CoChat
Sign Up
Cited by 40Advanced Drug Delivery SystemsImmunotherapy and Immune ResponsesNanoparticle-Based Drug Delivery

Use of lectin-functionalized particles for oral immunotherapy

Open access
Diesner, Susanne C, Wang, Xue-Yan, Jensen-Jarolim, Erika, Untersmayr, Eva, Gabor, Franz·2012·Therapeutic Delivery
DOI 10.4155/tde.11.146PMC PMC3572827
Open this paper in CoChat — free account

Abstract

Immunotherapy, in recent times, has found its application in a variety of immunologically mediated diseases. Oral immunotherapy may not only increase patient compliance but may, in particular, also induce both systemic as well as mucosal immune responses, due to mucosal application of active agents. To improve the bioavailability and to trigger strong immunological responses, recent research projects focused on the encapsulation of drugs and antigens into polymer particles. These particles protect the loaded antigen from the harsh conditions in the GI tract. Furthermore, modification of the surface of particles by the use of lectins, such as Aleuria aurantia lectin, wheatgerm agglutinin or Ulex europaeus-I, enhances the binding to epithelial cells, in particular to membranous cells, of the mucosa-associated lymphoid tissue. Membranous cell-specific targeting leads to an improved transepithelial transport of the particle carriers. Thus, enhanced uptake and presentation of the encapsulated antigen by antigen-presenting cells favor strong systemic, but also local, mucosal immune responses.

Integrity signals

Registry

Crossref · 10.4155/tde.11.146

Cites

130 of 130 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 170 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    The size range of particles able to cross the intestinal barrier is 700 nm to 10 μm.

    “The size of particles able to cross the intestinal barrier has been narrowed down to ranges between 700 nm and 10 μm [40].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] source

      Not checked in the free run.

  • Premisenone given

    Surface modification of particles with lectins such as Aleuria aurantia lectin, wheatgerm agglutinin, or Ulex europaeus-I increases binding to epithelial cells, especially membranous cells of mucosa-associated lymphoid tissue.

    “Furthermore, modification of the surface of particles by the use of lectins, such as Aleuria aurantia lectin, wheatgerm agglutinin or Ulex europaeus-I, enhances the binding to epithelial cells, in particular to membranous cells, of the mucosa-associated lymphoid tissue.”
    Quote in the paperNot a substantial claim
  • Interpretationreasoning

    Targeting membranous cells specifically improves transepithelial transport of particle carriers.

    “Membranous cell-specific targeting leads to an improved transepithelial transport of the particle carriers.”
    Quote in the paperSubstantial claim
  • Premisecitation

    Slight differences in NP size affect the availability of encapsulated drugs in the circulation.

    “Additionally, slight differences of NP size have an impact on the availability of encapsulated drugs in the circulation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] source

      Not checked in the free run.

    • cites [43] source

      Not checked in the free run.

  • Premisecitation

    Enterocytes and M cells are the two cell types in intestinal mucosa responsible for uptake of particulate structures.

    “In the intestinal mucosa, two different cell types are responsible for the uptake of particulate structures: enterocytes and ‘membranous’ or ‘microfold’ cells (M cells).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [24] source

      Not checked in the free run.

    • cites [25] source

      Not checked in the free run.

  • May combine two claims. 70
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Premisecitation

    PLGA and PLA are highly biocompatible and biodegradable, their degradation products are eliminated via the Krebs cycle, and their use in human patients has been approved by the US FDA.

    “Both PLGA and PLA are characterized by high biocompatibility and biodegradability, as their degradation products are eliminated via the Krebs cycle, which is why their application in human patients has been approved by the US FDA [3–5].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [3] source

      Not checked in the free run.

    • cites [4] source

      Not checked in the free run.

    • cites [5] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The harsh conditions in the gastrointestinal tract make oral immunotherapeutic drugs difficult to design and often lead to low bioavailability.

    “However, the harsh conditions of the gastrointestinal (GI) environment constitute a substantial challenge for designing immunotherapeutic drugs, which often suffer from low bioavailability when administered via the oral route.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The w/o/w method is relatively simple and economic, but it can have low encapsulation efficiency or payload and a large initial burst release because organic solvent removal is slow.

    “Although this w/o/w method is a relatively simple and economic technique [9], the sometimes low encapsulation efficiency or payload as well as the huge initial burst release, because of the limited speed of removal of organic solvent, are disadvantageous [10].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] source

      Not checked in the free run.

    • cites [10] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The solid-in-oil-in-water method may be useful for entrapping unstable antigens because the solid state favors protein stability and bioactivity.

    “Since the solid state is most favorable for protein stability and, thus, bioactivity, this technique might be useful for entrapment of unstable antigens [11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Encapsulating therapeutic agents in polymer particles in the nano- or micrometer range is a novel approach that improves oral application and bioavailability.

    “During recent years, one of these novel approaches has been the encapsulation of therapeutic agents into polymer particles within the nano- or micro-meter range in size.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Particle size is pivotal for stability, distribution, release of encapsulated antigens, and induction of immune responses.

    “The particles’ size is pivotal for stability, distribution, release of the encapsulated antigens and induction of immune responses [36,37].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] source

      Not checked in the free run.

    • cites [37] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NPs are rapidly internalized mainly by receptor-mediated endocytosis and then disseminated systemically.

    “NPs are rapidly internalized mainly by a process that involves receptor-mediated endocytosis, and are then disseminated systemically [5,38].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] source

      Not checked in the free run.

    • cites [38] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    MPs and NPs have properties that make them suitable for oral use and that raise the bioavailability of encapsulated substances.

    “These micro particles (MPs) or nanoparticles (NPs) display several features, which make them suitable for oral application and increase bioavailability of encapsulated substances.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    M cells have reduced digestive function because they lack brush-border enzymes such as alkaline phosphatase, which makes them interesting for drug targeting.

    “With the loss of brush-border enzymes, such as alkaline phosphatase, M cells show a reduced digestive function, which makes them even more interesting for drug targeting [26,27].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] source

      Not checked in the free run.

    • cites [27] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    M cells are part of the follicle-associated epithelium overlying organized gut-associated lymphoid tissue, which can be isolated or in Peyer's patches.

    “M cells are part of the follicle-associated epithelium overlying the organized gut-associated lymphoid tissue, which can either be located in isolated form or within organized follicular clusters, the so-called Peyer’s patches [24,25].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] source

      Not checked in the free run.

    • cites [25] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The double-emulsion technique and spray-drying technique are typically applied today to prepare vaccine-loaded particles.

    “It has become apparent that two techniques, the double-emulsion technique and spray-drying technique, are typically being applied today.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    M cells transport foreign material intact from the gut lumen to mucosa-associated lymphatic tissue, making them an optimal entry for antigens in oral immunotherapy.

    “These cells are responsible for antigen-specific intestinal immune responses by transporting foreign material from the gut lumen to the mucosa-associated lymphatic tissue in an intact form, making them an optimal entry for antigens in oral immunotherapy.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] source

      Not checked in the free run.

    • cites [25] source

      Not checked in the free run.

    • cites [28] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Caco-2 in vitro studies, 100-nm NPs showed high interaction rates (more than 6000 PLGA and 200,000 polystyrene particles per cell), while 1- or 2-μm particles interacted in very low numbers (12 and below).

    “NPs of 100-nm size showed a high interaction rate of more than 6000 PLGA and 200,000 polystyrene (PS) particles per Caco-2 cell. Particles with a size of 1 or 2 μm interacted in very low numbers (12 and below) with one Caco-2 cell [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After binding to the apical side of M cells, macromolecules are endocytosed via clathrin-coated vesicles, reach the lysosomal compartment, and are exocytosed basolaterally to be taken up by APCs.

    “Once bound to the apical side of M cells, macromolecules are endocytosed via clathrin-coated vesicles, thereby reaching the lysosomal compartment, from which they are exocytosed to the basolateral site to be taken up by antigen presenting cells (APCs) [34,35].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] source

      Not checked in the free run.

    • cites [35] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    The w/o/w double-emulsion technique permits entrapment of hydrophilic substances such as vaccines.

    “The water-in-oil-in-water (w/o/w) or double-emulsion technique allows for entrapment of hydrophilic substances such as vaccines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Particles of 150 nm have prolonged circulation time and sustained blood levels compared with particles below 100 nm or above 200 nm, which may be taken up by reticulo-endothelial system cells; NPs between 100 and 200 nm can escape reticulo-endothelial system uptake.

    “Particles with a size of 150 nm show a prolonged circulation time and sustained blood levels compared with particles with a size lower than 100 nm or above 200 nm, which may be taken up by the reticulo-endothelial system cells. In comparison, NPs between 100 and 200 nm can escape reticulo-endothelial system uptake [5,43].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] source

      Not checked in the free run.

    • cites [43] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When NPs shuttle through intestinal epithelial cells, encapsulated drugs avoid P-glycoprotein efflux from enterocytes and bypass liver metabolism, which increases oral bioavailability.

    “Upon shuttling of NPs through intestinal epithelial cells encapsulated drugs circumvent the P-glycoprotein efflux from enterocytes and bypass liver metabolism, which enhance their oral bioavailability [42].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [42] source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Functionalizing particles with targeting substances can direct their binding to specific cells and increase their uptake by intestinal cells.

    “Furthermore, functionalization of particles by special targeting substances can direct particle binding to specific cells and enhance the particle uptake capacity via intestinal cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The proportion of M cells in follicle-associated epithelium of Peyer's patches can be high in rabbits and mini-pigs, but is much lower in rodents (10%) and humans (<5%).

    “Although the proportion of M cells in follicle-associated epithelium of Peyer’s patches can be high in rabbits and mini-pigs, the occurrence in rodents (10%) and humans (<5%) is much lower [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oral immunotherapy is preferred over parenteral administration because patients comply better and complications occur less often.

    “Although immunotherapy is often applied parenterally, the oral administration route is preferred due to higher compliance of patients and lower complication rates [1].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [1] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Small NPs were detected intracellularly, including within nuclei, whereas particles larger than 300 nm attached to the apical membrane of Caco-2 cells.

    “Furthermore, while small NPs were detected intracellularly, also within the nuclei, particles bigger than 300 nm were attached to the apical membrane of Caco-2 cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Several new methods for manufacturing PLGA or PLA particles have been reported, including ultrasonic atomization, electrospray, microfluidic, pore-closing/thermoreversible-gel, and microfabrication.

    “Recently, several new methods to manufacture PLGA or PLA particles have been reported, such as the ultrasonic atomization method [14,15], the electrospray method [16], the microfluidic method [17,18], the pore-closing and thermoreversible-gel method [19,20], and the microfabrication method [21].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [14] source

      Not checked in the free run.

    • cites [15] source

      Not checked in the free run.

    • cites [16] source

      Not checked in the free run.

    • cites [17] source

      Not checked in the free run.

    • cites [18] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Encapsulation of antigens in particle carriers protects them from harsh GI degrading conditions, allows intestinal uptake of intact antigens and drugs, and avoids hepatic first-pass metabolism because the particle matrix protects the payload.

    “Encapsulation of antigens into particle carriers protects against these harsh GI degrading conditions [23], enabling an intestinal uptake of intact antigens and drugs, and the circumvention of the hepatic first-pass metabolism due to protection of the payload by the particle matrix.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] source

      Not checked in the free run.

    • cites [5] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Transcytosis through the intestinal epithelial layer depends on particle size, with below 1 μm optimal for M-cell absorption, and also on particle charge and hydrophilicity.

    “The capacity of transcytosis through the intestinal epithelial layer depends on the size, with a particle size of below 1 μm for optimal M-cell absorption [30], but also on the charge and hydrophilicity of the particle carrier [31–33].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [30] source

      Not checked in the free run.

    • cites [31] source

      Not checked in the free run.

    • cites [32] source

      Not checked in the free run.

    • cites [33] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Spray-drying allows easy tuning of particle characteristics and scale-up, but high product loss, especially in small batches, may be crucial.

    “This technique allows easy tuning of particle characteristics and scale-up, but high product loss, especially in small batches, might be crucial [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Peptides loaded into NPs targeting DC-SIGN were found in the lysosomal compartment of DCs within 24 h and were presented to T cells despite the presence of fluorescent labels.

    “In this study, peptides loaded into NPs, which specifically targeted DC-SIGN on DCs, were found in the lysosomal compartment of DCs within 24 h and were presented to T cells despite the presence of fluorescent labels [68].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mannan or PEG coating protects against protein opsonization, enabling specific receptor-ligand binding.

    “Mannan or PEG coating was shown to protect against protein opsonization, enabling specific receptor-ligand binding.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NPs surface modification with an antibody against the DC lectin DEC-205 receptor induced IL-10 production by DCs and T cells in vitro; intraperitoneal injection into OVA-primed mice produced a similar IL-10 pattern dependent on the density of surface modification.

    “Recently, NPs’ surface modification with an antibody against the DC lectin DEC-205 receptor induced the production of IL-10 by DCs and T cells in vitro. When these modified particles were intraperitoneally injected into ovalbumin (OVA) primed mice, a similar IL-10 pattern was observed, which was dependent on the density of surface modification [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Surface modification with poloxamer or particle preparation with different polymers influences particle surface charge, which could contribute to reduced intestinal uptake.

    “However, surface modification with poloxamer or particle preparation with different polymers influences the surface charge of the particles, which could contribute to reduced intestinal uptake [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mannosylated particles can specifically deliver antigens and drugs to DCs and enhance presentation to T cells.

    “Previous studies have shown that mannosylated particles can specifically deliver antigens and drugs to DCs and result in enhanced presentation to T cells [70].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [70] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Particle structures smaller than 5 μm are taken up by APCs such as dendritic cells and macrophages and transported directly to the lymph node, where encapsulated antigen can be presented to T cells.

    “Particle structures smaller than 5 μm are taken up by APCs, such as dendritic cells (DCs) and macrophages [59–61], and are transported directly to the lymph node [58], where the encapsulated antigen can be presented to T cells.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [59] source

      Not checked in the free run.

    • cites [60] source

      Not checked in the free run.

    • cites [61] source

      Not checked in the free run.

    • cites [58] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    PLGA affects the immune response through adjuvant properties, which were hypothesized to result from the particulate structure of the allergen carrier and sustained allergen release from particles.

    “PLGA is not only a highly biocompatible and bio degradable material, it further affects the immune response via its adjuvant properties [50], which were hypothesized to be due to the particulate structure of the allergen carrier and due to the sustained allergen release from the particles [51].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] source

      Not checked in the free run.

    • cites [51] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Encapsulated antigen is slowly and continuously released into the cell, leading to enhanced antibody responses, increased IL-4 production, and MHC-II upregulation, which together trigger a predominant humoral response.

    “Additionally, the encapsulated antigen is slowly and continuously released into the cell leading to enhanced antibody responses, increased production of IL-4 and upregulation of MHC-II molecules, which in concert triggers a predominant humoral response.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The impact of particle hydrophilicity on intestinal uptake has been described controversially in the literature.

    “The impact of particle hydrophilicity on intestinal uptake has been described very controversially in literature.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [47] source

      Not checked in the free run.

    • cites [48] source

      Not checked in the free run.

    • cites [49] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The capacity of PLGA particles to act as a vaccine adjuvant is high and comparable to conventional aluminum-adsorbed vaccine formulations.

    “Various studies demonstrated that the capacity of PLGA particles to act as vaccine adjuvant was high and comparable to the conventional aluminum-adsorbed vaccine formulations [52–54].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [52]

      Not checked in the free run.

    • cites [53] source

      Not checked in the free run.

    • cites [54] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Positively charging PLGA particles, for example with positively charged stabilizers, increases epithelial penetration and systemic uptake of encapsulated slightly soluble drugs; these favorable characteristics are not found with anionic stabilizers.

    “However, positively charging PLGA particles, for example using positively charged stabilizers, increases the epithelial penetration and systemic uptake of encapsulated, slightly soluble drugs. These favorable characteristics are not found in particulate carriers prepared with anionic stabilizers [5,46].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [5] source

      Not checked in the free run.

    • cites [46] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A high concentration of released soluble antigen leads to direct binding of antigen to MHC-II molecules and subsequent presentation.

    “The high concentration of released soluble antigen leads to direct binding of the antigen to MHC-II molecules and subsequent presentation [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gaumet et al. reported that coating PLGA particles with chitosan, which did not affect surface charge or particle size, enhanced interaction with intestinal Caco-2 cells.

    “A recent study by Gaumet et al. reported that modification of surface hydrophilicity by coating PLGA particles with chitosan, which did not affect surface charge or particle size, enhanced the interaction of particles with intestinal Caco-2 cells [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Continuous release of inoculated antigens from PLGA particles after the first burst is advantageous for restimulating memory cells and is responsible for long protection even after one vaccination.

    “The continuous release of inoculated antigens from PLGA particles after the first burst is advantageous to restimulate memory cells and responsible for a long protection time even after one vaccination [52], underlining the beneficial effects of PLGA as a carrier substance for novel vaccination approaches.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [52]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mannose coupling to microspheres initiated phagocytosis by C-type lectin receptor but could not stimulate DC maturation and activation toward T-cell responses.

    “However, mannose coupling to microspheres initiated the phagocytosis by C-type lectin receptor, it could not stimulate DC maturation and activation toward T-cell responses [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Oral immunomodulation with polymeric particulate carriers has been investigated for immunosuppressive drugs, viral and bacterial antigens, hormones, anticancer drugs, and allergens.

    “Oral immunomodulation with polymeric particulate carriers has been investigated for a wide range of therapeutic applications, such as immuno suppressive drugs [42], viral and bacterial antigens [58,65], hormones [5,73], anticancer drugs [74], and allergens [75].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [42] source

      Not checked in the free run.

    • cites [58] source

      Not checked in the free run.

    • cites [65] source

      Not checked in the free run.

    • cites [5] source

      Not checked in the free run.

    • cites [73] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hydrophobicity of polymer microspheres and a rough surface increase attachment to APC surfaces and enhance antibody response.

    “the hydrophobicity of polymer microspheres and a rough surface further increase the attachment to the surface of APCs [65], and enhance the antibody response [66].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [65] source

      Not checked in the free run.

    • cites [66] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Particle size determines the immune response outcome: MPs between 1 and 10 μm promote humoral responses, while NPs below 1 μm mainly induce cellular responses.

    “Only MPs between 1 and 10 μm in size promote humoral responses, whereas NPs below 1 μm mainly induce cellular responses (Figure 1) [58].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NPs loaded with FITC-bovine serum albumin were phagocytosed by APCs, causing a two- to threefold increase in cell size, and were continuously endocytosed and exocytosed; only low concentrations of intracellularly released antigen were observed over time.

    “NPs loaded with FITC–bovine serum albumin were shown to be phagocytosed by APCs, leading to a two–threefold increase of cell size, and were then continuously endocytosed and exocytosed from the cells. Thus, only low concentrations of intra cellularly released antigen could be observed over time [2].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Intestinal epithelial transport of nanometer-range particles might be optimal, but nanospheres are taken up with distinct intracellular distribution, which might lead to unknown side effects.

    “While the intestinal epithelial transport of particles in the nanometer range might be optimal, one has to keep in mind that nanospheres are taken up into the cells with distinct intracellular distribution, which might lead to side effects not yet known.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Immunizations with NPs containing hepatitis B surface antigen led to low IgG production, IFN-γ secretion, and MHC-I upregulation on APCs, indicating induction of a cellular immune response.

    “Interestingly, immunizations with NPs containing hepatitis B surface antigen (HBsAg) led to low production of IgG, secretion of IFN-γ and upregulation of MHC-I on APCs, which indicated the induction of a cellular immune response.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    WGA is a dietary nontoxic lectin contained in wheat flour.

    “WGA represents a dietary nontoxic lectin, which is contained in wheat flour [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gavages of UEA-I-coated NPs induced mucosal sIgA secretion and IL-2 and IFN-γ production in spleens, indicating Th1-dominant immune response.

    “Furthermore, gavages of these UEA-I coated NPs-induced mucosal secretion of sIgA and the production of IL-2 and IFN-γ in spleens, indicating a Th1-dominant immune response [113].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [113] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In diabetic rats, PLGA NPs loaded with insulin showed slower absorption and sustained elimination, while serum insulin concentration steadily increased over 6 h.

    “In a recent study, PLGA NPs loaded with insulin for oral application in diabetic rats revealed slower absorption and sustained elimination, while serum insulin concentration steadily increased over 6 h.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Epithelial glycosylation patterns in the gut are altered in colon cancer, questioning the value of the M-cell-like co-culture model.

    “As this model is based on the use of carcinoma cell lines, it should be noted that epithelial glycosylation patterns in the gut are altered in colon cancer, questioning the value of this experimental model [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lectins selectively bind to carbohydrate residues of epithelial cell glycocalyx and can be used on particle surfaces to target M cells.

    “Lectins are proteins that selectively bind to carbohydrate residues of epithelial cells’ glycocalyx and may serve as molecules on particle surface for specifically targeting M cells [103,104].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [103] source

      Not checked in the free run.

    • cites [104] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Possible M-cell interaction partners include TLR4, platelet activating factor receptor, α5β1 integrin, carbohydrates, and Claudin 4.

    “Possible interaction partners might be M-cell expressed TLR4, platelet activating factor receptor and α5β1 integrin [100], carbohydrates and Claudin 4.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Concanavalin A interacts with intestinal epithelium and immune cells like macrophages, activating them and upregulating TLRs and production of NO and proinflammatory cytokines.

    “Concanavalin A can not only interact with the intestinal epithelium but also with immune cells, such as macrophages, resulting in their activation and subsequent upregulation of TLRs as well as the production of NO and proinflammatory cytokines [110–112].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [110] source

      Not checked in the free run.

    • cites [111] source

      Not checked in the free run.

    • cites [112] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Encapsulation of antigens into PLGA particles both protects from GI digestion and initiates specific immune responses through IgG and IFN-γ production at very low antigen amounts.

    “Recently, it was observed that the encapsulation of antigens into PLGA particles did not only protect from GI digestion, but also initiated specific immune responses by the means of IgG and IFN-γ production at very low antigen amounts [76].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Coating CPE30 to PLGA NPs increased uptake by upper airways after intranasal administration and by intestinal M cells after ingestion.

    “CPE30, the C-terminal 30 amino acid part of CPE, was coated to PLGA NPs, which increased the uptake by upper airways when administered intranasally or by intestinal M cells after ingestion [101].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [101] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Enterocyte-specific targeting (e.g., by WGA) substantially increases transepithelial transport and induces a systemic IgG-mediated immune response.

    “Enterocyte-specific targeting, for example by WGA, substantially increases the transepithelial transport, which may especially be of interest for drug development where no mucosal immune response induction is needed. Enterocyte-specific targeting induces a rather systemic IgG-mediated immune response [22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] source

      Not checked in the free run.

    • Rests on an assumption: Enterocytes represent the majority of epithelial cells in the intestinal tract.

  • May combine two claims.

    Premisecitation

    Very low IL-4 and significantly higher IFN-γ production by spleen cells was observed in animals immunized with particles compared with mice fed unprotected OVA, and this was more pronounced when β1 integrin on M cells was targeted by an RGD-containing peptide.

    “Moreover, very low IL-4 and significantly higher IFN-γ production of spleen cells was observed in animals immunized with particles compared with mice being fed unprotected OVA, which was even more pronounced when the β1 integrin on M cells was specifically targeted by an RGD-containing peptide [76].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [76] source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Development of PLGA formulations is complicated when hydrophilic drugs such as insulin are encapsulated, and this problem can be solved by specific ampholytic surfactants such as phospholipids.

    “However, the development of these formulations becomes even more complicated when hydrophilic drugs, such as insulin, are subject to encapsulation. This problem can be solved by the use of specific ampholytic surfactants, such as phospholipids.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    WGA attached to carbopol used for surface modification of liposomes significantly increased receptor-mediated binding to Caco-2 cells and enhanced pharmacological efficacy of calcitonin loaded into nanocarriers.

    “WGA attached to carbopol has recently been used for surface modification of liposomes, which significantly increased the receptor mediated binding to Caco-2 cells and further enhanced the pharmaco logical efficacy of calcitonin, when loaded into the nanocarriers [109].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [109] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Functionalization of PLGA particle surface with bioactive substances targets mucosal cells, improving cellular uptake and transepithelial transport and inducing systemic and mucosal immune responses.

    “Following this approach, mucosal cells are specifically targeted, thereby improving the cellular uptake as well as transepithelial transport and inducing not only a systemic, but also a strong mucosal immune response.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Distribution of surface structures on human M cells may differ across intestinal regions, indicating local functionality.

    “it has to be kept in mind that the distribution of surface structures on human M cells of different intestinal regions may also differ [24], which may indicate a certain local functionality.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationnone given

    UEA-I originates from a highly toxic plant, making its beneficial application in humans questionable.

    “Although UEA-I may be a promising targeting substance, its origin is a highly toxic plant, which makes its beneficial application in humans questionable.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Orally applied PLA microspheres induced a more persistent and longer-lasting serum IgA antibody response, which could be explained by higher hydrophobicity of PLA and slower polymer degradation.

    “Orally applied PLA microspheres induced a more persistent and longer-lasting serum IgA antibody response, which could be explained by the higher hydro phobicity of PLA and the slower polymer degradation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    M-cell-specific targeting may increase efficiency of oral particle carriers in Th2 modulation because transcytosed particles reach lymphatic tissue and induce strong mucosal and systemic immune responses.

    “As targeting of orally applied particle carriers to epithelial cells in situations of Th2 modulation does not seem sufficient to trigger immune responses, a M-cell-specific targeting approach may increase the efficiency, because transcytosed particles reach the lymphatic tissue underlying the M cells and induce a strong mucosal, as well as systemic immune response.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    Lectins that bind specifically to α-l-fucose should result in M-cell-specific adherence when used as targeting moieties.

    “As the lectins listed below bind specifically to α-l-fucose, their use as targeting moieties should result in M-cell-specific adherence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Substantial differences in M-cell distribution and surface receptor expression between mice and men mean animal study data might not reflect human situation.

    “Due to substantial differences of M-cell distribution and surface receptor expression between mice and men [99], data generated in animal studies might not reflect the situation in humans.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    M cells account for only a minority in intestinal epithelium and might exert diverse functions in different intestinal regions.

    “these cells account for only a minority in the intestinal epithelium and might exert diverse functions in different intestinal regions [24]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AAL possesses α-l-fucose specificity and binds to murine Peyer's patches.

    “AAL from the edible, nontoxic orange peel mushroom Aleuria aurantia also possesses α-l-fucose specificity and, thus, was shown to bind to murine Peyer’s patches [115].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [115] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    WGA and AAL are nontoxic and highly resistant to gastric digestion, and enhance retention time and transepithelial transport of MPs at GI mucosa, improving efficacy.

    “The targeting substances WGA [120] and AAL are nontoxic and highly resistant against gastric digestion [Diesner SC, Schultz C, Wang X-Y et al., Unpublished Data] and enhance the retention time and transepithelial transport of MPs at the GI mucosa, finally resulting in improved efficacy, as reviewed by Des Rieux et al. [23].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [120] source

      Not checked in the free run.

    • cites [23] source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Clinical trials in human patients proving usability of PLGA particles for oral immunotherapy are still missing, making conclusions on efficacy and applicability impossible.

    “clinical trials in human patients proving the usability of PLGA particles for oral immunotherapy application are still missing, making conclusions on their efficacy and applicability impossible.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In birch pollen-sensitized mice, 15 oral treatments with AAL-functionalized allergen-loaded microspheres increased birch pollen-specific IgG2a without affecting IgE and IgG1, indicating Th1-biased immune response.

    “Animals fed with AAL-functionalized, allergen-loaded microspheres for 15-times revealed an increase of birch pollen-specific IgG2a, whereas IgE and IgG1 were not affected, indicating the induction of a prominent Th1-biased immune response.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Functionalized particles loaded with active agents to be delivered to GALT might represent successful novel treatment strategy, especially in Th2-biased situations like allergic diseases.

    “functionalized particles loaded with active agents to be delivered to the gut-associated lymphoid tissue, might represent a successful novel treatment strategy, especially in situations when the immune system is biased towards Th2, such as allergic diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    α-l-fucose is part of sparsely mucus-coated glycocalyx of M cells, so lectin-coated formulations can mediate binding of active substances.

    “Since α-l-fucose is part of the sparsely mucus-coated glycocalyx of M cells, binding of active substances can be mediated by lectin-coated formulations.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [130] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TLR9 expression is diverse in mice but restricted to B-cells and plasmacytoid DCs in humans, probably leading to different immunological responses.

    “especially the receptor of CpG, TLR9, is diversely expressed in mice, while in humans its expression is restricted to B-cells and plasmayctoid DCs [124], probably leading to different immunological responses.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [124] source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    For oral administration, lectins must resist GI transit, and carrier material must be nontoxic and non-immunogenic, achievable by synthetic modification or choice of WGA/AAL.

    “For oral administration, however, these certain lectins have to resist the harsh conditions during GI transit. Additional properties required are nontoxicity as well as non-immunogenicity of the carrier material, which can be achieved by synthetic modification of the carriers or by the careful choice of naturally derived targeting substances, such as WGA and AAL.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A tetragalloyl d-lysine amide construct leads to successful delivery of coated PS particles to mouse M cells and may specifically bind via α-l-fucose.

    “A tetragalloyl d-lysine amide construct, as the main compound of two UEA1 mimetics, leads to successful delivery of coated PS particles to mouse M cells and might specifically bind via α-l-fucose [117].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lectins are often toxic and susceptible to proteolytic degradation in GI tract, rendering some inappropriate for in vivo application.

    “lectins are often toxic and susceptible to proteolytic degradation in the GI tract, which renders some of them inappropriate for in vivo application [105,117].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [105] source

      Not checked in the free run.

    • cites [117] source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Cellular interaction is mediated by small units of lectin molecules, so designing neolectins with only binding domain might avoid undesired effects.

    “cellular interaction is mediated by only small units of most complex structured lectin molecules. Thus, undesired effects might be avoided by designing ‘neolectins’, which represent exclusively the binding domain, by using phage display techniques for example.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Cell-binding is only the first stage of a complex journey through epithelial layer to subjacent immune cells before efficient immune response.

    “cell-binding is only the first stage of a complex journey through the epithelial layer to the subjacent immune cells until an efficient immune response is elicited.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Conclusions on applicability of lectin-functionalized PLGA particles for oral immunotherapy in humans must be drawn with great caution as long as suitable M-cell models and human clinical studies are missing.

    “as long as suitable and physiological M-cell models, as well as human clinical studies are missing, conclusions on the applicability of lectin-functionalized PLGA particles for oral immunotherapy in humans have to be drawn with great caution.”
    Quote in the paperNot a substantial claim
80 of 80

  • The paper relies on this without support.

    Epithelial cells and mucus of the gastrointestinal tract carry a negative charge.

    “As epithelial cells and mucus of the GI tract are negatively charged, the uptake of PLGA and PLA particles without surface modification may be poor.”

  • The paper relies on this without support.

    Aluminum hydroxide triggers a Th2-driven immune response.

    “In contrast, the widely used vaccine component aluminum hydroxide triggers a Th2-driven immune response.”

  • The paper relies on this without support.

    Particles below 1 μm are optimally taken up by Peyer's patches and can lead to sufficient antigen processing.

    “It is generally accepted that particles below 1 μm are optimally taken up by Peyer’s patches and can thus, lead to sufficient antigen processing.”

  • The paper relies on this without support.

    Enterocytes represent the majority of epithelial cells in the intestinal tract.

    “Enterocytes represent the majority of epithelial cells in the intestinal tract.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Hermanson GT . Bioconjugate Techniques. Academic Press San Diego CA USA 170–176 (1996).

Cited by

Sorted by citations

Related

Authors
Diesner, S. C., Wang, X.-Y., Jensen-Jarolim, E., Untersmayr, E., & Gabor, F.
Affiliations
  • Medical University of Vienna (AT)
  • Department of Pharmaceutical Technology &amp; Biopharmaceutics University of Vienna Althanstrasse 14 Vienna 1090 Austria
  • Department of Pathophysiology &amp; Allergy Research Center of Pathophysiology Immunology &amp; Infectiology Medical University of Vienna Vienna Austria
  • University of Vienna (AT)
Corresponding author
Gabor, Franz
ORCID
Venue
Therapeutic Delivery
Publisher
Informa UK Limited
Published
2012-02
Volume
3
Issue
2
Pages
277-290
ISSN
  • 2041-5990 (ISSN-L)
  • 2041-6008
DOI
10.4155/tde.11.146
PMC
PMC3572827
OpenAlex
W2035801110
Cited by
40
References
130
Citations by year
2026: 2 · 2025: 1 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 5 · 2015: 3 · 2014: 3 · 2013: 3 · 2012: 1
FWCI
0.40
Type
journal article
Language
en
Open access
Locations
  • Therapeutic Delivery (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
Austrian Science Fund
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Advanced Drug Delivery Systems
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
oral immunotherapy, polymer particles, antigen encapsulation, mucosal immune response, Aleuria aurantia lectin, wheat germ agglutinin, Ulex europaeus I lectin, mucosa-associated lymphoid tissue, transepithelial transport, antigen-presenting cells, bioavailability, immune-mediated diseases
MeSH terms
Polylactic Acid-Polyglycolic Acid Copolymer, Administration, Oral, Animals, Antigens, Biological Availability, Biological Transport, Drug Carriers, Humans, Immunologic Factors, Immunotherapy, Intestinal Absorption, Intestinal Mucosa, Intestines, Polyglycolic Acid, Immunity, Mucosal, Lactic Acid, Lectins

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review