Table 3.
Representative drug delivery systems targeting receptors for the treatment of IBD.
| Receptor | Ligand | Carrier | Loading cargo | Delivery route | Characterization | Experimental model | Principal finding | Ref. |
|---|---|---|---|---|---|---|---|---|
| Mannose receptor | Mannose | Nanoparticle: PLGA–PEG | Ovalbumin | Ex vivo | S: 212.0 ± 8.0 Z: −7.0 ± 2.0 |
Proinflammatory cytokines treated Caco-2 cell, DSS-induced female C57BL/6 mice colitis | Mannose modification enhanced the endocytosis by Caco-2 cells and accumulation in inflamed colon | 34 |
| Mannose | Nanoparticle: TPP/poly (CBA-bPEI)-PEG | siTNF-α | Ex vivo | S:275.00 Z: ‒ |
Raw264.7 macrophage, DSS-induced male FVB mice colitis | Introduction of mannose demonstrated a significant increase in intracellular uptake, gene silencing in vitro and ex vivo | 35 | |
| Mannose | Nanoparticle: lipid phase: Compritol 888 ATO/Labrafac WL 1349/stearylamine/Span 80 aqueous phase: Poloxamer 188/ Polysorbate 80 | Budesonide | Oral | S: 301.7 ± 2.88 Z: +7.51 ± 0.71 |
Oxazolone-induced Wistar rat colitis | Surface conjugation of mannose led to superior effects in reduction of MPO, inflammatory cytokines (TNF-α, IL-1β) in vivo | 36 | |
| Mannose | Nanoparticle: trimethyl chitosan | Mir-146b | Oral | S: 213.6 ± 16.6 Z: +28.3 ± 6.3 |
Bone marrow-derived macrophage, DSS-induced C57BL/6 mice colitis | Mannosylated nanoparticles could be efficiently recognized and endocytosized by activated intestine macrophages | 37 | |
| Mannose | Nanoparticle: trimethyl chitosan | siTNF-α | Oral | S: 143.3 ± 1.1 Z: +18.7 ± 0.6 |
Raw264.7 macrophage, DSS-induced C57BL/6 mice colitis | Different densities of mannose on nanoparticle displayed different effects on the intracellular uptake and therapeutic efficacy in vitro and in vivo | 38 | |
| Macrophage galactose lectin | Lactobionic acid | Nanoparticle: chitosan-PLGA | siTNF-α | Oral | S: 245.60 ± 0.33 Z: +13.03 ± 0.65 |
Raw264.7 macrophage, DSS-induced male C57BL/6 mice colitis | Galactosylation remarkedly improved the targeted delivery into macrophage and TNF-α silencing effect in vitro and in vivo | 39 |
| Lactobionic acid | Nanoparticle: trimethyl chitosan-cysteine | siMap4k4 | Oral | S: 147.2 ± 7.8 Z: +26.2 ± 2.0 |
LPS-stimulated Raw264.7 macrophage, DSS-induced C57/BL6 mice colitis | The endocytosis kinetics and gene silencing effect of galactosylated nanoparticle outperformed those nanoparticles without galactosylation | 40 | |
| Lactobionic acid | Nanoparticle: PLGA/PVA/chitosan | siTNF-α & IL-22 | Oral | S: 261.3 ± 5.6 Z: −6.3 ± 1.4 |
Raw264.7 macrophage, DSS-induced male FVB mice colitis | Co-delivery of siTNF-α and recombinant human IL-22 could significantly inhibit the infiltration of mucosal neutrophils, promoted the colon epithelia regeneration and mucosal integrity | 41 | |
| Lactobionic acid | Nanoparticle: LMWC |
TNF-α antisense oligonucleotide |
Oral | S: ‒ Z: ‒ |
TNBS-induced mice colitis, CD45RBhi transferred mice colitis | Activated macrophages in the colon lamina propria of colitis mice efficiently absorbed galactosylated TNF-α antisense oligonucleotide nanoparticles | 42 | |
| Lactobionic acid | Nanoparticle: LMWC | Mir-16 | Rectal | S: ‒ Z: ‒ |
TNBS-induced BALB/c mice colitis | Galactosylated nanoparticle significantly accumulated in inflamed colon and delivers Mir-16 into colonic macrophages rather than T cells and colonic epithelial cells | 43 | |
| CD44 | HA | Nanoparticle: BSA-KPV/PLGA/PVA-chitosan | KPV | Oral | S: 272.3 Z: −5.3 |
LPS-stimulated Raw264.7 macrophage, DSS-induced FVB mice colitis | Colon-26 cells and Raw264.7 macrophages selectively absorbed HA modified nanoparticles | 44 |
| HA | Nanoparticle: spermidine/PLGA/chitosan | Curcumin& siCD98 | Oral | S: 246.2 ± 7.8 Z: −13.7 ± 4.1 |
LPS-stimulated Raw264.7 macrophage, DSS-induced FVB mice colitis | Surface grafting with HA enhanced the nanoparticles binding to colitis tissues and to be endocytosed by colonic macrophages | 45 | |
| HA | Copolymer: HA-bilirubin | Bilirubin | Oral | S:171 ± 30 Z: −39.1 ± 0.7 |
M0/M1/M2 J774A.1 macrophage, DSS-induced C57BL/6 mice colitis | HA-bilirubin copolymer could accumulate in inflamed colon epithelia and be internalized into M1 macrophages | 46 | |
| CS | Nanoparticle: silk fibroin | Curcumin | Oral or I.V. injection | S: 180.8 Z: −30 |
LPS-stimulated Raw264.7 macrophage, DSS-induced mice colitis | CS functionalization facilitated nanoparticle to be internalized into macrophage via CD44-mediated endocytosis | 47 | |
| HA | Hydrogel: methylcellulose/HA | BSA | Rectal | S: ‒ Z: ‒ |
Caco-2 monolayer | HA/ Methylcellulose hydrogel could rapidly permeate across Caco-2 monolayer | 48 | |
| Folate receptor | Folate | Nanoparticle: PLGA/PLA–PEG | 6-shogaol | Oral | S: 249.60 ± 1.30 Z: −24.17 ± 0.41 |
Raw264.7 macrophage, DSS-induced FVB/NJ mice colitis | Efficacy of 6-shogaol increased significantly after loading into folate modified nanoparticle, compared to drug suspension | 49 |
| Folate | Dendrimer: PAMAM-PEG/acetic anhydride | – | Tail vein injection | S: ‒ Z: ‒ |
Raw264.7 macrophage, DSS-induced C57BL6 mice colitis | Folate conjugation facilitated dendrimers binding to macrophages and accumulating in inflamed colon sites after tail vein injection | 50 | |
| Folate | Liposome: DSPC/cholesterol/PEG3400-DSPE | Betamethasone | Tail vein injection | S:100 ± 10 Z: ‒ |
Raw264.7 and peritoneal macrophage, DSS-induced C57/BL6 mice colitis | Folate grafting directed the liposomes to significantly accumulate in the inflamed colon and bind to peritoneal macrophages | 51 | |
| CD98 | CD98 Fab’ | Nanoparticle: PLA/bPEI/PVA/Mal-PEG | Quantum dots | Ex vivo | S: 458 Z: +19 |
Colon-26 cell and Raw264.7 macrophage, DSS-induced FVB mice colitis | CD98 Fab’ dramatically promoted the nanoparticle transporting into the CD98 glycoprotein overexpressed cells and inflamed colon. | 52 |
| Single-chain CD98 Ab | Nanoparticle: PEI/UAC- PEG-scCD98 | siCD98 | Oral | S: 210 Z: +15 |
Raw264.7 macrophage, colon-26 cells, DSS-induced C57/BL6 mice colitis, CD4+ CD45RBhigh T cell transferred RAG–/– mice colitis | Antibody conjugation endowed the nanoparticle with excellent biometrics capacity to bind CD98 glycoprotein on activated macrophage and polarized colon epithelia | 53 | |
| Transferrin receptor | TfR antibody | Liposome: HSPC/HSPG/DSPE-PEG-NHS | – | Ex vivo | S:105.60 ± 7.00 Z: −14.10 ± 3.30 |
Proinflammatory cytokines co-incubated Caco-2 cell, DNBS-induced rat colitis | Surface modification with TfR antibody resulted in more endocytosis by Caco-2 cells and accumulation in inflamed colon sites ex vivo | 54 |
| Seven peptides | Nanoparticle: PEG-b-PCL | Coumarin 6 | In vitro | S: 35.94 ± 2.76 Z: −3.10 ± 0.84 |
Caco-2 cell | Specific 7 peptides conjugation exhibited faster absorption rate in live cells | 55 | |
| Peptide transporter 1 | KPV | Nanoparticle: PLGA/montmorillonite/chitosan | Cyclosporine A | Oral | S:185.7 ± 3.0 Z:30 |
DSS-induced mice colitis | Surface modification with KPV promote nanoparticle to accumulate in inflamed colon. | 56 |
| F4/80 | F4/80 Ab Fab’ | Nanoparticle: PLA–PEG | siTNF-α | Oral | S: 609 ± 37 Z: ‒ |
LPS-stimulated Raw264.7 macrophage, DSS-induced mice colitis | F4/80 Ab Fab’ introduction increased the phagocytosis of nanoparticles by intestinal macrophages in mice | 57 |
‒, not applicable; BSA, bovine serum albumin; CS, chondroitin sulfate; DSS, dextran dulfate sodium salt; HA, hyaluronic acid; I.V., intravenous; LMWC, low molecular weight chitosan; LPS, lipopolysaccharide; MPO, myeloperoxidase; KPV, lysine-proline-valine tripeptide; S, size (nm); Z, zeta potential (mV).