more
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easily identifiable [23]. Further cellular uptake study confirmed firm entrapment because GMs internalized by macrophages were retained within the cells for at least
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24 h without much degradation (Fig. 3C) [17, 23] [17, 23] [17, 23] [17, 23] [15,21]. However, a few fluorescent GMs were detected in liver, spleen and lung, indicating
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escaping from the dome trap [17]. Similarly, De Jesus et al demonstrated that GMs accumulated in DCs of SED in large amount following M cell- mediated
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transepithelial transport (Fig. 3B1,B2) [44]. For vaccine delivery, it is preferred that the particles are immediately taken up by lymphocytes and stay there to initiate
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efficient immune responses. On the contrary, therapeutic drugs should reach the systemic circulation first before re-distribution to target tissues; thus, entrapped
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particles should escape the dome trap first to achieve more efficient drug delivery. The biological fate of particles in the dome trap is determined by various physicochemical
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properties of the particles. For instance, larger particles (> 5 µm) tend to stay in PPs for longer time, while smaller particles are able to escape the dome trap to reach distant sites via lymphatic circulation [45, 46]. It is of high importance to clarify the
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factors influencing the fate of particles in the dome trap. 3. In vitro and in vivo evaluation models 3.1. M-like cell models Caco-2 cells derived from human colorectal adenocarcinoma have long been used to simulate enterocytes. Caco-2 cell monolayers have been extensively employed to assess permeation of substances across intestinal epithelia, and Caco-2/HT29-MTX co-culture models are used to mimick the function of various mucus-secreting cells such as the goblet cells [47, 48]. To mimick the function of M cells, lymphocytes or macrophages are usually employed to infiltrate Caco-2 cell monolayers. Kerneis et al
ACCEPTED MANUSCRIPT developed the first in vitro FAE model that comprised of a co-culture of Caco-2 cells and mouse B lymphocytes isolated from PPs. In practice, Caco-2 cells were seeded onto the basolateral side of Transwell® inserts to grow the monolayers, and then mouse B lymphocytes were added to the apical side and let to infiltrate into Caco-2 monolayers [49]. Further, Glullberg et al promoted this model merely by replacing
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mouse B lymphocytes with human Burkitt’s lymphoma Raji B cells [50]. The model was validated by assessing the translocation capacity of particles and microorganisms.
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However, the model as established suffers from wide variations between different experiments and poor contact between Caco-2 cells and Raji B cells. The poor
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reproducibility is partly ascribed to the “non-inverted” nature of this model. Thus, Des Rieux et al developed an “inverted” protocol to address the limitations of the
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“non- inverted” model (Fig. 4) [51]. This new protocol has better reproducibility and better mimicks the in vivo situation as the Raji B cells make close contact with Caco-2
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cells directly on the opposite side via filter pores. Furthermore, Beloqui et al described this experiment protocol in detail with sufficient validation data by various
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approaches such as scanning electron microscopy [48]. The three “M-like” cell models [49-51] were recently compared within the framework of a single study for
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the first time, and the model developed by the “inverted” protocol is proved to be more consistent between different experiments in the functionality and more intimate
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contact between Caco-2 cells and Raji B cells [52]. Recently, a triple co-culture model
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Fig. 4 Schemes of establishment of in vitro human- like FAE models by either the “non- inverted” (A) or the “inverted” (B) methods. Adap ted with permission from ref. 49.
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combining Caco-2 cells, mucus-secreting HT29-MTX cells and Raji B cells, was also developed to evaluate the transport of particles, demonstrating superiority over
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previous binary co-cultures in mimicking the multiple functions of the intestinal epithelia [53]. There is also a “gut-on-a-chip” microfluidic model reported as a potential substitute for the transwell models[54-58], which nevertheless is still in its
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initial developing stages and cannot mimick the M cell function [59]. To date, there is not a universal model to date that is fully consistent with FAE. It should be careful to interpret the results obtained by in vitro models. 3.2. In vivo models
Particles captured by the dome trap will be handled by the lymphocytes in there, or be drained via lymph to systemic circulation. Measurement of the total amount of lymphatic transportation reflects the contribution of the M cell pathway to systemic exposure of the therapeutics. Collecting all lymph fluid that contains the particles by lymphatic cannulation, followed by quantitative analysis, is proved to be a pragmatic
ACCEPTED MANUSCRIPT measure [60, 61]. This in vivo model has been established on various animals, either anesthetized or conscious, including rat, mouse and dog [62]. The conscious model is always preferred because the experiment can be conducted in the absence of anesthetics and the lymph flow is not influenced significantly. Generally, mesenteric lymph cannulation is of choice because the mesenteric lymph duct is the main passage
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for particles from intestine [23]. However, some studies alternatively cannulated the thoracic duct due to more convenient surgical operations than mesenteric lymph
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cannulation [63]. In order to assess the absorption via both lymph and portal vein, a triple-cannulated conscious model, which allows sampling of thoracic duct lymph,
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portal and systemic blood simultaneously, has been developed [64]. From a view of clinical translation, the dog model seems to be more relevant to human than the rat
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model [65] because it is possible to allow administration of dosage forms of identical size to those administered to human. Moreover, the bile flow of rat is continuous due
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to the lack of a gallbladder, which is significantly different from either human or dog [66, 67].
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In order to highlight and accurately weigh the contribution of the M cell pathway to overall lymphatic transportation, the most direct approach is to block the M cells.
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There are two M cell-blocking models reported to date: that is the NF-kB ligand (RANKL) neutralization model [41] and the B cell knock-out model [68]. RANKL
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expressed by intestinal epithelia controls the differentiation of RANK-expressing enterocytes into M cells. RANKL neutralization depletes the M cells in vivo. In actual operation, the IK22-5 rat anti- mouse RANKL-specific mAb was administered to mice every two days for eight consecutive days to establish the M cell-deficient mouse model [41]. B cell-knockout animals that lack PPs and M cells are also an efficient tool to characterize the roles of M cells. For instance, Bermudez et al employed B cell-deficient mice to confirm if M. avium subsp. Paratuberculosis crossed the intestinal mucosa via uptake by M cells [68]. Both models are functional to confirm the effect of M cells in uptake of antigens or particles in vivo in comparison with normal animals.
ACCEPTED MANUSCRIPT 4. Oral immunization based on particulate adjuvants Although oral administration is more convenient and more preferred than other routes, only a limited number of oral vaccine formulations have been licensed [69]. The challenges lie in not only the harsh GIT environment but also the lack of efficiency in mucosal uptake and subsequent elicit of immunization [70, 71]. The major barriers are
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the presence of gastric acid and proteolytic enzymes that readily degrade the vaccines, most of which are labile biomacromolecules [72]. Moreover, the intestinal epithelia
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and the mucus layers greatly limit the entry of vaccines [73]. Encapsulation into
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particles works to protect the vaccines and facilitate uptake by M cells simultaneously, and thus promote efficacy of oral immunization [74, 75]. Table 2 lists typical
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particulate adjuvants developed recently for oral vaccines. 4.1. Polymeric particles
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Polymeric particles made from versatile synthetic or natural polymers have been extensively explored for oral vaccines. In terms of synthetic polymeric particles,
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polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA) are popular polymers
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Table 2 List of typical particulate adjuvants for oral vaccines Particles
Decorations
Antigens
or Viruses
Particle
ζ
size
(mV)
Immunization effects
R e fs
None
OVA and
325±8.
-20.1
sIgA stimulated towards
[
MPLA
5 nm
±0.26
(OVA/MPLA) PLGA
7
nanoparticles 2.7-fold higher
6
than those induced by OVA in
]
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PLGA NPs
PBS solution. SIP
50 nm
100% of tilapia was vaccinated,
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PMMMA
TLRL
418±88 nm
OVA
200 nm
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UEA-1
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FS30D
RGD-PEGyl
Chitosan NPs
UEA-1
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PLA NPs
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ated
OVA
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PCL NPs
None
None
whereas the control groups (SIP
7
solutions) did not work at all.
7
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Eudragit
200 nm
[
]
Induction of T cell immunity
[
against viral infection up to 2
7
times compared to control group
8
(TLRL).
]
IgA titers for OVA-UEA-NPs
[
4.5-fold higher than for OVA
2
alone and 2.2-fold higher than
1
for OVA-NPs
]
Increased transport of
[
nanoparticles across the M cell
7
model, with a factor of 3.5
9
compared to the non-targeted
]
formulation 200-25
-40
0 nm
Delivery to DC cells by 3-4
[
times more than plain PLA NPs
8 0 ]
Peanut
100-20
allergy gene
0 nm
+10
Higher levels of gene expression
[
in both stomach and small
8
intestine induced by
1
nanoparticles than naked DNA.
]
Tripolyphos
pcDNA3.1-V
The
antibodies
[
phate
P2
expression in vaccinated fish
8
with CS-TPP nanoparticles were
2
5 times more than naked DNA.
]
Gluco mann osylated
BSA
levels
of
150-19
Gluco mannosylation
of
[
0 nm
stabilized chitosan NPs elicited
8
a 4.0- and 3.8- fold h igher sIgA
3
titer
]
in
salivary
flu id
and
ACCEPTED MANUSCRIPT intestinal content than chitosan NPs. UEA-1
BSA
250
36.8 ;
Microparticles
by
[
nm;
-28.6
UEA-1 produced around 2.5-
8
and 1.5- fold than BSA absorbed
4
NPs
]
1.5 μm
and
modified
BSA
entrapped
microparticles Thiolated
BmpB
MPs
Thiolated
Thiolated
MPs
[
μm
produced 1.52- or 1.68- fold
8
high sIgA level than Eudragit
5
MPs in mice.
]
The delivery of antigen by
[
3.7 μm
M-BmpB
Eudragit
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HPMCP
1-10
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Eudragit
Thiolated HPM CP M Ps was
8
higher by an average of 2.7-fold
6
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MPs
in compared to the delivery by
]
HPMCP MPs.
None
pDNA
The TNF-α and IFN-γ was 1.2-
[
shape
and
by
8
1
polyplex NPs coated antigen
7
high than antigen.
]
292 n m
Mann-modified nanogels were
[
to
internalized
macrophages
8
unmodified
8
Rod
NPs
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Polyplex
μm/
PHM
Mannan
OVA
nanogel
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10 μm
1.5
Liposome/
Cationic
4-fold
fo ld
produced
by
than
counterparts.
]
166.5±
+48.7
The serum OVA specific Ig G1 is
[
9.0 nm
±1.4
around
by
8
cationic liposome than by PLGA
9
NPs.
]
5-fold
induced
Gluco manna
Tetanus
198±17
Gluco mannan
modified
[
n
toxoid
nm
bilosomes exhibited 2.0 and 1.4
9
folds higher immune response in
0
comparison with niosomes and
]
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Porous
OVA
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Biolosomes
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μm
4-
None
bilosomes, respectively. BSA
silica NPs
130
The Ig G and IgA titers induced
[
nm,
by loading BSA was as follows:
9
430 n m
S1 (130 n m) > S2 (430 n m)>
1
and 1-2
SBA-15 (1-2 μm) .
]
μm β-Glucan
None
OVA
particles
3.7±0.2
-6.4±
More divided OVA-specific
[
μm
0.3
cells (51.5 ± 11.2%) were found
9
in the spleen (P = 0.009) of
2
glucan-OVA-fed mice in
]
comparison with the PBS group GRGDS
PR8
200-30
-13
The anti-PR8 IgG titer of NPs
[
ACCEPTED MANUSCRIPT 0 nm
were around 10-, 1.8- and 6-fold
9
higher than PR8 solutions in
3
intestine, mucus and serum,
]
respectively. Virus-like
Yeast cell
U 65
Protection against systemic
[
particles
wall
scaffolded
polyoma virus and reducing
9
antigens
viral DNA levels in spleen and
4
liver by >98%.
]
Recombinant LL-mInlA + and
[
t
LL-FnBPA+ strains showed
9
Lactococcus
100-fold greater invasion rate
5
Lactis (LL)
compared to the wt strains
]
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DNA
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Recombinan
(NZ9000 and MG1363). Hemagglutini
benthamiana
n of H1 or
135 nm
Enterovirus 7
7
(EV7)
9 6 ]
The levels of antibodies induced
[
by VLPs were around 3- fold
9
than control group (yeast cell).
7 ]
3.5 μm
A single dose of spray-dried
[
bacteriophag
VLPs induced high-titer anti-L2
9
e
IgG responses, which were
8
similar to mice immunized with
]
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ge
30 nm
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Enterovirus
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viruses
L2
[
transient IgG
H5 influenza
Bacteriopha
34% of subjects developed
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Nicotiana
freshly prepared (non-spray-dried) L2-VLPs.
Early
80-200
3-4 folds enhancement of IgG
[
virus
secretory
nm
levels against ESAT-6 protein
9
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Influenza
Live
antigenic
9
target 6
]
protein (ESAT-6) Invasin
Antigen delivered to PPs by
[
engineered
VLPs 6.38 folds more than
1
E. coli
naked counterpart.
0 0 ]
Abbreviations:
NPs,
nanoparticles;
MPs,
microparticles;
PLGA,
poly(lactic-co-glycolic acid); PCL, polycaprolactone; PLA, polylactic acid; HPMCP, hydroxypropyl methylcellulose phthalate; MCC, microcrystalline cellulose; PMMMA, poly[(methyl methacrylate)-co-(methyl acrylate)-co-(methacrylic acid)]; HEMA,
ACCEPTED MANUSCRIPT poly(2-hydroxiethyl
methacrylate-co-methacrylic
acid);
PHM,
Poly(HEMA-co-MAA); MAA, methacrylic acid; UEA, Ulexeuropaeus agglutinin; RGD,
arginylglycylaspartic acid; GRGDS,
acid-Serine;
BSA,
bovine
serum
Glycine-Arginine-Glycine-Aspartic
albumin;
OVA,
Ovalbumin;
MPLA,
Monophosphoryl lipid A ; SIP, Surface immunogenic protein; BmpB, Brachyspira
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hyodysenteriae.employed in clinical studies for oral vaccines due to their biocompatibility and approval status by U.S. Food & Drug Administration (FDA) [79,
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101]. In addition to protection and uptake enhancement, polymeric particles prolong antigen release, thus creating opportunities for reduced immunization frequency, or
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even single-dose immunization [102, 103]. Some studies demonstrated much longer terms of IgA and IgG antibody titers than soluble antigen by a single dose of several
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antigens as encapsulated in biodegradable particles [21, 104]. The chemical stability of vaccines is further improved through combination of two or more materials. For
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instance, the pH-sensitive methacrylate-based polymer Eudragit FS30D, which dissolves at pH > 7.0, was employed to coat PLGA nanoparticles to reinforce the
ED
chemical stability of antigens in stomach [105]. Another class of synthetic polymers for vaccines are polyanhydrides, which show superiority over polyesters in
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improvement of antigen stability [106]. What’s more, polyanhydrides are able to modulate immune responses very well without the help of additional adjuvants [107,
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108].
Natural polymers are always more favorable than synthetic ones due to reduced toxicity, good biocompatibility and mild conditions for encapsulation. The most common natural polymers for oral vaccines are polysaccharides that possess promising properties for oral delivery including mucoadhesion [109, 110], opening epithelial tight junctions transiently (as for chitosans) [111, 112] and active targeting to M cells (as for glucans) [44, 92]. Currently, β-glucan is gaining interest because of its high efficiency in facilitating uptake by M cells [92, 113]. However, it should be minded that oral vaccines induces substantial mucosal immunization but very limited systemic immune response even with the help of polymeric particles because they are
ACCEPTED MANUSCRIPT firmly retained by the dome trap and hardly reach the systemic circulation in sufficient amount [23]. 4.2. Liposomes Lipid-based particles are nice vehicles for delivery of chemicals via various routes for versatile therapeutic purposes because they are mainly composed of endogenous
PT
lipids or lipid derivatives [114-116]. This is equally true for oral delivery of vaccines. Among various lipid-based particles, liposomes offer the ability to deliver multiple
RI
active ingredients with widely different properties [117]. In general, hydrophilic
SC
entities such as proteins, RNAs and DNAs are encapsulated into the inner aqueous compartments of liposomes. DNA vaccine encapsulated in cationic liposomes
NU
increased the humoral and cellular immune responses by oral delivery, stimulating more cytokine production concurrently [118]. However, liposomes are self-assembled
MA
vehicles that suffer from severe instability when subjecting to gastric acid, bile salts and enzymes in GIT [119-121]. Paradoxically, bilosomes, a novel type of liposomes
ED
containing bile salts (e.g. sodium deoxycholate), are found to have improved stability than conventional liposomes [122]. A variety of fragile antigens have been entrapped
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in bilosomes with improved chemical stability for oral immunization, such as diphtheria toxoid, Bac-VP1, GnRH antibody and tetanus toxoid [123]. These systems were shown to elicit Th1/Th2 immunity by generating mucosal and systemic
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immunity [124]. Furthermore, the efficacy of these vehicles can be highly enhanced by modification with moieties targeting M cells [90]. 4.3. Biomimetic particles As mentioned above, pathogens like bacteria and viruses are recognized by M cells and thereby carried to the dome trap for further handling. This is a highly efficient mechanism that can be mimicked to facilitate uptake of particles. The most common approaches for constructing biomimetic particles are to functionalize particle surfaces with microbial ligands such as lipopolysaccharide (LPS) and its derivatives, flagellin and lectins [125]. These ligands are able to not only target
ACCEPTED MANUSCRIPT M cells but also work as immunomodulators to enhance immune responses [126-128]. The LPS are recognized as one of the main pathogen-associated molecular patterns (PAMPs), but have deleterious side effects [129, 130]. Therefore, many researches attempted to modify the structure of LPS to remove its toxicity while preserving its biomimetic properties, for example monophosphoryl lipid A (MPL) [131], whose
PT
liposomal formulation enhanced both mucosal and systemic immunity significantly [132]. Flagellin, a monomeric protein, determines the virulence of some pathogens by
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offering motility and improving adhesion [133]. It serves as a PAMP due to the advantages of binding toll- like receptor 5 (TLR5), inducing the maturation of DCs
SC
and activating CD4+ T cells [134]. Flagellin- functionalized nanoparticles firmly bound the epithelial surfaces following oral delivery, while inducing higher secretion
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of balanced antibodies (Th1 and Th2) as well as a much stronger mucosal IgA than non-decorated nanoparticles [135]. In addition, lectins are extensively employed as
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ligands to target M cells and enhance uptake [101]. For example, microspheres modified with wheat germ agglutinin (WGA) and aleuriaaurantia lectins facilitate
ED
uptake by M cells [136].
Virus-like particles (VLPs) mimick natural viruses by inserting viral capsid
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proteins into particles [137, 138]. Since VLPs have been deprived of the viral genomic materials, there is no concern over the chance of wild-type virus infections.
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Most VLPs, such as inactivated virus or bacteria, keep their own antigenic activity and stimulate immune response. On the other hand, VLPs can be used as carriers to deliver antigens as well [139]. Various vaccines for influenza, hepatitis B, human papilloma virus (HPV) and hand- foot- mouth disease have been entrapped and delivered by VLPs to elicit protective immunity against viral diseases [39, 140]. Owing to ease of production, both plant and yeast cells are commonly engineered to produce the single viral capsid protein of VLPs [141, 142]. Recombivax HB® was the first VLP-based nanoparticulate formulation for immunization by intramuscular injection approved in 1986 [143]. Currently, a few other veterinary vaccines based on VLP have been approved as well, such as Gardasil® and Cervarix® against HPV [144].
ACCEPTED MANUSCRIPT However, current VLP-based vaccines have to be administered intramuscularly for efficient immunization and the biggest challenge of VLPs-based vehicles is probably potential infection due to residues of virulence gene sequences [145]. In this respect, edible microorganism such as yeast and lactic acid bacteria are more advantageous than VLPs as vehicles for oral delivery of vaccines.
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5. Oral drug delivery via the M cell pathway It is generally accepted that small molecular drugs are absorbed via enterocytes (to
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portal vein) in GIT. In this case, the M cell pathway seems to be unimportant, if not
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negligible, because M cells only occupy approximately 5% of the human FAE and even less than 1% of the total intestinal surface [14, 48]. Because of this limitation, it
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is unwise to take this pathway to deliver drugs capable of absorption via the enterocytes. However, for biomacromolecules, the absorptive epithelia are not
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permeable and therefore the M cell pathway is currently the only choice to reach the systemic circulation. Numerous biomacromolecules exhibit extremely low, even no,
ED
oral bioavailability via oral delivery due to high vulnerability or poor solubility or low permeability across intestinal epithelia [146, 147]. Particulate carriers are able to
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overcome, more or less, these problems and thereby improve oral bioavailability [148]. However, the enhancement is not significant enough to elicit clinical effect [149]. One of the leading reasons is that particles may be trapped by the dome trap,
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significantly reducing the systemic exposure of the drugs. Measures should be taken to facilitate escape of the entrapped particles to enhance bioavailability. 5.1. Polymeric and lipidic particles Polymeric and lipidic particles are also extensively studied for oral delivery of drugs [115, 150]. For example, polyalkylcyanoacrylate nanoparticles of 285 nm were evaluated via oral delivery and found to be predominantly captured by M cells and adjacent enterocytes in PPs of an isolated ileal loop model in rats [151]. The integral lipidic nanoemulsions could be transported across the M cell model and through the lymphatics with a fraction of approximately 3-6% [61]. Many researches employed
ACCEPTED MANUSCRIPT the model drug insulin to study the impact of the M cell pathway on oral delivery [14]. Insulin- loaded
liposomes
containing
sodium
glycocholate
showed
obvious
size-dependency and those ranging between 150 and 400 nm facilitated oral absorption [152]. However, particles without surface functionalization are only taken up via non-specific mechanisms depending on size, charge or material prope rties.
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Hence, the transport amount is limited [53, 153]. In order to increase the total amount of transportation by M cells, particles are usually functionalized with ligands targeting
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the receptors on M cell membranes [24, 154]. WGA and tomato lectins (TL) have been proven to be stable when challenged by high concentrations of pepsin, trypsin,
SC
pancreatin or elastase [155]. Liposomes [156] and solid lipid nanoparticles (SLNs) [24], modified with WGA, TL and UEA-1, promoted the oral absorption of insulin
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and elicited remarkable hypoglycemic effects in compariso n with conventional non-decorated particles. Higher concentrations of WGA-SLNs (< 100 nm) were
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observed by microscopy in PPs than in non-PP tissues, which implied that most of
5.2. Biomimetic particles
ED
SLNs were transported through PPs [154].
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Another attractive way for M cell targeting is represented by the direct administration of recombinant bacteria as carriers for therapeutics [157, 158]. The most extensively investigated
microorganisms
for
oral
delivery
are
recombinant
or
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biotechnologically- modified lactic acid bacteria (LAB) because of their wide applications as food ingredients [159, 160]. For instance, LAB was employed to deliver interleukin-10 (IL10) to treat inflammatory bowel disease successfully [161]. The yeast cells derived microparticles (YCM) also draw much attention for oral drug delivery [23, 162]. YCM is 2-4 µm in diameter and has a hollow core enclosed within a porous shell. Moreover, the primary component of YCM is β-1,3-D glucan which can target M cells mediated by CR3 or dectin-1 receptors. Insulin was encapsulated in the inner cavities of YCM by a thermosensitive gel, and its hypoglycemic effect and pharmacological bioavailability (9-10%) were improved significantly in rats. Coincidently, the cumulative lymphatic transport of YCM was over 8% in 24h, which
ACCEPTED MANUSCRIPT was highly correlated to pharmacological bioavailability [23]. The YCM migrated to the serosal side of the ileum through PPs. However, the YCM was not detected in all other organs for 12 h following oral administration, but they appeared in the liver, lung, and spleen after then and around 2.3% of total amount was recovered in these organs [17]. In order to entrap more drugs, the liposomes were constructed in the core
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of YCM directly through the reverse phase evaporation method for loading diverse drug molecules [163]. Plant cells are increasingly becoming an oral delivery system
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for protein drugs because they can protect the encapsulated drugs from gastric acids and intestinal enzymes, and release drugs into the gut lumen upon microbial digestion.
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Additionally, intact plant cells are also absorbed into circulation by transcytosis
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through M cells [164].
6. Factors influencing the in vivo fate of oral particulates
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The elicit of efficacy as well as toxicity depends highly on the absorption, distribution and disposition of ingested particles. Therefore, understanding the in vivo fate of oral
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particulates is of high significance. Influencing factors extensively investigated include particle size, shape, surface charges, modification with ligands, etc.
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6.1. Particle size
It is well known that reduction in particle size accelerates the dissolution of particles.
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Thus, smaller particles have faster release rate than larger ones [165]. More importantly, particle size significantly influences the bio- interaction of particles with tissues and subsequently the in vivo fate [166, 167]. An earlier report showed that cellular uptake of 100-nm PLGA nanoparticles in Caco-2 cell lines is 2.5-fold greater than that of 1- µm microparticles [46]. In a case study with gold nanoparticles, ultra-small nanoparticles showed the highest permeation rate across intestinal membranes [43]. After 24 h, 0.37% of 1.4-nm particles were transported into the systemic circulation, while there were only 0.05%, 0.03% and 0.01% of gold nanoparticles found in circulation with sizes of 5, 80 and 200 nm, respectively [43]. However, histological examination revealed that 80- nm lipid-based nanoemulsions
ACCEPTED MANUSCRIPT could be taken up by enterocytes and distributed into basolateral tissues, whereas 500-nm and 1000- nm counterparts primarily adhered to villi surfaces [61]. Besides uptake by enterocytes, M cells take up particles in a size-dependent mode [46, 168, 169]. It is believed that M cells are able to take up particles less than 1 µm efficiently. However, the PLGA microparticles below 10 µm can also be specifically taken up
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into the PPs and particles larger than 5 µm remained in the PPs for an extended period, while the counterparts lower than 5 µm were found disseminating into the mesenteric
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lymph nodes, spleen and blood [103]. Size dependency was also observed for the uptake of organosilica particles. The relative uptake percentage by the dome trap with
SC
sizes of 95, 130, 200, 340, 695 and 1050 nm was 124.0, 89.1, 73.8, 20.2, 9.2 and 0.5%, respectively, in comparison with 100- nm particles [169]. Meanwhile,
uptake of
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smaller organosilica particles (100, 180 and 365 nm) was accompanied by a significantly grown number of IgA+ cells and CD11b+ macrophages in the dome trap,
MA
while particles with large sizes of 745 and 925 nm were only associated with increased mucosal IgA and -L-fucose on M cell surfaces [170]. There is no surprise
ED
that most studies on particle size effect are based on inorganic particles, whose size is uniform and more easily controllable. However, the size distribution of organic
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particles is hardly satisfactory due to a lack of appropriate manufacturing approaches. A polydispersity index (PDI) lower than 0.1 are generally regarded as monodisperse [171], which nevertheless is a goal very difficult to achieve for organic particles.
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Therefore, future investigations into the size effect call for strict controlling on particle size and size distribution. 6.2. Particle shape
Early in 1983, a study demonstrated that particle shape affected drug release, opening a new field of interesting research [172]. Over the years, the influence of particle geometry on drug delivery nevertheless is still not well understood, mainly due to a lack of strategies to control particle shape precisely. Limited information available indicates that particle shape is one of the most important factors in biorecognition and biointeraction [166, 173]. It was shown that spherical particles contacted with
ACCEPTED MANUSCRIPT macrophages from any point due to their structural symmetry, but the internalization of ellipse particles depends highly on the contact regions [166]. Particle shape affects the kinetics, efficiency and mechanisms of cellular uptake as well [174-177]. The internalization mechanisms depend highly on particle shape; for instance, mesoporous silica
spheres
prefer
the
clathrin-pathway,
while
long
rods
prefer
the
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caveolae-pathway instead [178]. Similarly, particle shape influences the distribution and elimination of gold nanoparticles after injection [174]. Banerjee et al
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demonstrated that polystyrene nanorods outperform spheres in transport across Caco-2/Raji monolayers [53], suggesting shape dependency. Meanwhile, shape also
SC
influenced the movement of nanoparticles in GIT. The cylindrical mesoporous silica nanoparticles (MSNs) have higher diffusivity than spherical counterparts, which leads
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to penetration deep into mucus and extended retention in GIT [179].
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6.3. Surface charges
Since biomembranes as well as various mucous linings (e.g. gastrointestinal mucus)
ED
are negatively charged, the effect of surface charges, especially positive ones, on biointeraction should not be ignored and sometimes it might be substantial. Follo wing
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this logic, there is a consensus that the positively charged particles have greater affinity with cells and longer retention time in mucus layer s than negatively charged or non- ionized ones [180-182]. Surface charges of particles are generally
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characterized as zeta potential for colloidal systems, which can be easily changed in response to different surface coatings such as polyvinyl alcohol (PVA) for negative and chitosan for positive charge [183, 184]. For example, the neutral surface charges of naked polystyrene nanoparticles (+1.1 mV) can be changed to positive by coating with chitosan (+17.5 mV) or negative by polyethylene glycol (PEG)-PLA (-23.9 mV) [185]. The corresponding capacity of internalization of polystyrene nanoparticles by MTX-E12
cells
was
in
the
following
order:
chitosan-coated
>
naked >>PEG-PLA-coated [185]. The chitosan-coated polyplex- loaded liposomes deliver more DNAs to distal intestine than conventional liposomes, indicating increased uptake owing to the positive surface charges [118]. Furthermore,
ACCEPTED MANUSCRIPT enrichment of surface charges reinforces cellular uptake of particles. A case study of densely charged SLNs coated with hydroxypropyltrimethyl ammonium chloride chitosan revealed enhanced uptake by PPs in rodents [186]. However, there are exceptions too; negatively charged gold nanoparticles were found accumulating mostly into secondary organs (e.g. liver, spleen and kidney) following absorption than
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positively charged nanoparticles [43]. 6.4. Ligand-based active targeting
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Modification of particles with active targeting ligands is meant to enhance either the
SC
biorecognition or internalization or both via ligand-receptor (transporter) interactions. Molecules that can be actively recognized by the intestinal epithelia such as nutrients
NU
(vitamins, amino acids, saccharides), peptides and polysaccharides are potential ligands for active targeting (Table 3). There are different cells residing in the intestinal
MA
epithelia (Table 1) and the distribution of receptors/transporters varies with each cell type. Therefore, it is possible to achieve active targeting to a specific group of cells.
ED
The apical region of intestinal epithelial cells expresses neonatal Fc receptors. Modification with Fc fragments significantly enhanced
the absorption of
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nanoparticles into systemic circulation up to 13.7%, in sharp contrast with only 1.2% for non-decorated ones [199]. Mucus-secreting goblet cells were also targeted using peptide ligand CSKSSDYQC with improved oral bioavailability of insulin [200]. As
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the M cell pathway holds promising potential for both oral immunization and delivery of labile biomacromolecules, M cells might be the hottest target in studies of active targeting to intestinal epithelia. Lectins are the most broadly investigated category of M cell-targeting molecules, which bind to specific carbohydrate residues presenting on the surfaces of M cell with high affinity, such as α-L- fucose residues [187]. The lectin- functionalized liposome stimulated systemic immune response to obtain anti-hepatitis B IgG in serum after three consecutive days following oral administration and higher sIgA level in mucous secretion, which indicated more lectinized liposomes were captured by the dome trap to stimulate mucosal immune response [187]. Similarly, almost all M cell-targeting particles were found
ACCEPTED MANUSCRIPT accumulating in the dome region of PPs and being able to stimulate higher mucosal immune responses [21, 111, 201]. The lectinized nanoparticles were also found to increase peroral delivery of proteins via the M cell pathway [150, 202]. The lectin mimetics have more advantages than lectins such as small molecule weight, low immunogenicity and ease of synthesis. The lectin analogues-conjugated PEG
PT
constructs form a tetragalloyl- D- lysine dendrimer (TGDK) for oral delivery of Rhesus CCR5-derived cyclopeptide antigen [193]. More specific human M cell
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markers were developed by many studies, such as sialyl Lewis A antigen (SLAA) and galectin 9 [192, 203]. In addition, many enteropathogenic microorganisms were taken
SC
up due to high-affinity interaction with integrins (α5β1) overexpressed in human M cells. Therefore, RGD-conjugated PLGA nanoparticles improved the in vitro transport
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by human M-like cells significantly [79]. However, the extent of enhancement is very limited because not only M cells occupy merely about 1% of all epithelial cell
MA
population but also only a limited number of nanoparticles entrapped are able to
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escape the dome trap and migrate into systemic circulation.
ACCEPTED MANUSCRIPT Table 3 Typical ligands used to modify particles or antigens for targeting to M cells
WGA
Liposomes, SLNs
Liposomes, lipid NPs
Drugs
Size (nm)
ζ (mV)
Efficiency
Refs
Insulin
191.0±13.62 (Liposomes)
+5.78 (Liposomes)
[154]
75.3±16.79 (SLNs)
-13.11 (SLNs)
OVA (Lipid NPs);
215.3±3.5 (Lipid NPs);
-4 (Liposomes)
HBsAg (Liposomes)
450 nm (Liposomes)
The relative absorption effeciency is WGA-liposomes > WGA-SLNs> SLNs > liposomes > insulin solution The cumulative amount of UEA-lipid NPs was around 3-fold higher than that of lipid NPs; The antibody levels induced by lectinized liposomes were around 1.6 folds than non-lectinized counterpart. About 10 times more coated liposomes
[188]
Liposome
110
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PLGA NPs
HBsAg
300
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LTA
Claudin-4 targeted protein
PLGA NPs
HA protein
472±25
RGD
Pegylated PLGA NPs
OVA
200 nm
[21, 187]
became associated with Peyer’s patches than uncoated liposomes.
ED
RO1
MA
NU
SC
UEA-1
or
PT
Particles antigens
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Ligands
-6.6 ⁓-13.8
Distinct binding of lectinized nanoparticles to the peyer’s paches as compared to control nanoparticles which showed little or no binding to the M cell in mice. CTP modified NPs enhanced 2 folds uptake by M cells compared to unmodified counterpart.
[101]
The RGD modified NPs increased
[79]
the transport across the M cell model, with a
[189]
ACCEPTED MANUSCRIPT
Chitosan NPs
Chitosan NPs
SA
Ovalbumin peptide
Galectin-9
None
TGDK
rhesus CCR5-derived cyclopeptide
FimH
Escherichia coli and Salmonella enterica serovar Typhimurium None
pVP1
300
approximately 1.5-fold higher than CNs after 3 h of uptake by M cells. 37.5% of chitosan NPs and 62.5% of CPE30-chitosan NPs immunized mice survived to day 28 post infection.
+22
[111]
[190]
ASLF
ED
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AC C
L-HIV
MA
NU
SC
RI
CPE 30
226.2±41.9
PT
CKS9
factor of 3.5 compared to the unmodified formulation. The accumulated amount of CKS9-CNs was
None
SA conjugation induced higher sIGA titer with a factor of 3 compared to naked OVA by targeting to M cells. Galectin-9 expression in M cells is 2.3 folds higher than epithelial cells. The transport of TGDK conjugated antigens was around 4 folds higher than naked antigens. FimH increased antibody levels up to aound 2.5 folds by targeting to M cells.
[191]
A L-HIV-1 strain crosses M cell monolayers and infects underlying CD4+ target cells, but the monotropic (R5) HIV-1 strain can not. SLF is expressed on mounse M cells in the small intestine and ASLF antibody injected into mouse intestine
[195]
[192]
[193]
[194]
[196]
ACCEPTED MANUSCRIPT
Co1 ligand
Enhanced GFP
The serum IgG and fecal IgA levels were improved up to 1.6- and 1.4- fold due to the Co 1-mediated trascytosis.
[197]
[198]
PT
ED Ⅲ antigen
SC
RI
OmpH ligand
bound to M cells. The number of EDⅢ-specific IgG-secreting cells in splenic lymphocyte from EDⅢ-OmpH are 2.5-fold higher than EDⅢ group by oral administration.
ED
6.5. Escaping the dome trap
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Abbreviations: WGA, Wheat germ agglutinin; UEA-1, Ulexeuropaeus agglutinin 1; LTA, Lotus tetragonolobus from Asparagus pea; CTP, Claudin-4 targeted protein; CKS9, CDSTHPLSC peptide; SA, Anti-GP2-streptavidin; CPE 30, C terminal 30 amino acids of clostridium perfringens enterotoxin; SLAA, Sialyl lewis A antigen; TGDK, Tetragalloyl- D- lysine dendrimer; RO1, Recombinant σ1 or OVA- σ1 fusion protein; L-HIV, Lymphotropic HIV-1 strain; ASLF, Anti-sialic acid-binding immunoglobulin- like lectin F; NPs, Nanoparticles; SLNs, Solid lipid nanoparticles.
As discussed above, prolonged retention of particulates by the dome trap might be
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beneficial for oral immunization. However, drug delivery demands the translocation of the particulates from the dome trap to lymph and finally to the systemic circulation. If the particulates can be manipulated to escape the dome trap actively, the
AC C
bioavailability of drug delivery might be greatly elevated. Unfortunately, there are still no reports on this issue to date to the best of our knowledge. Previous experience tells that there is possibility of escaping from the dome trap by manipulating exocytosis. Exocytosis of nanoparticles is energy-consuming and influenced by cell types and physicochemical properties of particles such as size, shape and surface chemistry. In general, smaller nanoparticles are excreted more quickly than bigger ones. For example, the exocytosis rate of MSNs with sizes of 60, 180, 370 and 600 nm was 63, 67, 58 and 38%, respectively [204]. The particle shape is also considered an important factor influencing exocytosis. In the case of gold nanoparticles, rods
ACCEPTED MANUSCRIPT were expelled from Hela and SNB 19 cells more easily than spheres, which however might vary with different cell types. Surface chemistry also plays a role in exocytosis of nanoparticles. The gold nanoparticles functionalized with KPPQPSLP peptide, which was taken up via non-specific endocytosis, were excreted more after 4 h than those modified with another peptide KATWLPPR [205]. A counter evidence is that
PT
co-delivery with an efficient exocytosis inhibitor (dimethylamyloride) improves the retention in cells [206]. Yet it should be aware that exocytosis of nanoparticles has
RI
two opposite directions: the basolateral-to-apical and the apical-to-basolateral direction. Apparently, the former should be avoided or reduced to as low as possible.
SC
Whether it is plausible to manipulate exocytosis in vivo is still awaiting evidence.
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6.6. Mucoadhesion
To reinforce uptake of particles by M cells, it is a prerequisite for the particles to
MA
make close contact with FAE. Mucoadhesive delivery systems prolong the residence time of particles in GIT and render intimate contact with M cells, thus increasing the
ED
opportunity of uptake through the M-cell pathway. In many researches, surface modification by mucoadhesive materials such as chitosans [207] or by sulfhydrylation
EP T
[208] mucoadhesive materials are employed to improve the mucoadhesive capability of nanoparticles. However, nanoparticles would be dispersed and adhere everywhere including sites without presence of PPs due to the high dispersity of the particles
AC C
along with the digestive motion, significantly compromising the efficiency of M-cell uptake. A new intestinal patch device were developed to localize large amount of drug molecules near the mucosa to generate a high concentration gradient from apical to basolateral side, which improved the absorption of biomacromolecules [209, 210]. If this device is used to deliver nanoparticles to intestinal segments where PPs are abundant such as ileum, extended and reinforced absorption of nanoparticles via the M-cell pathway could be envisaged. 7. Conclusions and perspectives The M cell pathway has long been recognized as an effective portal for oral
ACCEPTED MANUSCRIPT immunization or for oral drug delivery, especially biomacromolecules. However, various related concepts are not easily understandable, especially for non-experts. The conceptualization of the dome trap, which is p hysically comprised of the FAE and sub-FAE lymphatics as well as various functional cells including M cells, lymphocytes and macrophages highlights the significance of this physiological barrier
PT
in respect to either oral immunization or drug delivery. To reinforce therapeutic efficacy, the first thing to do is to encapsulate therapeutic drugs, vaccines or
RI
biomacromolecules, into particulate vehicles and protect them from the detrimental GIT environment. Particles together with the payloads are captured by M cells and
SC
immediately transported to sub-FAE lymphatics. The retention of particles by the dome trap depends highly on their interaction with various immunocytes.
NU
Functionalization of the particle surfaces with ligands targeting M cells such as lectins greatly enhances the uptake by M cells and subsequent retention in lymphatics as well
MA
owing to the presence of the same receptors as M cells for various lymphocytes. In addition, biomimetic particles derived from bacteria, fungi or viruses are functional
ED
carriers to deliver therapeutic entities to the dome trap due to their natural affinity with M cells. This mechanism is beneficial for oral immunization because it mimicks
EP T
natural immunization against invading pathogens. The biggest challenges are with drug delivery, which demands substantial uptake of the particles by M cells and easy escape from the dome trap simultaneously. Unfortunately, particle properties that
AC C
favor escape do not favor uptake by M cells; properties that favor uptake do not favor escape as well. Ideal systems might be able to be taken up quickly and substantially and be diverted to cross the dome trap easily. The uptake by M cells can be evaluated by both in vitro M-cell like models or in vivo blocking model. However, there is a lack of efficient models to assess the escaping from the dome trap. Conflicts of interest The authors report no conflict of interest. Acknowledgements
ACCEPTED MANUSCRIPT This work is financially supported by Science and Technology Commission of Shanghai Municipality (15ZR1403000), and National Natural Science Foundation of
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ED
MA
NU
SC
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China (81573363, 81690263).
ACCEPTED MANUSCRIPT References [1] B.F. Choonara, Y.E. Choonara, P. Ku mar, D. Biju ku mar, L.C. du Toit, V. Pillay, A review of advanced oral drug delivery technologies facilitating the protection and absorption of protein and peptide molecules, Biotechnol. Adv., 32 (2014) 1269-1282. [2] C. Liu, Y. Kou, X. Zhang, H. Cheng, X. Chen, S. Mao, Strategies and industrial perspectives to improve oral absorption of biological macromolecules, Expert Opin. Drug Deliv., 15 (2017) 223-233. [3] P. Shekhawat, V. Po kharkar, Understanding peroral absorption: regulatory aspects and contemporary approaches to tackling solubility and permeability hurdles, Acta Pharm. Sinica B, 7
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[4] C.A. Lip inski, F. Lo mbardo, B.W. Do miny, P.J. Feeney, Experimental and computational
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approaches to estimate solubility and permeability in drug d iscovery and development settings, Adv. Drug Deliver. Rev., 23 (1997) 3-25.
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[5] B. Hens, M. Corsetti, R. Spiller, L. Marciani, T. Vanuytsel, J. Tack, A. Talattof, G.L. A midon, M. Koziolek, W. Weitschies, Exp loring gastrointestinal variables affecting drug and formulation behavior: methodologies, challenges and opportunities, Int. J. Pharm., 519 (2016) 79-97.
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[6] P. Lundquist, P. Artursson, Oral absorption of peptides and nanoparticles across the human intestine: Opportunities, limitations and studies in human tissues, Adv. Drug Deliver. Rev., 106 (2016) 256-276. [7] C.Y. Wong, H. Al-Salami, C.R. Dass, Potential of insulin nanoparticle formulat ions for oral delivery
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[8] E. Moroz, S. Matoori, J.-C. Lerou x, Oral delivery of macro mo lecular drugs: Where we are after almost 100years of attempts, Adv. Drug Deliver. Rev., 101 (2016) 108-121. [9] A.A. Date, J. Hanes, L.M . Ensign, Nanoparticles for oral delivery: Design, evaluation and
ED
state-of-the-art, J. Control. Release, 240 (2016) 504-526.
[10] D.J. Brayden, M.A. Jepson, A.W. Baird, Keynote rev iew : intestinal Peyer's patch M cells and oral vaccine targeting, Drug Discov. Today, 10 (2005) 1145-1157.
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[11] N.A. Mabbott, D.S. Donaldson, H. Ohno, I.R. Williams, A. Mahajan, Microfo ld (M) cells: important immunosurveillance posts in the intestinal epithelium, Mucosal Immunol., 6 (2013) 666-677. [12] M.A. Clark, M.A. Jepson, B.H. Hirst, Exp loit ing M cells fo r drug and vaccine delivery, Adv. Drug Deliver. Rev., 50 (2001) 81-106.
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ACCEPTED MANUSCRIPT
Table 1 The function of different epithelial cells and sub-FAE immunocytes. Location
Function
Absorptive cells
Apical side of intestinal epithelium
Take charge of absorption of all kinds of nutrients
Goblet cells
Apical side of intestinal epithelium
Secrete mucus to protect the intestinal epithelia
Peneth cells
Apical side of intestinal epithelium
Secrete enzymes to combat xenobiotics
M cells
Apical side of Peyer’s patch
Capture foreign particles or pathogens and hand over to sub-FAE lymphatics
Dendritic cells
Sub-epithelial dome; some fuse with epithelium
Capture antigens or particles and present to T or B cells
Macrophages
Sub-epithelial dome
B cells
Sub-epithelial dome
T cells
Sub-epithelial dome
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Engulf and process particles; eliminate microorganisms; present to T or B cells
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Cell types
Stimulate immune response Stimulate immune response
ACCEPTED MANUSCRIPT Table 2 List of typical particulate adjuvants for oral vaccines Particles
Decorations
Antigens
or Viruses
Particle
ζ
size
(mV)
Immunization effects
R e fs
PLGA NPs
None
OVA and
325±8.
-20.1
sIgA stimulated towards
[
MPLA
5 nm
±0.26
(OVA/MPLA) PLGA
7
nanoparticles 2.7-fold higher
6
than those induced by OVA in
]
PBS solution.
TLRL
418±88 nm
PCL NPs
RGD-PEGyl
OVA
OVA
NPs
None
None
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Chitosan
UEA-1
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PLA NPs
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ated
200 nm
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UEA-1
[
whereas the control groups (SIP
7
solutions) did not work at all.
7 ]
Induction of T cell immunity
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FS30D
100% of tilapia was vaccinated,
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50 nm
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Eudragit
SIP
[
SC
PMMMA
200 nm
against viral infection up to 2
7
times compared to control group
8
(TLRL).
]
IgA titers for OVA-UEA-NPs
[
4.5-fold higher than for OVA
2
alone and 2.2-fold higher than
1
for OVA-NPs
]
Increased transport of
[
nanoparticles across the M cell
7
model, with a factor of 3.5
9
compared to the non-targeted
]
formulation 200-25
-40
0 nm
Delivery to DC cells by 3-4
[
times more than plain PLA NPs
8 0 ]
Peanut
100-20
allergy gene
0 nm
+10
Higher levels of gene expression
[
in both stomach and small
8
intestine induced by
1
nanoparticles than naked DNA.
]
Tripolyphos
pcDNA3.1-V
The
antibodies
[
phate
P2
expression in vaccinated fish
8
with CS-TPP nanoparticles were
2
5 times more than naked DNA.
]
Gluco mann osylated
BSA
levels
of
150-19
Gluco mannosylation
of
[
0 nm
stabilized chitosan NPs elicited
8
a 4.0- and 3.8- fold h igher sIgA
3
titer
]
in
salivary
flu id
and
intestinal content than chitosan NPs.
ACCEPTED MANUSCRIPT UEA-1
BSA
250
36.8 ;
Microparticles
by
[
nm;
-28.6
UEA-1 produced around 2.5-
8
and 1.5- fold than BSA absorbed
4
NPs
]
1.5 μm
and
modified
BSA
entrapped
microparticles Thiolated
BmpB
MPs
HPMCP
Thiolated
1-10
Thiolated
MPs
[
μm
produced 1.52- or 1.68- fold
8
high sIgA level than Eudragit
5
MPs in mice.
]
The delivery of antigen by
[
Thiolated HPM CP M Ps was
8
higher by an average of 2.7-fold
6
3.7 μm
M-BmpB
Eudragit
PT
Eudragit
RI
MPs
in compared to the delivery by
]
Polyplex
None
pDNA
The TNF-α and IFN-γ was 1.2-
[
and
by
8
polyplex NPs coated antigen
7
10 μm
high than antigen.
]
292 n m
Mann-modified nanogels were
[
to
internalized
macrophages
8
unmodified
8
Rod shape 1
PHM
Mannan
OVA
1.5
MA
nanogel
μm/
NU
NPs
SC
HPMCP MPs.
μm
Cationic
Biolosomes
4-fold
fo ld
produced
by
than
counterparts.
]
166.5±
+48.7
The serum OVA specific Ig G1 is
[
9.0 nm
±1.4
around
by
8
cationic liposome than by PLGA
9
NPs.
]
5-fold
induced
Tetanus
198±17
Gluco mannan
modified
[
n
toxoid
nm
bilosomes exhibited 2.0 and 1.4
9
folds higher immune response in
0
comparison with niosomes and
]
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Gluco manna
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Porous
OVA
ED
Liposome/
4-
None
BSA
silica NPs
bilosomes, respectively. 130
The Ig G and IgA titers induced
[
nm,
by loading BSA was as follows:
9
430 n m
S1 (130 n m) > S2 (430 n m)>
1
and 1-2
SBA-15 (1-2 μm) .
]
μm β-Glucan
None
OVA
particles
3.7±0.2
-6.4±
More divided OVA-specific
[
μm
0.3
cells (51.5 ± 11.2%) were found
9
in the spleen (P = 0.009) of
2
glucan-OVA-fed mice in
]
comparison with the PBS group GRGDS
PR8
200-30 0 nm
-13
The anti-PR8 IgG titer of NPs
[
were around 10-, 1.8- and 6-fold
9
higher than PR8 solutions in
3
ACCEPTED MANUSCRIPT intestine, mucus and serum,
]
respectively. Virus-like
Yeast cell
U 65
Protection against systemic
[
particles
wall
scaffolded
polyoma virus and reducing
9
antigens
viral DNA levels in spleen and
4
liver by >98%.
]
Recombinant LL-mInlA + and
[
t
LL-FnBPA+ strains showed
9
Lactococcus
100-fold greater invasion rate
5
Lactis (LL)
compared to the wt strains
]
DNA
PT
Recombinan
(NZ9000 and MG1363). Hemagglutini
benthamiana
n of H1 or
135 nm
34% of subjects developed transient IgG
viruses Enterovirus 7
7
(EV7)
ge
3.5 μm
6 ]
The levels of antibodies induced
[
by VLPs were around 3- fold
9
than control group (yeast cell).
7 ]
A single dose of spray-dried
[
bacteriophag
VLPs induced high-titer anti-L2
9
e
IgG responses, which were
8
similar to mice immunized with
]
ED
MA
L2
30 nm
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Enterovirus
9
SC
H5 influenza
Bacteriopha
[
RI
Nicotiana
freshly prepared (non-spray-dried) L2-VLPs.
Early
80-200
3-4 folds enhancement of IgG
[
virus
secretory
nm
levels against ESAT-6 protein
9
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Influenza
antigenic
9
target 6
]
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protein
Live
(ESAT-6) Invasin
Antigen delivered to PPs by
[
engineered
VLPs 6.38 folds more than
1
E. coli
naked counterpart.
0 0 ]
Abbreviations:
NPs,
nanoparticles;
MPs,
microparticles;
PLGA,
poly(lactic-co-glycolic acid); PCL, polycaprolactone; PLA, polylactic acid; HPMCP, hydroxypropyl methylcellulose phthalate; MCC, microcrystalline cellulose; PMMMA, poly[(methyl methacrylate)-co-(methyl acrylate)-co-(methacrylic acid)]; HEMA, poly(2-hydroxiethyl
methacrylate-co-methacrylic
acid);
PHM,
ACCEPTED MANUSCRIPT Poly(HEMA-co-MAA); MAA, methacrylic acid; UEA, Ulexeuropaeus agglutinin; RGD,
arginylglycylaspartic acid; GRGDS,
acid-Serine;
BSA,
bovine
serum
Glycine-Arginine-Glycine-Aspartic
albumin;
OVA,
Ovalbumin;
MPLA,
Monophosphoryl lipid A ; SIP, Surface immunogenic protein; BmpB, Brachyspira
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ED
MA
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SC
RI
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hyodysenteriae.
ACCEPTED MANUSCRIPT Table 3 Typical ligands used to modify particles or antigens for targeting to M cells
WGA
Liposomes, SLNs
Liposomes, lipid NPs
Drugs
Size (nm)
ζ (mV)
Efficiency
Refs
Insulin
191.0±13.62 (Liposomes)
+5.78 (Liposomes)
[154]
75.3±16.79 (SLNs)
-13.11 (SLNs)
OVA (Lipid NPs);
215.3±3.5 (Lipid NPs);
-4 (Liposomes)
HBsAg (Liposomes)
450 nm (Liposomes)
The relative absorption effeciency is WGA-liposomes > WGA-SLNs> SLNs > liposomes > insulin solution The cumulative amount of UEA-lipid NPs was around 3-fold higher than that of lipid NPs; The antibody levels induced by lectinized liposomes were around 1.6 folds than non-lectinized counterpart. About 10 times more coated liposomes
[188]
Liposome
110
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PLGA NPs
HBsAg
300
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LTA
Claudin-4 targeted protein
PLGA NPs
HA protein
472±25
RGD
Pegylated PLGA NPs
OVA
200 nm
[21, 187]
became associated with Peyer’s patches than uncoated liposomes.
ED
RO1
MA
NU
SC
UEA-1
or
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Particles antigens
RI
Ligands
-6.6 ⁓-13.8
Distinct binding of lectinized nanoparticles to the peyer’s paches as compared to control nanoparticles which showed little or no binding to the M cell in mice. CTP modified NPs enhanced 2 folds uptake by M cells compared to unmodified counterpart.
[101]
The RGD modified NPs increased
[79]
the transport across the M cell model, with a
[189]
ACCEPTED MANUSCRIPT
Chitosan NPs
Chitosan NPs
SA
Ovalbumin peptide
Galectin-9
None
TGDK
rhesus CCR5-derived cyclopeptide
FimH
Escherichia coli and Salmonella enterica serovar Typhimurium None
pVP1
300
approximately 1.5-fold higher than CNs after 3 h of uptake by M cells. 37.5% of chitosan NPs and 62.5% of CPE30-chitosan NPs immunized mice survived to day 28 post infection.
+22
[111]
[190]
ASLF
ED
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L-HIV
MA
NU
SC
RI
CPE 30
226.2±41.9
PT
CKS9
factor of 3.5 compared to the unmodified formulation. The accumulated amount of CKS9-CNs was
None
SA conjugation induced higher sIGA titer with a factor of 3 compared to naked OVA by targeting to M cells. Galectin-9 expression in M cells is 2.3 folds higher than epithelial cells. The transport of TGDK conjugated antigens was around 4 folds higher than naked antigens. FimH increased antibody levels up to aound 2.5 folds by targeting to M cells.
[191]
A L-HIV-1 strain crosses M cell monolayers and infects underlying CD4+ target cells, but the monotropic (R5) HIV-1 strain can not. SLF is expressed on mounse M cells in the small intestine and ASLF antibody injected into mouse intestine
[195]
[192]
[193]
[194]
[196]
ACCEPTED MANUSCRIPT
Co1 ligand
Enhanced GFP
The serum IgG and fecal IgA levels were improved up to 1.6- and 1.4- fold due to the Co 1-mediated trascytosis.
[197]
[198]
PT
ED Ⅲ antigen
SC
RI
OmpH ligand
bound to M cells. The number of EDⅢ-specific IgG-secreting cells in splenic lymphocyte from EDⅢ-OmpH are 2.5-fold higher than EDⅢ group by oral administration.
AC C
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ED
MA
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Abbreviations: WGA, Wheat germ agglutinin; UEA-1, Ulexeuropaeus agglutinin 1; LTA, Lotus tetragonolobus from Asparagus pea; CTP, Claudin-4 targeted protein; CKS9, CDSTHPLSC peptide; SA, Anti-GP2-streptavidin; CPE 30, C terminal 30 amino acids of clostridium perfringens enterotoxin; SLAA, Sialyl lewis A antigen; TGDK, Tetragalloyl- D- lysine dendrimer; RO1, Recombinant σ1 or OVA- σ1 fusion protein; L-HIV, Lymphotropic HIV-1 strain; ASLF, Anti-sialic acid-binding immunoglobulin- like lectin F; NPs, Nanoparticles; SLNs, Solid lipid nanoparticles.
MA
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SC
RI
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ACCEPTED MANUSCRIPT
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Graphical Abstract
Jianping Qi, Jie Zhuang, Yongjiu Lv, Yi Lu, Wei Wu PII: DOI: Reference:
S0168-3659(18)30081-6 doi:10.1016/j.jconrel.2018.02.021 COREL 9169
To appear in:
Journal of Controlled Release
Received date: Revised date: Accepted date:
11 December 2017 14 February 2018 14 February 2018
Please cite this article as: Jianping Qi, Jie Zhuang, Yongjiu Lv, Yi Lu, Wei Wu , Exploiting or overcoming the dome trap for enhanced oral immunization and drug delivery. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Corel(2017), doi:10.1016/j.jconrel.2018.02.021
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Exploiting or overcoming the dome trap for enhanced oral immunization and drug delivery
Key Laboratory of Smart Drug Delivery of MOE and PLA, School of Pharmacy,
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1
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Jianping Qi1†, Jie Zhuang2†, Yongjiu Lv1 , Yi Lu1 , Wei Wu1,*
Institute of Nanotechnology and Health, School of Pharmacy, Shanghai University of
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2
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Fudan University, Shanghai 201203, China
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Medicine & Health Sciences, Shanghai 201318, China
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These authors contributed equally to this article.
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†
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Corresponding author. Tel. & fax: +86 21 51980084. E-mail: [email protected]
ACCEPTED MANUSCRIPT Abstract The microfold cells (M cells) residing in the outmost follicle-associated epithelia (FAE) of Peyer ’s patches capture foreign particles and hand over to sub-FAE lymphatics, where the particles are retained and disposed subsequently. A concept of “dome trap” is proposed to highlight the significance of this mechanism. For oral
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immunization, it is better to exploit the entrapment capacity to maximize immune response, whereas for drug delivery it is better to overcome the dome trap to transport
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drugs into the systemic circulation. By optimizing the size, shape, surface charges and
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surface properties of particles, either oral immunization or drug delivery can be potentially enhanced.
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Keywords: dome trap; oral; immunization; drug delivery; M cells; endocytosis;
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lymphatics
ACCEPTED MANUSCRIPT List of abbreviations DCs: dendritic cells FAE: follicle-associated epithelia GALT: gut-associated lymphatic tissues GC: germinal center GIT: gastrointestinal tract
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GMs: glucan microparticles GRAS: generally recognized as safe
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HPV: human papilloma virus IBD: inflammatory bowel disease
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IFR: intrafollicular region LAB: lactic acid bacteria
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LPS: lipopolysaccharide MPL: monophosphoryl lipid A
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PAMPs: pathogen-associated molecular patterns PEG: polyethylene glycol PLA: poly(lactic acid) PPs: Peyer’s patches
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PVA: poly(vinyl alcohol)
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PLGA: poly(lactic-co-glycolic acid)
SED: subepithelial dome region SLNs: solid lipid nanoparticles
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TL: tomato lectins
UEA-1: ulexeuropaeus 1 VLPs: Virus-like particles WGA: wheat germ agglutinin YCM: yeast cell derived microparticles
ACCEPTED MANUSCRIPT 1.
Introduction
Oral drug delivery is more promising than other routes because of ease of administration, multiple selectivity of dosage forms, safety issues and good patient compliance [1-3]. However, not all therapeutic drugs are absorbable via the gastrointestinal tract (GIT). The intestinal epithelia only admit a limited fraction of
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small molecules with properties favorable for absorption [4, 5]. Macromolecules and particles are not welcomed all the time. Paradoxically, researchers have long been
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intrigued with the challenge of delivering biomacromolecules (peptides, proteins,
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polysaccharides, nucleic acids, vaccines, etc.) via the oral route [6-8]. It is fortunate that the GIT "opens" a small window for us to achieve the goal; that is the
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long-recognized microfold cells (M cells) pathway [9-13]. Fig. 1 summarizes the general route and highlights the role of M cell pathway for the entry of various
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therapeutic drugs into the human body.
The M cells residing in the intestinal epithelia have long been recognized as
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scavengers to clear up pathogens entering the digestive tract [11]. On the other hand,
Fig. 1 The schematic diagram of general routes for the entry of various therapeutic drugs into the human body. Abbreviations: APC, antigen-presenting cells; GALT, gut-associated lymphoid tissue.
ACCEPTED MANUSCRIPT
the M-cell passage also opens a portal for the entry of therapeutic drugs into the systemic circulation [14, 15]. Now it is clear that M cells take up particulates and transport them very quickly to the subepithelial gut-associated lymphoid tissues (GALT) for further processing [16, 17]. By mimicking pathogens, antigens could be
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delivered to GALT in sufficient amount, where antigen-presenting cells (APC) are abundant, to elicit efficient oral immunization [18, 19]. Albeit beneficial from a
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perspective of oral immunization, the entrapment by GALT creates a barrier to
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systemic drug delivery [17].
Both oral immunization and oral delivery via M cells have a long history of
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almost thirty years [20-22]. In spite of years of efforts, the gross oral bioavailability of particles is limited to a maximum of 5-7% owing to the bottleneck of the M cell
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pathway [17, 23, 24]. On the contrary, oral immunization using particulate adjuvant is resurging recently [25], partly thanks for improved understanding of the underlying
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mechanisms. To better explain the situation, we proposed a concept of "dome trap" to highlight the significance of the lymphatic uptake and retention mechanisms. The
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current task is to either exploit the trapping capacity of the dome trap to optimize immune response or cross it for more efficient drug delivery. This paper will clearly outline the concept of “dome trap” and make updated
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reviews on recent approaches to optimize the efficacy of either oral immunization or drug delivery. The clarification of this concept is of scientific significance to point the way for future researches. 2. The concept of dome trap 2.1.Structure and physiology of the dome trap Small intestine serves as not only an important organ for the absorption of nutrients but also a physiological guard to fend off microorganisms. The lumen side of small intestine is lined with epithelial cell monolayers covered by gut mucus. There are different types of cells residing in the intestinal epithelia, each of which has specific
ACCEPTED MANUSCRIPT functions (Table 1). A majority of intestinal epithelial cells are absorptive cells that form the intestinal villi together with goblet cells [26]. Intestinal crypts are other important absorptive and digestive sites, which are consisted of absorptive, goblet and paneth cells. The villi and crypts in small intestine mainly take charge of digestion , absorption and protection from microorganisms and toxins [26]. There are some
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granular aggregation areas observed from intestinal subserosal side as well (Fig. 2A), which are called PPs [27]. PPs have the highest density in human ileum and are one of
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the largest organized lymphoid tissues that differ from both crypts and villi by its cellular phenotypes (Fig. 2B), functions, ultrastructural and biochemical properties
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[28, 29]. The outmost surfaces of PPs are covered by follicle-associated epithelia (FAE), which takes a dome shape, and characterized by the presence of little or no
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mucus due to very limited population of goblet cells in this area [30]. In addition, the
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digestive functions in the brush border of FAE are very low compared to villi or
Table 1 The function of different epithelial cells and sub-FAE immunocytes. Location
Function
Absorptive cells
Apical side of intestinal epithelium
Take charge of absorption of all kinds of nutrients
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Goblet cells
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Cell types
Apical side of intestinal epithelium
Secrete mucus to protect the intestinal epithelia
Apical side of intestinal epithelium
Secrete enzymes to combat xenobiotics
Apical side of Peyer’s patch
Capture foreign particles or pathogens and hand over to sub-FAE lymphatics
Dendritic cells
Sub-epithelial dome; some fuse with epithelium
Capture antigens or particles and present to T or B cells
Macrophages
Sub-epithelial dome
Engulf and process particles; eliminate microorganisms; present to T or B cells
B cells
Sub-epithelial dome
Stimulate immune response
T cells
Sub-epithelial dome
Stimulate immune response
M cells
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Peneth cells
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ACCEPTED MANUSCRIPT
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Fig. 2 The schematic diagram showing the location of PPs in small intestine (A); the diagram of FAE and adjacent normal epithelia (B); distribution of cells in PPs according to immunohistochemical data (C-F). Color staining to identify different cells and tissues: 4’, 6-diamidino-2-phenylindole: FO- follicle, FAE- follicleassociated epithelium, GC-germinal center, IFR-intrafollicular region, SED-subepithelial dome (C); anti-CD11c: dendritic cells (D); anti-CD4: T cells (E); anti-B220: B cells (F). Adapted with permission from ref. 32 and 35. crypts due to low levels of membrane-associated hydrolases [31]. The main structural
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characteristics of FAE are the presence of M cells and numerous intra-epithelial lymphocytes and macrophages [32]. The M cells are the main cell type in the PPs, which selectively transport foreign particulates to sub-FAE lymphoid tissues [33]. M cells differ significantly from the adjacent epithelial cells in both shape and function. The distinctive character of the apical surface of M cells is the presence of a thin mucus layer and very short microvilli [34], which allows for efficient uptake of particles. The basolateral membrane of M cells is usually invaginated to be a pocket filled with intra-epithelial lymphocytes and macrophages. These immunocytes constitute the lymphatic systems under FAE, which can be divided into five distinct regions including subepithelial dome region (SED), follicle (FO), germinal center
ACCEPTED MANUSCRIPT (GC) and two parts of intra- follicular region (IFR), respectively (Fig. 2C) [35]. Numerous dendritic cells (DCs) reside in SED and play an important role in oral immunization [36]. DCs distribute in not only SED but also other four parts under SED, for instance CD11c+ DCs in SED, CD8α+ DCs in T cell- rich IFRs and double-negative DCs in both SED and IFRs. B cells account for 75% of PP cells and
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reside primarily in the FO region. B cells in PPs could be at several differentiation and maturation stages due to the creation of molecular and cellular environment for class
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switching from IgM to IgA (e.g. IgM+ B220+ : 70%; IgM+IgA+B220 + : 1%; IgA+ B220+ : 3%; IgA+ B220- : 0.5%) [37]. T cells account for approximately 20% of PP cells and
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primarily reside in IFRs [36]. Altogether, the network of M cells and various types of immunocytes in both FAE and sub-FAE lymphatics (SED, FO, GC, IFR) form a
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physiological construct that we name as a "dome trap" (Fig. 3A), owing to not only
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the dome shape but also its capacity for entrapment of particles. Many researches confirm that PPs are able to take up a wide variety of particulates including pathogens and polymeric particles [38, 39]. However, the
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structure and function of PPs vary with species according to host-pathogen biology [37]. M cell numbers are generally thought to be regulated by bacterial challenge in
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the lumen, but there is also exception that abundant PP-like follicles are found in the small intestine of sterile neonatal ruminants and pigs [10]. In addition, the population
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of PP-like lymphoid follicles tends to reduce with age [40]. 2.2. Trafficking and trapping of particulates If take guards as a metaphor for M cells, the lymphatic tissues might be prisons for particles. The M cells recognize and imprison foreign particles and pathogens in the dome trap. Most particles are efficiently transported by M cells without much degradation because of the presence of relatively few lysosomes in M cell cytoplasm [21]. It is noticeable that entrance of particles into the body might be through the M
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ACCEPTED MANUSCRIPT
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Fig. 3 Diagram of the “dome trap” (A) that shows four possible pathways for transportation of particles in the “dome trap”: transport across M cells and subsequently capture by DC cells (1) or macrophage (4); particles across M cells migrate into lymph vessel without undergoing any uptake (2); particles across M cells are taken up by macrophages or DC cells and subsequently escape from these cells and enter lymph vessels (3). The accumulation of glucan particles within DC cells in SED following oral administration to mice (B1 and B2) and within macrophages in triple cells co-culture model (C). Adapted with permission from ref. 15 and 42, respectively.
cell pathway only because M cell-depletion completely blocks oral prion disease pathogenesis [41]. Particles internalized by M cells are immediately transported across the M cell cytoplasm, subsequently excreted as integral particles into the M cell pockets, and then migrate across the porous epithelial basal membrane to SED, where particles are identified and taken up by numerous residing lymphocytes and macrophages [17, 38]. Lymphocytes and macrophages identify and take up particles. Meanwhile, antigen processing occurs to initiate immune response if antigens or microorganisms are involved [42]. On the other hand, particles transported by M cells
ACCEPTED MANUSCRIPT are
disseminated
into
the
mesenteric
lymph
and
further
distributed
to
reticulo-endothelial organs like liver and spleen via systemic circulation [17, 43]. Thus, the dome trap plays a significant role in the biological fate of particles. Direct evidence of dome entrapment was obtained by tracking the translocation of glucan microparticles (GMs) with particle sizes (2-4 m) large enough to render them more
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easily identifiable [23]. Further cellular uptake study confirmed firm entrapment because GMs internalized by macrophages were retained within the cells for at least
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24 h without much degradation (Fig. 3C) [17, 23] [17, 23] [17, 23] [17, 23] [15,21]. However, a few fluorescent GMs were detected in liver, spleen and lung, indicating
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escaping from the dome trap [17]. Similarly, De Jesus et al demonstrated that GMs accumulated in DCs of SED in large amount following M cell- mediated
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transepithelial transport (Fig. 3B1,B2) [44]. For vaccine delivery, it is preferred that the particles are immediately taken up by lymphocytes and stay there to initiate
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efficient immune responses. On the contrary, therapeutic drugs should reach the systemic circulation first before re-distribution to target tissues; thus, entrapped
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particles should escape the dome trap first to achieve more efficient drug delivery. The biological fate of particles in the dome trap is determined by various physicochemical
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properties of the particles. For instance, larger particles (> 5 µm) tend to stay in PPs for longer time, while smaller particles are able to escape the dome trap to reach distant sites via lymphatic circulation [45, 46]. It is of high importance to clarify the
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factors influencing the fate of particles in the dome trap. 3. In vitro and in vivo evaluation models 3.1. M-like cell models Caco-2 cells derived from human colorectal adenocarcinoma have long been used to simulate enterocytes. Caco-2 cell monolayers have been extensively employed to assess permeation of substances across intestinal epithelia, and Caco-2/HT29-MTX co-culture models are used to mimick the function of various mucus-secreting cells such as the goblet cells [47, 48]. To mimick the function of M cells, lymphocytes or macrophages are usually employed to infiltrate Caco-2 cell monolayers. Kerneis et al
ACCEPTED MANUSCRIPT developed the first in vitro FAE model that comprised of a co-culture of Caco-2 cells and mouse B lymphocytes isolated from PPs. In practice, Caco-2 cells were seeded onto the basolateral side of Transwell® inserts to grow the monolayers, and then mouse B lymphocytes were added to the apical side and let to infiltrate into Caco-2 monolayers [49]. Further, Glullberg et al promoted this model merely by replacing
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mouse B lymphocytes with human Burkitt’s lymphoma Raji B cells [50]. The model was validated by assessing the translocation capacity of particles and microorganisms.
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However, the model as established suffers from wide variations between different experiments and poor contact between Caco-2 cells and Raji B cells. The poor
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reproducibility is partly ascribed to the “non-inverted” nature of this model. Thus, Des Rieux et al developed an “inverted” protocol to address the limitations of the
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“non- inverted” model (Fig. 4) [51]. This new protocol has better reproducibility and better mimicks the in vivo situation as the Raji B cells make close contact with Caco-2
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cells directly on the opposite side via filter pores. Furthermore, Beloqui et al described this experiment protocol in detail with sufficient validation data by various
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approaches such as scanning electron microscopy [48]. The three “M-like” cell models [49-51] were recently compared within the framework of a single study for
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the first time, and the model developed by the “inverted” protocol is proved to be more consistent between different experiments in the functionality and more intimate
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contact between Caco-2 cells and Raji B cells [52]. Recently, a triple co-culture model
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ACCEPTED MANUSCRIPT
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Fig. 4 Schemes of establishment of in vitro human- like FAE models by either the “non- inverted” (A) or the “inverted” (B) methods. Adap ted with permission from ref. 49.
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combining Caco-2 cells, mucus-secreting HT29-MTX cells and Raji B cells, was also developed to evaluate the transport of particles, demonstrating superiority over
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previous binary co-cultures in mimicking the multiple functions of the intestinal epithelia [53]. There is also a “gut-on-a-chip” microfluidic model reported as a potential substitute for the transwell models[54-58], which nevertheless is still in its
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initial developing stages and cannot mimick the M cell function [59]. To date, there is not a universal model to date that is fully consistent with FAE. It should be careful to interpret the results obtained by in vitro models. 3.2. In vivo models
Particles captured by the dome trap will be handled by the lymphocytes in there, or be drained via lymph to systemic circulation. Measurement of the total amount of lymphatic transportation reflects the contribution of the M cell pathway to systemic exposure of the therapeutics. Collecting all lymph fluid that contains the particles by lymphatic cannulation, followed by quantitative analysis, is proved to be a pragmatic
ACCEPTED MANUSCRIPT measure [60, 61]. This in vivo model has been established on various animals, either anesthetized or conscious, including rat, mouse and dog [62]. The conscious model is always preferred because the experiment can be conducted in the absence of anesthetics and the lymph flow is not influenced significantly. Generally, mesenteric lymph cannulation is of choice because the mesenteric lymph duct is the main passage
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for particles from intestine [23]. However, some studies alternatively cannulated the thoracic duct due to more convenient surgical operations than mesenteric lymph
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cannulation [63]. In order to assess the absorption via both lymph and portal vein, a triple-cannulated conscious model, which allows sampling of thoracic duct lymph,
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portal and systemic blood simultaneously, has been developed [64]. From a view of clinical translation, the dog model seems to be more relevant to human than the rat
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model [65] because it is possible to allow administration of dosage forms of identical size to those administered to human. Moreover, the bile flow of rat is continuous due
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to the lack of a gallbladder, which is significantly different from either human or dog [66, 67].
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In order to highlight and accurately weigh the contribution of the M cell pathway to overall lymphatic transportation, the most direct approach is to block the M cells.
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There are two M cell-blocking models reported to date: that is the NF-kB ligand (RANKL) neutralization model [41] and the B cell knock-out model [68]. RANKL
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expressed by intestinal epithelia controls the differentiation of RANK-expressing enterocytes into M cells. RANKL neutralization depletes the M cells in vivo. In actual operation, the IK22-5 rat anti- mouse RANKL-specific mAb was administered to mice every two days for eight consecutive days to establish the M cell-deficient mouse model [41]. B cell-knockout animals that lack PPs and M cells are also an efficient tool to characterize the roles of M cells. For instance, Bermudez et al employed B cell-deficient mice to confirm if M. avium subsp. Paratuberculosis crossed the intestinal mucosa via uptake by M cells [68]. Both models are functional to confirm the effect of M cells in uptake of antigens or particles in vivo in comparison with normal animals.
ACCEPTED MANUSCRIPT 4. Oral immunization based on particulate adjuvants Although oral administration is more convenient and more preferred than other routes, only a limited number of oral vaccine formulations have been licensed [69]. The challenges lie in not only the harsh GIT environment but also the lack of efficiency in mucosal uptake and subsequent elicit of immunization [70, 71]. The major barriers are
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the presence of gastric acid and proteolytic enzymes that readily degrade the vaccines, most of which are labile biomacromolecules [72]. Moreover, the intestinal epithelia
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and the mucus layers greatly limit the entry of vaccines [73]. Encapsulation into
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particles works to protect the vaccines and facilitate uptake by M cells simultaneously, and thus promote efficacy of oral immunization [74, 75]. Table 2 lists typical
NU
particulate adjuvants developed recently for oral vaccines. 4.1. Polymeric particles
MA
Polymeric particles made from versatile synthetic or natural polymers have been extensively explored for oral vaccines. In terms of synthetic polymeric particles,
AC C
EP T
ED
polylactic acid (PLA) and poly(lactic-co-glycolic acid) (PLGA) are popular polymers
ACCEPTED MANUSCRIPT
Table 2 List of typical particulate adjuvants for oral vaccines Particles
Decorations
Antigens
or Viruses
Particle
ζ
size
(mV)
Immunization effects
R e fs
None
OVA and
325±8.
-20.1
sIgA stimulated towards
[
MPLA
5 nm
±0.26
(OVA/MPLA) PLGA
7
nanoparticles 2.7-fold higher
6
than those induced by OVA in
]
PT
PLGA NPs
PBS solution. SIP
50 nm
100% of tilapia was vaccinated,
RI
PMMMA
TLRL
418±88 nm
OVA
200 nm
MA
UEA-1
NU
FS30D
RGD-PEGyl
Chitosan NPs
UEA-1
AC C
PLA NPs
EP T
ated
OVA
ED
PCL NPs
None
None
whereas the control groups (SIP
7
solutions) did not work at all.
7
SC
Eudragit
200 nm
[
]
Induction of T cell immunity
[
against viral infection up to 2
7
times compared to control group
8
(TLRL).
]
IgA titers for OVA-UEA-NPs
[
4.5-fold higher than for OVA
2
alone and 2.2-fold higher than
1
for OVA-NPs
]
Increased transport of
[
nanoparticles across the M cell
7
model, with a factor of 3.5
9
compared to the non-targeted
]
formulation 200-25
-40
0 nm
Delivery to DC cells by 3-4
[
times more than plain PLA NPs
8 0 ]
Peanut
100-20
allergy gene
0 nm
+10
Higher levels of gene expression
[
in both stomach and small
8
intestine induced by
1
nanoparticles than naked DNA.
]
Tripolyphos
pcDNA3.1-V
The
antibodies
[
phate
P2
expression in vaccinated fish
8
with CS-TPP nanoparticles were
2
5 times more than naked DNA.
]
Gluco mann osylated
BSA
levels
of
150-19
Gluco mannosylation
of
[
0 nm
stabilized chitosan NPs elicited
8
a 4.0- and 3.8- fold h igher sIgA
3
titer
]
in
salivary
flu id
and
ACCEPTED MANUSCRIPT intestinal content than chitosan NPs. UEA-1
BSA
250
36.8 ;
Microparticles
by
[
nm;
-28.6
UEA-1 produced around 2.5-
8
and 1.5- fold than BSA absorbed
4
NPs
]
1.5 μm
and
modified
BSA
entrapped
microparticles Thiolated
BmpB
MPs
Thiolated
Thiolated
MPs
[
μm
produced 1.52- or 1.68- fold
8
high sIgA level than Eudragit
5
MPs in mice.
]
The delivery of antigen by
[
3.7 μm
M-BmpB
Eudragit
RI
HPMCP
1-10
PT
Eudragit
Thiolated HPM CP M Ps was
8
higher by an average of 2.7-fold
6
SC
MPs
in compared to the delivery by
]
HPMCP MPs.
None
pDNA
The TNF-α and IFN-γ was 1.2-
[
shape
and
by
8
1
polyplex NPs coated antigen
7
high than antigen.
]
292 n m
Mann-modified nanogels were
[
to
internalized
macrophages
8
unmodified
8
Rod
NPs
NU
Polyplex
μm/
PHM
Mannan
OVA
nanogel
MA
10 μm
1.5
Liposome/
Cationic
4-fold
fo ld
produced
by
than
counterparts.
]
166.5±
+48.7
The serum OVA specific Ig G1 is
[
9.0 nm
±1.4
around
by
8
cationic liposome than by PLGA
9
NPs.
]
5-fold
induced
Gluco manna
Tetanus
198±17
Gluco mannan
modified
[
n
toxoid
nm
bilosomes exhibited 2.0 and 1.4
9
folds higher immune response in
0
comparison with niosomes and
]
AC C
Porous
OVA
EP T
Biolosomes
ED
μm
4-
None
bilosomes, respectively. BSA
silica NPs
130
The Ig G and IgA titers induced
[
nm,
by loading BSA was as follows:
9
430 n m
S1 (130 n m) > S2 (430 n m)>
1
and 1-2
SBA-15 (1-2 μm) .
]
μm β-Glucan
None
OVA
particles
3.7±0.2
-6.4±
More divided OVA-specific
[
μm
0.3
cells (51.5 ± 11.2%) were found
9
in the spleen (P = 0.009) of
2
glucan-OVA-fed mice in
]
comparison with the PBS group GRGDS
PR8
200-30
-13
The anti-PR8 IgG titer of NPs
[
ACCEPTED MANUSCRIPT 0 nm
were around 10-, 1.8- and 6-fold
9
higher than PR8 solutions in
3
intestine, mucus and serum,
]
respectively. Virus-like
Yeast cell
U 65
Protection against systemic
[
particles
wall
scaffolded
polyoma virus and reducing
9
antigens
viral DNA levels in spleen and
4
liver by >98%.
]
Recombinant LL-mInlA + and
[
t
LL-FnBPA+ strains showed
9
Lactococcus
100-fold greater invasion rate
5
Lactis (LL)
compared to the wt strains
]
PT
DNA
RI
Recombinan
(NZ9000 and MG1363). Hemagglutini
benthamiana
n of H1 or
135 nm
Enterovirus 7
7
(EV7)
9 6 ]
The levels of antibodies induced
[
by VLPs were around 3- fold
9
than control group (yeast cell).
7 ]
3.5 μm
A single dose of spray-dried
[
bacteriophag
VLPs induced high-titer anti-L2
9
e
IgG responses, which were
8
similar to mice immunized with
]
EP T
ED
ge
30 nm
MA
Enterovirus
NU
viruses
L2
[
transient IgG
H5 influenza
Bacteriopha
34% of subjects developed
SC
Nicotiana
freshly prepared (non-spray-dried) L2-VLPs.
Early
80-200
3-4 folds enhancement of IgG
[
virus
secretory
nm
levels against ESAT-6 protein
9
AC C
Influenza
Live
antigenic
9
target 6
]
protein (ESAT-6) Invasin
Antigen delivered to PPs by
[
engineered
VLPs 6.38 folds more than
1
E. coli
naked counterpart.
0 0 ]
Abbreviations:
NPs,
nanoparticles;
MPs,
microparticles;
PLGA,
poly(lactic-co-glycolic acid); PCL, polycaprolactone; PLA, polylactic acid; HPMCP, hydroxypropyl methylcellulose phthalate; MCC, microcrystalline cellulose; PMMMA, poly[(methyl methacrylate)-co-(methyl acrylate)-co-(methacrylic acid)]; HEMA,
ACCEPTED MANUSCRIPT poly(2-hydroxiethyl
methacrylate-co-methacrylic
acid);
PHM,
Poly(HEMA-co-MAA); MAA, methacrylic acid; UEA, Ulexeuropaeus agglutinin; RGD,
arginylglycylaspartic acid; GRGDS,
acid-Serine;
BSA,
bovine
serum
Glycine-Arginine-Glycine-Aspartic
albumin;
OVA,
Ovalbumin;
MPLA,
Monophosphoryl lipid A ; SIP, Surface immunogenic protein; BmpB, Brachyspira
PT
hyodysenteriae.employed in clinical studies for oral vaccines due to their biocompatibility and approval status by U.S. Food & Drug Administration (FDA) [79,
RI
101]. In addition to protection and uptake enhancement, polymeric particles prolong antigen release, thus creating opportunities for reduced immunization frequency, or
SC
even single-dose immunization [102, 103]. Some studies demonstrated much longer terms of IgA and IgG antibody titers than soluble antigen by a single dose of several
NU
antigens as encapsulated in biodegradable particles [21, 104]. The chemical stability of vaccines is further improved through combination of two or more materials. For
MA
instance, the pH-sensitive methacrylate-based polymer Eudragit FS30D, which dissolves at pH > 7.0, was employed to coat PLGA nanoparticles to reinforce the
ED
chemical stability of antigens in stomach [105]. Another class of synthetic polymers for vaccines are polyanhydrides, which show superiority over polyesters in
EP T
improvement of antigen stability [106]. What’s more, polyanhydrides are able to modulate immune responses very well without the help of additional adjuvants [107,
AC C
108].
Natural polymers are always more favorable than synthetic ones due to reduced toxicity, good biocompatibility and mild conditions for encapsulation. The most common natural polymers for oral vaccines are polysaccharides that possess promising properties for oral delivery including mucoadhesion [109, 110], opening epithelial tight junctions transiently (as for chitosans) [111, 112] and active targeting to M cells (as for glucans) [44, 92]. Currently, β-glucan is gaining interest because of its high efficiency in facilitating uptake by M cells [92, 113]. However, it should be minded that oral vaccines induces substantial mucosal immunization but very limited systemic immune response even with the help of polymeric particles because they are
ACCEPTED MANUSCRIPT firmly retained by the dome trap and hardly reach the systemic circulation in sufficient amount [23]. 4.2. Liposomes Lipid-based particles are nice vehicles for delivery of chemicals via various routes for versatile therapeutic purposes because they are mainly composed of endogenous
PT
lipids or lipid derivatives [114-116]. This is equally true for oral delivery of vaccines. Among various lipid-based particles, liposomes offer the ability to deliver multiple
RI
active ingredients with widely different properties [117]. In general, hydrophilic
SC
entities such as proteins, RNAs and DNAs are encapsulated into the inner aqueous compartments of liposomes. DNA vaccine encapsulated in cationic liposomes
NU
increased the humoral and cellular immune responses by oral delivery, stimulating more cytokine production concurrently [118]. However, liposomes are self-assembled
MA
vehicles that suffer from severe instability when subjecting to gastric acid, bile salts and enzymes in GIT [119-121]. Paradoxically, bilosomes, a novel type of liposomes
ED
containing bile salts (e.g. sodium deoxycholate), are found to have improved stability than conventional liposomes [122]. A variety of fragile antigens have been entrapped
EP T
in bilosomes with improved chemical stability for oral immunization, such as diphtheria toxoid, Bac-VP1, GnRH antibody and tetanus toxoid [123]. These systems were shown to elicit Th1/Th2 immunity by generating mucosal and systemic
AC C
immunity [124]. Furthermore, the efficacy of these vehicles can be highly enhanced by modification with moieties targeting M cells [90]. 4.3. Biomimetic particles As mentioned above, pathogens like bacteria and viruses are recognized by M cells and thereby carried to the dome trap for further handling. This is a highly efficient mechanism that can be mimicked to facilitate uptake of particles. The most common approaches for constructing biomimetic particles are to functionalize particle surfaces with microbial ligands such as lipopolysaccharide (LPS) and its derivatives, flagellin and lectins [125]. These ligands are able to not only target
ACCEPTED MANUSCRIPT M cells but also work as immunomodulators to enhance immune responses [126-128]. The LPS are recognized as one of the main pathogen-associated molecular patterns (PAMPs), but have deleterious side effects [129, 130]. Therefore, many researches attempted to modify the structure of LPS to remove its toxicity while preserving its biomimetic properties, for example monophosphoryl lipid A (MPL) [131], whose
PT
liposomal formulation enhanced both mucosal and systemic immunity significantly [132]. Flagellin, a monomeric protein, determines the virulence of some pathogens by
RI
offering motility and improving adhesion [133]. It serves as a PAMP due to the advantages of binding toll- like receptor 5 (TLR5), inducing the maturation of DCs
SC
and activating CD4+ T cells [134]. Flagellin- functionalized nanoparticles firmly bound the epithelial surfaces following oral delivery, while inducing higher secretion
NU
of balanced antibodies (Th1 and Th2) as well as a much stronger mucosal IgA than non-decorated nanoparticles [135]. In addition, lectins are extensively employed as
MA
ligands to target M cells and enhance uptake [101]. For example, microspheres modified with wheat germ agglutinin (WGA) and aleuriaaurantia lectins facilitate
ED
uptake by M cells [136].
Virus-like particles (VLPs) mimick natural viruses by inserting viral capsid
EP T
proteins into particles [137, 138]. Since VLPs have been deprived of the viral genomic materials, there is no concern over the chance of wild-type virus infections.
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Most VLPs, such as inactivated virus or bacteria, keep their own antigenic activity and stimulate immune response. On the other hand, VLPs can be used as carriers to deliver antigens as well [139]. Various vaccines for influenza, hepatitis B, human papilloma virus (HPV) and hand- foot- mouth disease have been entrapped and delivered by VLPs to elicit protective immunity against viral diseases [39, 140]. Owing to ease of production, both plant and yeast cells are commonly engineered to produce the single viral capsid protein of VLPs [141, 142]. Recombivax HB® was the first VLP-based nanoparticulate formulation for immunization by intramuscular injection approved in 1986 [143]. Currently, a few other veterinary vaccines based on VLP have been approved as well, such as Gardasil® and Cervarix® against HPV [144].
ACCEPTED MANUSCRIPT However, current VLP-based vaccines have to be administered intramuscularly for efficient immunization and the biggest challenge of VLPs-based vehicles is probably potential infection due to residues of virulence gene sequences [145]. In this respect, edible microorganism such as yeast and lactic acid bacteria are more advantageous than VLPs as vehicles for oral delivery of vaccines.
PT
5. Oral drug delivery via the M cell pathway It is generally accepted that small molecular drugs are absorbed via enterocytes (to
RI
portal vein) in GIT. In this case, the M cell pathway seems to be unimportant, if not
SC
negligible, because M cells only occupy approximately 5% of the human FAE and even less than 1% of the total intestinal surface [14, 48]. Because of this limitation, it
NU
is unwise to take this pathway to deliver drugs capable of absorption via the enterocytes. However, for biomacromolecules, the absorptive epithelia are not
MA
permeable and therefore the M cell pathway is currently the only choice to reach the systemic circulation. Numerous biomacromolecules exhibit extremely low, even no,
ED
oral bioavailability via oral delivery due to high vulnerability or poor solubility or low permeability across intestinal epithelia [146, 147]. Particulate carriers are able to
EP T
overcome, more or less, these problems and thereby improve oral bioavailability [148]. However, the enhancement is not significant enough to elicit clinical effect [149]. One of the leading reasons is that particles may be trapped by the dome trap,
AC C
significantly reducing the systemic exposure of the drugs. Measures should be taken to facilitate escape of the entrapped particles to enhance bioavailability. 5.1. Polymeric and lipidic particles Polymeric and lipidic particles are also extensively studied for oral delivery of drugs [115, 150]. For example, polyalkylcyanoacrylate nanoparticles of 285 nm were evaluated via oral delivery and found to be predominantly captured by M cells and adjacent enterocytes in PPs of an isolated ileal loop model in rats [151]. The integral lipidic nanoemulsions could be transported across the M cell model and through the lymphatics with a fraction of approximately 3-6% [61]. Many researches employed
ACCEPTED MANUSCRIPT the model drug insulin to study the impact of the M cell pathway on oral delivery [14]. Insulin- loaded
liposomes
containing
sodium
glycocholate
showed
obvious
size-dependency and those ranging between 150 and 400 nm facilitated oral absorption [152]. However, particles without surface functionalization are only taken up via non-specific mechanisms depending on size, charge or material prope rties.
PT
Hence, the transport amount is limited [53, 153]. In order to increase the total amount of transportation by M cells, particles are usually functionalized with ligands targeting
RI
the receptors on M cell membranes [24, 154]. WGA and tomato lectins (TL) have been proven to be stable when challenged by high concentrations of pepsin, trypsin,
SC
pancreatin or elastase [155]. Liposomes [156] and solid lipid nanoparticles (SLNs) [24], modified with WGA, TL and UEA-1, promoted the oral absorption of insulin
NU
and elicited remarkable hypoglycemic effects in compariso n with conventional non-decorated particles. Higher concentrations of WGA-SLNs (< 100 nm) were
MA
observed by microscopy in PPs than in non-PP tissues, which implied that most of
5.2. Biomimetic particles
ED
SLNs were transported through PPs [154].
EP T
Another attractive way for M cell targeting is represented by the direct administration of recombinant bacteria as carriers for therapeutics [157, 158]. The most extensively investigated
microorganisms
for
oral
delivery
are
recombinant
or
AC C
biotechnologically- modified lactic acid bacteria (LAB) because of their wide applications as food ingredients [159, 160]. For instance, LAB was employed to deliver interleukin-10 (IL10) to treat inflammatory bowel disease successfully [161]. The yeast cells derived microparticles (YCM) also draw much attention for oral drug delivery [23, 162]. YCM is 2-4 µm in diameter and has a hollow core enclosed within a porous shell. Moreover, the primary component of YCM is β-1,3-D glucan which can target M cells mediated by CR3 or dectin-1 receptors. Insulin was encapsulated in the inner cavities of YCM by a thermosensitive gel, and its hypoglycemic effect and pharmacological bioavailability (9-10%) were improved significantly in rats. Coincidently, the cumulative lymphatic transport of YCM was over 8% in 24h, which
ACCEPTED MANUSCRIPT was highly correlated to pharmacological bioavailability [23]. The YCM migrated to the serosal side of the ileum through PPs. However, the YCM was not detected in all other organs for 12 h following oral administration, but they appeared in the liver, lung, and spleen after then and around 2.3% of total amount was recovered in these organs [17]. In order to entrap more drugs, the liposomes were constructed in the core
PT
of YCM directly through the reverse phase evaporation method for loading diverse drug molecules [163]. Plant cells are increasingly becoming an oral delivery system
RI
for protein drugs because they can protect the encapsulated drugs from gastric acids and intestinal enzymes, and release drugs into the gut lumen upon microbial digestion.
SC
Additionally, intact plant cells are also absorbed into circulation by transcytosis
NU
through M cells [164].
6. Factors influencing the in vivo fate of oral particulates
MA
The elicit of efficacy as well as toxicity depends highly on the absorption, distribution and disposition of ingested particles. Therefore, understanding the in vivo fate of oral
ED
particulates is of high significance. Influencing factors extensively investigated include particle size, shape, surface charges, modification with ligands, etc.
EP T
6.1. Particle size
It is well known that reduction in particle size accelerates the dissolution of particles.
AC C
Thus, smaller particles have faster release rate than larger ones [165]. More importantly, particle size significantly influences the bio- interaction of particles with tissues and subsequently the in vivo fate [166, 167]. An earlier report showed that cellular uptake of 100-nm PLGA nanoparticles in Caco-2 cell lines is 2.5-fold greater than that of 1- µm microparticles [46]. In a case study with gold nanoparticles, ultra-small nanoparticles showed the highest permeation rate across intestinal membranes [43]. After 24 h, 0.37% of 1.4-nm particles were transported into the systemic circulation, while there were only 0.05%, 0.03% and 0.01% of gold nanoparticles found in circulation with sizes of 5, 80 and 200 nm, respectively [43]. However, histological examination revealed that 80- nm lipid-based nanoemulsions
ACCEPTED MANUSCRIPT could be taken up by enterocytes and distributed into basolateral tissues, whereas 500-nm and 1000- nm counterparts primarily adhered to villi surfaces [61]. Besides uptake by enterocytes, M cells take up particles in a size-dependent mode [46, 168, 169]. It is believed that M cells are able to take up particles less than 1 µm efficiently. However, the PLGA microparticles below 10 µm can also be specifically taken up
PT
into the PPs and particles larger than 5 µm remained in the PPs for an extended period, while the counterparts lower than 5 µm were found disseminating into the mesenteric
RI
lymph nodes, spleen and blood [103]. Size dependency was also observed for the uptake of organosilica particles. The relative uptake percentage by the dome trap with
SC
sizes of 95, 130, 200, 340, 695 and 1050 nm was 124.0, 89.1, 73.8, 20.2, 9.2 and 0.5%, respectively, in comparison with 100- nm particles [169]. Meanwhile,
uptake of
NU
smaller organosilica particles (100, 180 and 365 nm) was accompanied by a significantly grown number of IgA+ cells and CD11b+ macrophages in the dome trap,
MA
while particles with large sizes of 745 and 925 nm were only associated with increased mucosal IgA and -L-fucose on M cell surfaces [170]. There is no surprise
ED
that most studies on particle size effect are based on inorganic particles, whose size is uniform and more easily controllable. However, the size distribution of organic
EP T
particles is hardly satisfactory due to a lack of appropriate manufacturing approaches. A polydispersity index (PDI) lower than 0.1 are generally regarded as monodisperse [171], which nevertheless is a goal very difficult to achieve for organic particles.
AC C
Therefore, future investigations into the size effect call for strict controlling on particle size and size distribution. 6.2. Particle shape
Early in 1983, a study demonstrated that particle shape affected drug release, opening a new field of interesting research [172]. Over the years, the influence of particle geometry on drug delivery nevertheless is still not well understood, mainly due to a lack of strategies to control particle shape precisely. Limited information available indicates that particle shape is one of the most important factors in biorecognition and biointeraction [166, 173]. It was shown that spherical particles contacted with
ACCEPTED MANUSCRIPT macrophages from any point due to their structural symmetry, but the internalization of ellipse particles depends highly on the contact regions [166]. Particle shape affects the kinetics, efficiency and mechanisms of cellular uptake as well [174-177]. The internalization mechanisms depend highly on particle shape; for instance, mesoporous silica
spheres
prefer
the
clathrin-pathway,
while
long
rods
prefer
the
PT
caveolae-pathway instead [178]. Similarly, particle shape influences the distribution and elimination of gold nanoparticles after injection [174]. Banerjee et al
RI
demonstrated that polystyrene nanorods outperform spheres in transport across Caco-2/Raji monolayers [53], suggesting shape dependency. Meanwhile, shape also
SC
influenced the movement of nanoparticles in GIT. The cylindrical mesoporous silica nanoparticles (MSNs) have higher diffusivity than spherical counterparts, which leads
NU
to penetration deep into mucus and extended retention in GIT [179].
MA
6.3. Surface charges
Since biomembranes as well as various mucous linings (e.g. gastrointestinal mucus)
ED
are negatively charged, the effect of surface charges, especially positive ones, on biointeraction should not be ignored and sometimes it might be substantial. Follo wing
EP T
this logic, there is a consensus that the positively charged particles have greater affinity with cells and longer retention time in mucus layer s than negatively charged or non- ionized ones [180-182]. Surface charges of particles are generally
AC C
characterized as zeta potential for colloidal systems, which can be easily changed in response to different surface coatings such as polyvinyl alcohol (PVA) for negative and chitosan for positive charge [183, 184]. For example, the neutral surface charges of naked polystyrene nanoparticles (+1.1 mV) can be changed to positive by coating with chitosan (+17.5 mV) or negative by polyethylene glycol (PEG)-PLA (-23.9 mV) [185]. The corresponding capacity of internalization of polystyrene nanoparticles by MTX-E12
cells
was
in
the
following
order:
chitosan-coated
>
naked >>PEG-PLA-coated [185]. The chitosan-coated polyplex- loaded liposomes deliver more DNAs to distal intestine than conventional liposomes, indicating increased uptake owing to the positive surface charges [118]. Furthermore,
ACCEPTED MANUSCRIPT enrichment of surface charges reinforces cellular uptake of particles. A case study of densely charged SLNs coated with hydroxypropyltrimethyl ammonium chloride chitosan revealed enhanced uptake by PPs in rodents [186]. However, there are exceptions too; negatively charged gold nanoparticles were found accumulating mostly into secondary organs (e.g. liver, spleen and kidney) following absorption than
PT
positively charged nanoparticles [43]. 6.4. Ligand-based active targeting
RI
Modification of particles with active targeting ligands is meant to enhance either the
SC
biorecognition or internalization or both via ligand-receptor (transporter) interactions. Molecules that can be actively recognized by the intestinal epithelia such as nutrients
NU
(vitamins, amino acids, saccharides), peptides and polysaccharides are potential ligands for active targeting (Table 3). There are different cells residing in the intestinal
MA
epithelia (Table 1) and the distribution of receptors/transporters varies with each cell type. Therefore, it is possible to achieve active targeting to a specific group of cells.
ED
The apical region of intestinal epithelial cells expresses neonatal Fc receptors. Modification with Fc fragments significantly enhanced
the absorption of
EP T
nanoparticles into systemic circulation up to 13.7%, in sharp contrast with only 1.2% for non-decorated ones [199]. Mucus-secreting goblet cells were also targeted using peptide ligand CSKSSDYQC with improved oral bioavailability of insulin [200]. As
AC C
the M cell pathway holds promising potential for both oral immunization and delivery of labile biomacromolecules, M cells might be the hottest target in studies of active targeting to intestinal epithelia. Lectins are the most broadly investigated category of M cell-targeting molecules, which bind to specific carbohydrate residues presenting on the surfaces of M cell with high affinity, such as α-L- fucose residues [187]. The lectin- functionalized liposome stimulated systemic immune response to obtain anti-hepatitis B IgG in serum after three consecutive days following oral administration and higher sIgA level in mucous secretion, which indicated more lectinized liposomes were captured by the dome trap to stimulate mucosal immune response [187]. Similarly, almost all M cell-targeting particles were found
ACCEPTED MANUSCRIPT accumulating in the dome region of PPs and being able to stimulate higher mucosal immune responses [21, 111, 201]. The lectinized nanoparticles were also found to increase peroral delivery of proteins via the M cell pathway [150, 202]. The lectin mimetics have more advantages than lectins such as small molecule weight, low immunogenicity and ease of synthesis. The lectin analogues-conjugated PEG
PT
constructs form a tetragalloyl- D- lysine dendrimer (TGDK) for oral delivery of Rhesus CCR5-derived cyclopeptide antigen [193]. More specific human M cell
RI
markers were developed by many studies, such as sialyl Lewis A antigen (SLAA) and galectin 9 [192, 203]. In addition, many enteropathogenic microorganisms were taken
SC
up due to high-affinity interaction with integrins (α5β1) overexpressed in human M cells. Therefore, RGD-conjugated PLGA nanoparticles improved the in vitro transport
NU
by human M-like cells significantly [79]. However, the extent of enhancement is very limited because not only M cells occupy merely about 1% of all epithelial cell
MA
population but also only a limited number of nanoparticles entrapped are able to
AC C
EP T
ED
escape the dome trap and migrate into systemic circulation.
ACCEPTED MANUSCRIPT Table 3 Typical ligands used to modify particles or antigens for targeting to M cells
WGA
Liposomes, SLNs
Liposomes, lipid NPs
Drugs
Size (nm)
ζ (mV)
Efficiency
Refs
Insulin
191.0±13.62 (Liposomes)
+5.78 (Liposomes)
[154]
75.3±16.79 (SLNs)
-13.11 (SLNs)
OVA (Lipid NPs);
215.3±3.5 (Lipid NPs);
-4 (Liposomes)
HBsAg (Liposomes)
450 nm (Liposomes)
The relative absorption effeciency is WGA-liposomes > WGA-SLNs> SLNs > liposomes > insulin solution The cumulative amount of UEA-lipid NPs was around 3-fold higher than that of lipid NPs; The antibody levels induced by lectinized liposomes were around 1.6 folds than non-lectinized counterpart. About 10 times more coated liposomes
[188]
Liposome
110
EP T
PLGA NPs
HBsAg
300
AC C
LTA
Claudin-4 targeted protein
PLGA NPs
HA protein
472±25
RGD
Pegylated PLGA NPs
OVA
200 nm
[21, 187]
became associated with Peyer’s patches than uncoated liposomes.
ED
RO1
MA
NU
SC
UEA-1
or
PT
Particles antigens
RI
Ligands
-6.6 ⁓-13.8
Distinct binding of lectinized nanoparticles to the peyer’s paches as compared to control nanoparticles which showed little or no binding to the M cell in mice. CTP modified NPs enhanced 2 folds uptake by M cells compared to unmodified counterpart.
[101]
The RGD modified NPs increased
[79]
the transport across the M cell model, with a
[189]
ACCEPTED MANUSCRIPT
Chitosan NPs
Chitosan NPs
SA
Ovalbumin peptide
Galectin-9
None
TGDK
rhesus CCR5-derived cyclopeptide
FimH
Escherichia coli and Salmonella enterica serovar Typhimurium None
pVP1
300
approximately 1.5-fold higher than CNs after 3 h of uptake by M cells. 37.5% of chitosan NPs and 62.5% of CPE30-chitosan NPs immunized mice survived to day 28 post infection.
+22
[111]
[190]
ASLF
ED
EP T
AC C
L-HIV
MA
NU
SC
RI
CPE 30
226.2±41.9
PT
CKS9
factor of 3.5 compared to the unmodified formulation. The accumulated amount of CKS9-CNs was
None
SA conjugation induced higher sIGA titer with a factor of 3 compared to naked OVA by targeting to M cells. Galectin-9 expression in M cells is 2.3 folds higher than epithelial cells. The transport of TGDK conjugated antigens was around 4 folds higher than naked antigens. FimH increased antibody levels up to aound 2.5 folds by targeting to M cells.
[191]
A L-HIV-1 strain crosses M cell monolayers and infects underlying CD4+ target cells, but the monotropic (R5) HIV-1 strain can not. SLF is expressed on mounse M cells in the small intestine and ASLF antibody injected into mouse intestine
[195]
[192]
[193]
[194]
[196]
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Co1 ligand
Enhanced GFP
The serum IgG and fecal IgA levels were improved up to 1.6- and 1.4- fold due to the Co 1-mediated trascytosis.
[197]
[198]
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ED Ⅲ antigen
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OmpH ligand
bound to M cells. The number of EDⅢ-specific IgG-secreting cells in splenic lymphocyte from EDⅢ-OmpH are 2.5-fold higher than EDⅢ group by oral administration.
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6.5. Escaping the dome trap
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Abbreviations: WGA, Wheat germ agglutinin; UEA-1, Ulexeuropaeus agglutinin 1; LTA, Lotus tetragonolobus from Asparagus pea; CTP, Claudin-4 targeted protein; CKS9, CDSTHPLSC peptide; SA, Anti-GP2-streptavidin; CPE 30, C terminal 30 amino acids of clostridium perfringens enterotoxin; SLAA, Sialyl lewis A antigen; TGDK, Tetragalloyl- D- lysine dendrimer; RO1, Recombinant σ1 or OVA- σ1 fusion protein; L-HIV, Lymphotropic HIV-1 strain; ASLF, Anti-sialic acid-binding immunoglobulin- like lectin F; NPs, Nanoparticles; SLNs, Solid lipid nanoparticles.
As discussed above, prolonged retention of particulates by the dome trap might be
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beneficial for oral immunization. However, drug delivery demands the translocation of the particulates from the dome trap to lymph and finally to the systemic circulation. If the particulates can be manipulated to escape the dome trap actively, the
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bioavailability of drug delivery might be greatly elevated. Unfortunately, there are still no reports on this issue to date to the best of our knowledge. Previous experience tells that there is possibility of escaping from the dome trap by manipulating exocytosis. Exocytosis of nanoparticles is energy-consuming and influenced by cell types and physicochemical properties of particles such as size, shape and surface chemistry. In general, smaller nanoparticles are excreted more quickly than bigger ones. For example, the exocytosis rate of MSNs with sizes of 60, 180, 370 and 600 nm was 63, 67, 58 and 38%, respectively [204]. The particle shape is also considered an important factor influencing exocytosis. In the case of gold nanoparticles, rods
ACCEPTED MANUSCRIPT were expelled from Hela and SNB 19 cells more easily than spheres, which however might vary with different cell types. Surface chemistry also plays a role in exocytosis of nanoparticles. The gold nanoparticles functionalized with KPPQPSLP peptide, which was taken up via non-specific endocytosis, were excreted more after 4 h than those modified with another peptide KATWLPPR [205]. A counter evidence is that
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co-delivery with an efficient exocytosis inhibitor (dimethylamyloride) improves the retention in cells [206]. Yet it should be aware that exocytosis of nanoparticles has
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two opposite directions: the basolateral-to-apical and the apical-to-basolateral direction. Apparently, the former should be avoided or reduced to as low as possible.
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Whether it is plausible to manipulate exocytosis in vivo is still awaiting evidence.
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6.6. Mucoadhesion
To reinforce uptake of particles by M cells, it is a prerequisite for the particles to
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make close contact with FAE. Mucoadhesive delivery systems prolong the residence time of particles in GIT and render intimate contact with M cells, thus increasing the
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opportunity of uptake through the M-cell pathway. In many researches, surface modification by mucoadhesive materials such as chitosans [207] or by sulfhydrylation
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[208] mucoadhesive materials are employed to improve the mucoadhesive capability of nanoparticles. However, nanoparticles would be dispersed and adhere everywhere including sites without presence of PPs due to the high dispersity of the particles
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along with the digestive motion, significantly compromising the efficiency of M-cell uptake. A new intestinal patch device were developed to localize large amount of drug molecules near the mucosa to generate a high concentration gradient from apical to basolateral side, which improved the absorption of biomacromolecules [209, 210]. If this device is used to deliver nanoparticles to intestinal segments where PPs are abundant such as ileum, extended and reinforced absorption of nanoparticles via the M-cell pathway could be envisaged. 7. Conclusions and perspectives The M cell pathway has long been recognized as an effective portal for oral
ACCEPTED MANUSCRIPT immunization or for oral drug delivery, especially biomacromolecules. However, various related concepts are not easily understandable, especially for non-experts. The conceptualization of the dome trap, which is p hysically comprised of the FAE and sub-FAE lymphatics as well as various functional cells including M cells, lymphocytes and macrophages highlights the significance of this physiological barrier
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in respect to either oral immunization or drug delivery. To reinforce therapeutic efficacy, the first thing to do is to encapsulate therapeutic drugs, vaccines or
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biomacromolecules, into particulate vehicles and protect them from the detrimental GIT environment. Particles together with the payloads are captured by M cells and
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immediately transported to sub-FAE lymphatics. The retention of particles by the dome trap depends highly on their interaction with various immunocytes.
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Functionalization of the particle surfaces with ligands targeting M cells such as lectins greatly enhances the uptake by M cells and subsequent retention in lymphatics as well
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owing to the presence of the same receptors as M cells for various lymphocytes. In addition, biomimetic particles derived from bacteria, fungi or viruses are functional
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carriers to deliver therapeutic entities to the dome trap due to their natural affinity with M cells. This mechanism is beneficial for oral immunization because it mimicks
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natural immunization against invading pathogens. The biggest challenges are with drug delivery, which demands substantial uptake of the particles by M cells and easy escape from the dome trap simultaneously. Unfortunately, particle properties that
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favor escape do not favor uptake by M cells; properties that favor uptake do not favor escape as well. Ideal systems might be able to be taken up quickly and substantially and be diverted to cross the dome trap easily. The uptake by M cells can be evaluated by both in vitro M-cell like models or in vivo blocking model. However, there is a lack of efficient models to assess the escaping from the dome trap. Conflicts of interest The authors report no conflict of interest. Acknowledgements
ACCEPTED MANUSCRIPT This work is financially supported by Science and Technology Commission of Shanghai Municipality (15ZR1403000), and National Natural Science Foundation of
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China (81573363, 81690263).
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Hamura, S.I. Fukuoka, A.W. Lowe, K. Itoh, H. Kiyono, H. Ohno, Uptake through glycoprotein 2 of FimH+ bacteria by M cells initiates mucosal immune response, Nature, 462 (2009) 226. [195] G. Fotopoulos, A. Harari, P. Michetti, D. Trono, G. Pantaleo, J.-P. Kraehenbuhl, Transepithelial
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transport of HIV-1 by M cells is receptor-mediated, Proc. Natl. Acad. Sci. USA, 99 (2002) 9410-9414. [196] N. Gicheva, M.S. Macauley, B.M . Arlian, J.C. Paulson, N. Kawasaki, Sig lec-F is a novel intestinal M cell marker, Biochem. Bioph. Res. Commun., 479 (2016) 1-4.
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[197] S.H. Kim, I.Y. Yang, S.H. Jang, J. Kim, T.T. Truong, T. Van Pham, N.U. Truong, K.-Y. Lee, Y.-S. Jang, C5a receptor-targeting ligand-med iated delivery of dengue virus antigen to M cells evokes antigen-specific systemic and mucosal immune responses in oral immunization, Microbes Infect., 15 (2013) 895-902.
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[198] S.H. Kim, K.W. Seo, J. Kim, K.Y. Lee, Y.S. Jang, The M cell-targeting ligand promotes antigen delivery and induces antigen-specific immune responses in mucosal vaccination, J. Immunol., 185 (2010) 5787-5795.
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[199] E.M. Pridgen, F. Alexis, T.T. Kuo, E. Levynissenbaum, R. Karnik, R.S. Blu mberg, R. Langer, O.C. Farokh zad, Transepithelial Transport of Fc -Targeted Nanoparticles by the Neonatal Fc Receptor for Oral Delivery, Sci. Trans. Med., 5 (2013) 213ra167. [200] T. Fan, C. Chen, H. Guo, J. Xu, J. Zhang, X. Zhu, Y. Yang, Z. Zhou, L. Li, Y. Huang, Design and
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evaluation of solid lipid nanoparticles modif ied with peptide ligand for oral delivery of protein drugs, Eur. J. Pharm. Biopharm., 88 (2014) 518-528. [201] N. Ro l, L. Favre, J. Benyacoub, B. Co rthesy, The role of secretory immunoglobulin A in the natural sensing of commensal bacteria by mouse Peyer's patch dendritic cells, J. Bio l. Chem., 287 (2012) 40074-40082.
[202] Y. Sheng, H. He, H. Zou, Poly (lact ic acid) nanoparticles coated with combined W GA and water-soluble chitosan for mucosal delivery of β-galactosidase, Drug Deliv., 21 (2014) 370-378. [203] P.J. Giannasca, K.T. Giannasca, A.M. Leichtner, M.R. Neutra, Hu man intestinal M cells display the sialyl Lewis A antigen, Infect. Immun., 67 (1999) 946-953. [204] L. Hu, Z. Mao, Y. Zhang, C. Gao, In fluences of size o f silica part icles on the cellular en docytosis, exocytosis and cell activity of HepG2 cells, J. Nanosci. Lett., 1 (2011) 1-16. [205] D. Bartczak, S. Nitti, T.M. M illar, A.G. Kanaras, Exocytosis of peptide functionalized gold nanoparticles in endothelial cells, Nanoscale, 4 (2012) 4470-4472. [206] S. Corvaglia, D. Guarnieri, P.P. Po mpa, Boosting the therapeutic efficiency of nanovectors:
ACCEPTED MANUSCRIPT exocytosis engineering, Nanoscale, 9 (2017) 3757-3765. [207] M . Lopes, N. Sherestha, A. Correia, M.A. Shahbazi, B. Sarmento, J. Hirvonen, F. Veiga, R. Seica, A. Ribeiro, H.A. Santos, Dual chitosan/albumin -coated alginate/dext ran sulfate nanoparticles for enhanced oral delivery of insulin, J. Control. Release, 232 (2016) 29-41. [208] Y. Yu , M. Huo, Y. Fu, W. Xu, H. Cai, L. Yao, Q. Chen, Y. Mu, J. Zhou, T. Yin , N -Deo xycholic acid-N,O-hydroxyethyl Ch itosan with a Sulfhydryl Modification To Enhance the Oral Absorptive Efficiency of Paclitaxel, Mol. Pharm., 14 (2017) 4539-4550. [209] K. Whitehead, Z. Shen, S. Mitragotri, Oral delivery of macro mo lecules using intestin al patches: applications for insulin delivery, J. Control. Release, 98 (2004) 37-45.
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[210] N. Venkatesan, K. Uchino, K. A magase, Y. Ito, N. Shibata, K. Takada, Gastro -intestinal patch
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system for the delivery of erythropoietin, J. Control. Release, 111 (2006) 19-26.
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Table 1 The function of different epithelial cells and sub-FAE immunocytes. Location
Function
Absorptive cells
Apical side of intestinal epithelium
Take charge of absorption of all kinds of nutrients
Goblet cells
Apical side of intestinal epithelium
Secrete mucus to protect the intestinal epithelia
Peneth cells
Apical side of intestinal epithelium
Secrete enzymes to combat xenobiotics
M cells
Apical side of Peyer’s patch
Capture foreign particles or pathogens and hand over to sub-FAE lymphatics
Dendritic cells
Sub-epithelial dome; some fuse with epithelium
Capture antigens or particles and present to T or B cells
Macrophages
Sub-epithelial dome
B cells
Sub-epithelial dome
T cells
Sub-epithelial dome
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Engulf and process particles; eliminate microorganisms; present to T or B cells
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Cell types
Stimulate immune response Stimulate immune response
ACCEPTED MANUSCRIPT Table 2 List of typical particulate adjuvants for oral vaccines Particles
Decorations
Antigens
or Viruses
Particle
ζ
size
(mV)
Immunization effects
R e fs
PLGA NPs
None
OVA and
325±8.
-20.1
sIgA stimulated towards
[
MPLA
5 nm
±0.26
(OVA/MPLA) PLGA
7
nanoparticles 2.7-fold higher
6
than those induced by OVA in
]
PBS solution.
TLRL
418±88 nm
PCL NPs
RGD-PEGyl
OVA
OVA
NPs
None
None
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Chitosan
UEA-1
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PLA NPs
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ated
200 nm
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UEA-1
[
whereas the control groups (SIP
7
solutions) did not work at all.
7 ]
Induction of T cell immunity
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FS30D
100% of tilapia was vaccinated,
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50 nm
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Eudragit
SIP
[
SC
PMMMA
200 nm
against viral infection up to 2
7
times compared to control group
8
(TLRL).
]
IgA titers for OVA-UEA-NPs
[
4.5-fold higher than for OVA
2
alone and 2.2-fold higher than
1
for OVA-NPs
]
Increased transport of
[
nanoparticles across the M cell
7
model, with a factor of 3.5
9
compared to the non-targeted
]
formulation 200-25
-40
0 nm
Delivery to DC cells by 3-4
[
times more than plain PLA NPs
8 0 ]
Peanut
100-20
allergy gene
0 nm
+10
Higher levels of gene expression
[
in both stomach and small
8
intestine induced by
1
nanoparticles than naked DNA.
]
Tripolyphos
pcDNA3.1-V
The
antibodies
[
phate
P2
expression in vaccinated fish
8
with CS-TPP nanoparticles were
2
5 times more than naked DNA.
]
Gluco mann osylated
BSA
levels
of
150-19
Gluco mannosylation
of
[
0 nm
stabilized chitosan NPs elicited
8
a 4.0- and 3.8- fold h igher sIgA
3
titer
]
in
salivary
flu id
and
intestinal content than chitosan NPs.
ACCEPTED MANUSCRIPT UEA-1
BSA
250
36.8 ;
Microparticles
by
[
nm;
-28.6
UEA-1 produced around 2.5-
8
and 1.5- fold than BSA absorbed
4
NPs
]
1.5 μm
and
modified
BSA
entrapped
microparticles Thiolated
BmpB
MPs
HPMCP
Thiolated
1-10
Thiolated
MPs
[
μm
produced 1.52- or 1.68- fold
8
high sIgA level than Eudragit
5
MPs in mice.
]
The delivery of antigen by
[
Thiolated HPM CP M Ps was
8
higher by an average of 2.7-fold
6
3.7 μm
M-BmpB
Eudragit
PT
Eudragit
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MPs
in compared to the delivery by
]
Polyplex
None
pDNA
The TNF-α and IFN-γ was 1.2-
[
and
by
8
polyplex NPs coated antigen
7
10 μm
high than antigen.
]
292 n m
Mann-modified nanogels were
[
to
internalized
macrophages
8
unmodified
8
Rod shape 1
PHM
Mannan
OVA
1.5
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nanogel
μm/
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NPs
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HPMCP MPs.
μm
Cationic
Biolosomes
4-fold
fo ld
produced
by
than
counterparts.
]
166.5±
+48.7
The serum OVA specific Ig G1 is
[
9.0 nm
±1.4
around
by
8
cationic liposome than by PLGA
9
NPs.
]
5-fold
induced
Tetanus
198±17
Gluco mannan
modified
[
n
toxoid
nm
bilosomes exhibited 2.0 and 1.4
9
folds higher immune response in
0
comparison with niosomes and
]
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Gluco manna
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Porous
OVA
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Liposome/
4-
None
BSA
silica NPs
bilosomes, respectively. 130
The Ig G and IgA titers induced
[
nm,
by loading BSA was as follows:
9
430 n m
S1 (130 n m) > S2 (430 n m)>
1
and 1-2
SBA-15 (1-2 μm) .
]
μm β-Glucan
None
OVA
particles
3.7±0.2
-6.4±
More divided OVA-specific
[
μm
0.3
cells (51.5 ± 11.2%) were found
9
in the spleen (P = 0.009) of
2
glucan-OVA-fed mice in
]
comparison with the PBS group GRGDS
PR8
200-30 0 nm
-13
The anti-PR8 IgG titer of NPs
[
were around 10-, 1.8- and 6-fold
9
higher than PR8 solutions in
3
ACCEPTED MANUSCRIPT intestine, mucus and serum,
]
respectively. Virus-like
Yeast cell
U 65
Protection against systemic
[
particles
wall
scaffolded
polyoma virus and reducing
9
antigens
viral DNA levels in spleen and
4
liver by >98%.
]
Recombinant LL-mInlA + and
[
t
LL-FnBPA+ strains showed
9
Lactococcus
100-fold greater invasion rate
5
Lactis (LL)
compared to the wt strains
]
DNA
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Recombinan
(NZ9000 and MG1363). Hemagglutini
benthamiana
n of H1 or
135 nm
34% of subjects developed transient IgG
viruses Enterovirus 7
7
(EV7)
ge
3.5 μm
6 ]
The levels of antibodies induced
[
by VLPs were around 3- fold
9
than control group (yeast cell).
7 ]
A single dose of spray-dried
[
bacteriophag
VLPs induced high-titer anti-L2
9
e
IgG responses, which were
8
similar to mice immunized with
]
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L2
30 nm
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Enterovirus
9
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H5 influenza
Bacteriopha
[
RI
Nicotiana
freshly prepared (non-spray-dried) L2-VLPs.
Early
80-200
3-4 folds enhancement of IgG
[
virus
secretory
nm
levels against ESAT-6 protein
9
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Influenza
antigenic
9
target 6
]
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protein
Live
(ESAT-6) Invasin
Antigen delivered to PPs by
[
engineered
VLPs 6.38 folds more than
1
E. coli
naked counterpart.
0 0 ]
Abbreviations:
NPs,
nanoparticles;
MPs,
microparticles;
PLGA,
poly(lactic-co-glycolic acid); PCL, polycaprolactone; PLA, polylactic acid; HPMCP, hydroxypropyl methylcellulose phthalate; MCC, microcrystalline cellulose; PMMMA, poly[(methyl methacrylate)-co-(methyl acrylate)-co-(methacrylic acid)]; HEMA, poly(2-hydroxiethyl
methacrylate-co-methacrylic
acid);
PHM,
ACCEPTED MANUSCRIPT Poly(HEMA-co-MAA); MAA, methacrylic acid; UEA, Ulexeuropaeus agglutinin; RGD,
arginylglycylaspartic acid; GRGDS,
acid-Serine;
BSA,
bovine
serum
Glycine-Arginine-Glycine-Aspartic
albumin;
OVA,
Ovalbumin;
MPLA,
Monophosphoryl lipid A ; SIP, Surface immunogenic protein; BmpB, Brachyspira
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hyodysenteriae.
ACCEPTED MANUSCRIPT Table 3 Typical ligands used to modify particles or antigens for targeting to M cells
WGA
Liposomes, SLNs
Liposomes, lipid NPs
Drugs
Size (nm)
ζ (mV)
Efficiency
Refs
Insulin
191.0±13.62 (Liposomes)
+5.78 (Liposomes)
[154]
75.3±16.79 (SLNs)
-13.11 (SLNs)
OVA (Lipid NPs);
215.3±3.5 (Lipid NPs);
-4 (Liposomes)
HBsAg (Liposomes)
450 nm (Liposomes)
The relative absorption effeciency is WGA-liposomes > WGA-SLNs> SLNs > liposomes > insulin solution The cumulative amount of UEA-lipid NPs was around 3-fold higher than that of lipid NPs; The antibody levels induced by lectinized liposomes were around 1.6 folds than non-lectinized counterpart. About 10 times more coated liposomes
[188]
Liposome
110
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PLGA NPs
HBsAg
300
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LTA
Claudin-4 targeted protein
PLGA NPs
HA protein
472±25
RGD
Pegylated PLGA NPs
OVA
200 nm
[21, 187]
became associated with Peyer’s patches than uncoated liposomes.
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UEA-1
or
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Particles antigens
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Ligands
-6.6 ⁓-13.8
Distinct binding of lectinized nanoparticles to the peyer’s paches as compared to control nanoparticles which showed little or no binding to the M cell in mice. CTP modified NPs enhanced 2 folds uptake by M cells compared to unmodified counterpart.
[101]
The RGD modified NPs increased
[79]
the transport across the M cell model, with a
[189]
ACCEPTED MANUSCRIPT
Chitosan NPs
Chitosan NPs
SA
Ovalbumin peptide
Galectin-9
None
TGDK
rhesus CCR5-derived cyclopeptide
FimH
Escherichia coli and Salmonella enterica serovar Typhimurium None
pVP1
300
approximately 1.5-fold higher than CNs after 3 h of uptake by M cells. 37.5% of chitosan NPs and 62.5% of CPE30-chitosan NPs immunized mice survived to day 28 post infection.
+22
[111]
[190]
ASLF
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CPE 30
226.2±41.9
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CKS9
factor of 3.5 compared to the unmodified formulation. The accumulated amount of CKS9-CNs was
None
SA conjugation induced higher sIGA titer with a factor of 3 compared to naked OVA by targeting to M cells. Galectin-9 expression in M cells is 2.3 folds higher than epithelial cells. The transport of TGDK conjugated antigens was around 4 folds higher than naked antigens. FimH increased antibody levels up to aound 2.5 folds by targeting to M cells.
[191]
A L-HIV-1 strain crosses M cell monolayers and infects underlying CD4+ target cells, but the monotropic (R5) HIV-1 strain can not. SLF is expressed on mounse M cells in the small intestine and ASLF antibody injected into mouse intestine
[195]
[192]
[193]
[194]
[196]
ACCEPTED MANUSCRIPT
Co1 ligand
Enhanced GFP
The serum IgG and fecal IgA levels were improved up to 1.6- and 1.4- fold due to the Co 1-mediated trascytosis.
[197]
[198]
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ED Ⅲ antigen
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OmpH ligand
bound to M cells. The number of EDⅢ-specific IgG-secreting cells in splenic lymphocyte from EDⅢ-OmpH are 2.5-fold higher than EDⅢ group by oral administration.
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Abbreviations: WGA, Wheat germ agglutinin; UEA-1, Ulexeuropaeus agglutinin 1; LTA, Lotus tetragonolobus from Asparagus pea; CTP, Claudin-4 targeted protein; CKS9, CDSTHPLSC peptide; SA, Anti-GP2-streptavidin; CPE 30, C terminal 30 amino acids of clostridium perfringens enterotoxin; SLAA, Sialyl lewis A antigen; TGDK, Tetragalloyl- D- lysine dendrimer; RO1, Recombinant σ1 or OVA- σ1 fusion protein; L-HIV, Lymphotropic HIV-1 strain; ASLF, Anti-sialic acid-binding immunoglobulin- like lectin F; NPs, Nanoparticles; SLNs, Solid lipid nanoparticles.
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ACCEPTED MANUSCRIPT
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Graphical Abstract