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Shinn, J.;  Lee, J.;  Lee, S.A.;  Lee, S.J.;  Choi, A.H.;  Kim, J.S.;  Kim, S.J.;  Kim, H.J.;  Lee, C.;  Kim, Y.; et al. Oral siRNA Delivery for Inflammatory Bowel Disease Treatments. Encyclopedia. Available online: https://encyclopedia.pub/entry/28778 (accessed on 04 July 2024).
Shinn J,  Lee J,  Lee SA,  Lee SJ,  Choi AH,  Kim JS, et al. Oral siRNA Delivery for Inflammatory Bowel Disease Treatments. Encyclopedia. Available at: https://encyclopedia.pub/entry/28778. Accessed July 04, 2024.
Shinn, Jongyoon, Juyeon Lee, Seon Ah Lee, Seon Ju Lee, Ah Hyun Choi, Jung Seo Kim, Su Jin Kim, Hyo Jin Kim, Cherin Lee, Yejin Kim, et al. "Oral siRNA Delivery for Inflammatory Bowel Disease Treatments" Encyclopedia, https://encyclopedia.pub/entry/28778 (accessed July 04, 2024).
Shinn, J.,  Lee, J.,  Lee, S.A.,  Lee, S.J.,  Choi, A.H.,  Kim, J.S.,  Kim, S.J.,  Kim, H.J.,  Lee, C.,  Kim, Y.,  Kim, J.,  Choi, J.,  Jung, B.,  Kim, T.,  Nam, H.,  Kim, H., & Lee, Y. (2022, October 11). Oral siRNA Delivery for Inflammatory Bowel Disease Treatments. In Encyclopedia. https://encyclopedia.pub/entry/28778
Shinn, Jongyoon, et al. "Oral siRNA Delivery for Inflammatory Bowel Disease Treatments." Encyclopedia. Web. 11 October, 2022.
Oral siRNA Delivery for Inflammatory Bowel Disease Treatments
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This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics14091969

RNA interference (RNAi) therapies have significant potential for the treatment of inflammatory bowel diseases (IBD). Oral nanomedicines carrying small interfering RNA (siRNA) drugs include the following two: (1) Polyplex or lipoplex. (2) Polyplex or lipoplex embedded in hydrogels or polymeric materials

oral drug delivery siRNA inflammatory bowel disease gene delivery

1. Introduction

More than 3.5 million patients worldwide suffer from inflammatory bowel disease (IBD), which is characterized by chronic inflammation of the gastrointestinal (GI) tract [1][2]. IBD comprises two clinically distinct conditions: ulcerative colitis (UC), which is confined to the colon, and Crohn’s disease (CD), which affects any part of the GI tract, especially the ilium and the colon [3]. Even though UC and CD are considered different conditions, they share many clinical characteristics including persistent diarrhea, abdominal pain, and rectal bleeding/bloody stools. The exact cause of IBD remains unknown, but IBD-susceptible individuals typically have dysbiotic gut microbiota, disrupted intestinal barriers, and dysregulated mucosal immunity [4][5].
Aminosalicylates, corticosteroids, and immunosuppressive agents are common treatment options for IBD patients, although they produce side effects that can include depression, osteoporosis, and susceptibility to infection due to the non-specificity of drug action [6][7][8]. However, the non-specific action of such drugs has shown limitations such as non-target site toxicity and limited efficacy in the complete remission of the severe last stages of IBD [4]. Thus, targeted therapeutics, especially antibody therapeutics, directed to a more specific mechanism of action have led to reduced side effects as well as improved therapeutic efficacy [9].
IBD progression and development are highly associated with several genes and target cytokine dysregulations [10][11]. Some examples of dysregulated proteins involved in IBD are TNF-α, IFN-γ, IL-4, IL-10, and IL-21 [12][13]. For example, since most cells in the inflamed regions express receptors for TNF-α, it has promiscuous effects, rendering it an effective therapeutic target in IBD patients [14]. Thus, anti-TNF-α antibodies such as infliximab, adalimumab, certolizumab pegol, and golimumab have been widely used for the treatment of IBD [15], with enhanced therapeutic efficacy even in severe stages of IBD, while also limiting systemic toxicity [16][17][18][19]. However, antibody therapeutics present several limitations such as frequent painful injections and patient noncompliance. Furthermore, they have significant side effects including serious infections, malignancies, demyelinating disease, congestive heart failure, and the induction of autoimmune conditions due to systemic cytokine depletion [20][21][22][23].
As an alternative to systemic antibody therapeutics, small interfering RNAs (siRNAs) directed against proinflammatory cytokines have gained great attention from many research groups due to their potential to treat intestinal inflammation via the silencing of pro-inflammatory cytokines [24]. Various siRNA-based therapeutics are under development for the efficient treatment of inflammatory bowel diseases [25]. However, systemic treatment with siRNA-based therapeutics has many limitations such as patient non-compliance and systemic side effects caused by the systemic depletion of cytokines [26], which has encouraged the development of strategies for the specific delivery of siRNA to the desired inflamed site of the GI tract.
Compared with other routes, oral administration is one of the most commonly used drug administration routes because of high patient compliance, simple self-administration, non-invasiveness, and low cost [4][27][28][29]. For macromolecular drugs, including siRNAs, most are prone to degradation and the loss of bioactivity from the harsh GI tract conditions such as pH variation and digestive enzymes. Thus, few orally administered macromolecular IBD drugs reach the target site of the colon [4][30][31][32]. Furthermore, penetrating lipid membranes of a target cell are another challenge for macromolecular drugs, including siRNA directed to intracellular target molecules (e.g., cytosolic mRNA for siRNA). Therefore, there is a great need for oral drug delivery systems with a demonstrated ability to protect siRNA from the harsh environment of the GI tract and selectively deliver siRNA to desired target sites—both the inflamed site and the intracellular cytosolic region [33].

2. Oral siRNA Delivery for IBD Treatments

To date, various gastrointestinal tract (GIT) barriers for the inflamed site-specific delivery of siRNA drugs and strategies to overcome limitations with oral nanomedicine encapsulation have been exploited. Orally administered nanomedicines should overcome the barriers with the various strategies. In this section, examples of oral nanomedicines carrying siRNA drugs will be discussed by category: (1) Polyplex or lipoplex. (2) Polyplex or lipoplex embedded in hydrogels or polymeric materials (Table 1).

2.1. Polyplex or Lipoplex

The nano-complexation of siRNA drugs with cationic lipids (lipoplex) or polymers (polyplex) endows the protection of siRNA against the harsh conditions of the GIT. Furthermore, the drug could be localized in the inflamed site via denuded mucus and leaky intestinal epithelium. The polyplex or lipoplex can easily penetrate into the remaining mucus layer of the inflamed tissue due to the comparatively smooth movement caused by a high density of charges at the surface. At the inflamed target site, the polyplex or lipoplex can be non-specifically taken up by intestinal epithelial cells or diverse immune cells (sometimes, even anti-inflammatory immune cells). For example, a polyplex—polymeric micelles (150–300 nm) composed of amphiphilic poly-allylamine complexed with an siRNA drug—was developed [34]. The polyplex was very stable in simulated gastric/intestinal fluids. In addition, the polyplex exerted intracellular uptake followed by efficient endosomal escape while showing potent gene knockdown activity in Caco-2 cells. As an example of a lipoplex, the commercially available transfection agent, lipofectamine, is a representative positively charged lipid that facilitates binding and fusion with the cellular membrane to release the complexed siRNA into cells [35][36]. Even though the transfection activity is very effective, toxicity is a limitation for the general application of lipofectamine [37]. To overcome the limitation of synthetic lipids such as lipofectamine, biocompatible non-toxic natural source-derived cationic lipoplexes could be utilized. Zhang et al. developed ginger-derived lipid nanoparticles (GDLNs) complexed with CD98 siRNA [38] for the treatment of a dextran sodium sulfate (DSS)-induced murine colitis model. GDLNs complexed with CD98 siRNA exhibited effective gene silencing under in vitro conditions (Colon-26 cells (inflamed epithelium cells) and RAW 264.7 cells (macrophage cells)) and in vivo conditions (the ileum and colon). Notably, orally administered GDLNs showed better therapeutic efficacy than the systemic administration of naked CD98 siRNA [39].
As demonstrated earlier, PEGylation can enhance mucus penetration and siRNA protection due to its anti-biofouling action. PEGylated lipoid nanoparticles (LNPs) composed of cholesterol, Distearoylphosphatidylcholine (DSPC), and PEG-lipid were developed to target inflamed intestinal epithelial cells while showing gene silencing [38][40]. The PEGylated LNPs complexed with Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) siRNA were stable in harsh environments, such as pH variation and enzymatic degradation, and showed the ability to target intestinal epithelial cells. However, GAPDH silencing in vivo was not statistically significant compared to the control group, indicating that PEGylation might inhibit the intracellular uptake of the nanoparticles. Thus, for this strategy, active targeting functionalization could be required to improve intracellular delivery. On the other hand, in other studies, PEGylated poly/lipoplexes carrying TNF-α siRNA showed the opposite activity. Combining a cationic lipid and PEG-PLGA (poly(lactic-co-glycolic acid)) polymer with TNF-α siRNA led to cationic PEGylated poly/lipoplexes [41]. PEGylated poly/lipoplex TNF-α carrying siRNA were very stable in gastric and intestinal fluid and RNase A. Of note, the cationic poly/lipoplex showed good inflamed colon targeting with potent anti-inflammatory activity in the DSS-induced colitis model.
The functionalization of active targeting ligands on the nanomaterial could induce target cell-specific distribution and enhance cellular membrane penetration via receptor-mediated endocytosis. Targeting receptors (mannose receptor [42] and galactose-type lectin [43]) on macrophages, known to be involved in gut inflammation, have also been investigated as a means of enhancing the oral delivery of siRNA. Mannosylated nanoparticles formulated using a cationic polymer and containing TNF-α siRNA were effectively taken up in vitro by macrophages and inhibited protein expression in colitis tissue ex vivo [44]. The oral administration of galactosylated trimethyl chitosan-cysteine nanoparticles loaded with Map4k4 siRNA decreased the severity of inflammation in a DDS colitis mouse model [45]. In these cases, net-negative charge nanoparticles could also be delivered into the intracellular region.
Even though these strategies have shown good efficacy in both in vitro and in vivo studies, there is a possibility for the lipoplex or polyplex to non-specifically bind to healthy intestinal barriers, especially the mucus layer. As the layer is typically composed of negatively charged molecules, complexes may not easily penetrate into the healthy mucus layer [46]. Furthermore, non-specific binding/trapping of the lipoplex or polyplex to/in the healthy tissue layer may compromise the therapeutic efficacy of the nanoparticles.

2.2. Polyplex or Lipoplex Embedded in Hydrogels or Polymeric Materials

To minimize the non-specific binding of the cationic lipoplex or polyplex, embedment into additional materials such as polymeric nanoparticles, microparticles, lipid droplets, or hydrogels could be utilized. These additional materials also endow the formulation with improved stability by providing an additional protective layer. Even though the embedment of the polyplex or lipoplex into stable materials increases the stability of loaded siRNA drugs in the harsh environment and non-specific binding of the polyplex or lipoplex into healthy tissue, robust loading of the polyplex or lipoplex could hamper the efficient release of loaded materials from the embedding materials. Thus, stimuli (pH, enzymes)-responsive polymers have been generally utilized for the target site-specific delivery of the loaded polyplex or lipoplex. For example, poly(epsilon-caprolactone) (PCL) microspheres were used to entrap type B gelatin nanoparticles encapsulating TNF-α siRNA (nanoparticles-in-microsphere oral system(NiMOS) formulation) [47]. The NiMOS formulation remained stable under acidic gastric conditions and released the gelatin nanoparticles only in the intestinal pH in the presence of lipase. Loaded siRNA was also very stable against RNase due to the dual nano/microstructures. The formulation also showed promising gene silencing while exerting anti-inflammatory activity in the DSS-induced murine colitis model. This formulation was also effective for the oral delivery of pDNA(plasmid DNA) [48]. A TNF-α siRNA-loaded pH-responsive nanogel encapsulated in a trypsin-mediated degradable microgel (P[Methacrylic acid (MAA)-co-N-Vinylpyrrolidone (NVP)] cross-linked with a trypsin-degradable peptide linker) protected the nanogel from release in the gastric acidic pH, while the nanogel was released by trypsin in the intestine. The released cationic nanogels could penetrate the mucus layer through the Polyethylene glycol (PEG) corona and be taken up by macrophages, followed by endosomal escape via the cationic Diethylaminoethyl Methacrylate (DEAEMA) polymer, resulting in the knockdown of TNF-α [49]. The β1,3-D-glucan-shell encapsulating polyplex composed of Map4k4 siRNA complexed with polyethylenimine (PEI) (Glucan-Encapsulated siRNA Particles (GeRPs)) is very stable in stomach and intestinal conditions, as well as against nuclease attacks [50]. GeRPs also show a high uptake by phagocytic cells and low non-specific binding en route to the gut. Thereby, GeRPs exhibited potent gene silencing activity and significant protective activity against lipopolysaccharide (LPS)-induced colitis in a mouse model.
Table 1. Oral siRNA nano-delivery systems for IBD treatment.
siRNA Delivery Methods Nanomaterials siRNA Target References
Lipo/polyplex formation - PEGylated poly/lipoplex TNF-α siRNA DSS-induced colitis (in vivo) [41]
Polymeric micelles Luciferase GL3 siRNA Caco 2 cell (in vitro) [34]
Ginger-derived lipid nanoparticle CD98 siRNA Colon-26 and RAW 264.7 cells (in vitro), CD98 mRNA expression in intestinal tract (in vivo) [38]
With targeting ligands Galactosylated trimethyl chitosan-cysteine nanoparticle Map4k4 siRNA Raw 264.7 cell (in vitro), DSS-induced colitis (in vivo) [45]
Mannosylated nanoparticle TNF-α siRNA Raw 264.7 cell (in vitro), DSS-induced colitis (ex vivo) [44]
Lipo/polyplex embedded in hydrogels or polymeric materials - Type B gelatin nanoparticle in PCL microsphere TNF-α siRNA DSS-induced colitis (in vivo) [47]
pH-responsive nanogel in trypsin-mediated degradable microgel TNF-α siRNA Raw 264.7 cell (in vitro) [49]
1,3-D-glucan-shell polyplex in PEI Map4k4 siRNA LPS-induced colitis (in vivo) [50]
With targeting ligands PEI polyplex in chitosan/alginate hydrogel with scCD98 antibody CD98 siRNA Colon-26 and RAW 264.7 cells (in vitro), DSS-induced colitis (in vivo) [39]
PEG-PLA nanoparticle in chitosan/alginate hydrogel with anti-F4/80 antibody TNF-α siRNA Raw 264.7 cell (in vitro), DSS-induced colitis (in vivo) [51]
Functionalization with active targeting ligands on the loaded nanomaterials could also improve target cell-specific distribution after the release of the nanomaterials from the embedding material. In addition, enhanced cellular membrane permeation could also be expected via receptor-mediated endocytosis. In these cases, a positive net charge is not necessary. For example, anti-F4/80 antibody-functionalized PEG-PLA nanoparticles carrying TNF-α siRNA complexed with polyethyleneimine were encapsulated in a chitosan/alginate hydrogel to improve the stability and siRNA delivery of the nanoparticles [51]. The hydrogel collapses in intestinal solutions at pH 5 or 6, which reflects the colonic pH under inflamed and non-inflamed states, leading to the specific release of loaded nanoparticles in the colonic lumen. Finally, the released nanoparticles (almost neutral net charge) penetrate the mucus layer through the PEG layer, targeting F4/80+ macrophage populations via anti-F4/80 antibody, to deliver loaded siRNA into cytosol via F4/80+ receptor-mediated endocytosis following proton sponge effects of PEI. This process leads to macrophage-specific gene silencing with dramatic therapeutic efficacy in a DSS-induced murine colitis model. Another study prepared an orally delivered chitosan/alginate hydrogel that releases CD98 siRNA/PEI polyplex-loaded single-chain CD98 (scCD98) antibody functionalized chitosan nanoparticles with a positive net charge [39]. scCD98 antibody was used to target macrophages as well as intestinal epithelium, and the roles of the other components are the same as those in the above work. This system also showed good gene silencing activity in macrophages and intestinal epithelial cells both in vitro and in vivo, with dramatic therapeutic efficacy in a CD4+CD45RBhigh T-cell transfer chronic colitis model. As another example, a degradable chitosan/alginate hydrogel loaded with IL-22 (pro-healing cytokine for the restoration of a disrupted intestinal barrier) and galactose (macrophage targeting moiety)-functionalized PLGA nanoparticles carrying anti-TNF-α with a net negative charge also showed good therapeutic efficacy in a DSS-induced mouse model of UC [52]. Three studies showed that a positive net charge is not necessary for active targeting functionalized nanoparticles. However, for efficient endosomal escape, an additional strategy such as the usage of PEI to perform the endosomal escape of complexed siRNA drugs via a proton sponge effect was utilized.
Inflamed site-specific release of the lipoplex or polyplex could be utilized to improve delivery and therapeutic efficacy [4]. The abnormally high levels of reactive oxygen species (ROS) produced at sites of intestinal inflammation could be exploited for inflamed site-specific release and action of polyplex or lipoplex [53][54][55]. Thioketal nanoparticles (TKNs) were developed by formulation from a polymer, poly-(1,4-pheyleneacetone dimethylene thioketal), which degrades selectively in response to ROS, encapsulating a polyplex composed of TNF-α siRNA complexed with DOTAP (1,2-dioleoyl-3-trimethylammonium-propane) [56]. The orally administered TKNs specifically release the polyplex at the inflamed site with higher levels of ROS, and the released polyplex specifically exerts strong siRNA gene silencing activity. Finally, these nanoparticles showed dramatic therapeutic efficacy in a DSS-induced murine colitis model, but the encapsulation of the polyplex in non-ROS-responsive nanoparticles instead of thio-ketal nanoparticles compromised the therapeutic efficacy, which is indicative of the crucial role of the ROS-mediated inflamed site-specific release of the polyplex in the therapeutic efficacy of the system.
The loading of the poly/lipoplex into additional materials could improve the stability of the system in the harsh GIT tract, but complexity issues hampering successful clinical translation should be considered.

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Subjects: Pharmacology & Pharmacy
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Jongyoon Shinn
,
Juyeon Lee
,
Seon Ah Lee
,
Seon Ju Lee
,
Ah Hyun Choi
,
Jung Seo Kim
,
Su Jin Kim
,
Hyo Jin Kim
,
Cherin Lee
,
Yejin Kim
,
Joohyeon Kim
,
Jonghee Choi
,
Byungchae Jung
,
Taeho Kim
,
HyeonTaek Nam
,
Hyungjun Kim
,
Yonghyun Lee
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Revisions: 2 times (View History)
Update Date: 11 Oct 2022
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