Surface engineered lipid nanoparticle-mediated site-specific drug delivery system for the treatment of inflammatory bowel disease

Abstract

The major challenge for the treatment of inflammatory bowel disease (IBD) is the incompetence to deliver the drug molecule selectively at the site of inflammation. Taking this into consideration, we proposed development of mannosylated nanostructured lipid carrier system (Mn-NLCs) for active targeting and site-specific delivery of budesonide to the inflamed tissues. The developed Mn-NLCs were characterized for particle size and size distribution, zeta potential, %entrapment efficiency, FTIR and TEM analysis. Furthermore, to ensure delivery of developed cargo to the colonic region, the Mn-NLCs were encapsulated using Eudragit S100 coated pellets. The in vivo evaluation of developed system was performed by employing oxazolone colitis rat model. The average particle size of Mn-NLCs (301.7 ± 2.88 nm) was found to be more than that of unconjugated NLCs (284.0 ± 4.53 nm) with marginally reduced % entrapment efficiency (90.88 ± 3.86%). The in vitro cytotoxicity studies using J774A.1 cell line revealed that Mn-NLCs were non-toxic as compared to pure drug. The in vivo evaluation depicted that Mn-NLCs showed significant reduction in clinical activity scoring, macroscopic and microscopic indexing, colonic myeloperoxidase activity and inflammatory cytokines. In conclusion, the developed Mn-NLCs appear to be promising for the treatment of IBD by selectively targeting inflamed colonic region as compared to unconjugated nanoparticulate system.

Receptor-mediated targeted drug delivery systems for treatment of inflammatory bowel disease: Opportunities and emerging strategies

“…Drug delivery systems superficially modified with related ligands can specifically bind to receptors on inflamed cells, deliver drug into target area and achieve great curative effect. Based on the ligand–receptor interaction, receptor-mediated active targeted drug delivery systems could be a promising therapeutic strategy for IBD, as listed in Table 3 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 .…”

“… 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-1 β ) 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 ± ...…”

“…Mannose receptor (MR), also named as cluster of differentiation 206 (CD206), is an effective endocytic carbohydrate-binding receptor 58 , 59 . MR is overexpressed on the surface of macrophages and dendritic cells (DCs) under inflammation conditions 36 , 60 . It's a transmembrane receptor contains C-type lectin-like domains (CTLD), fibronectin type II domains (FNII), R-type cysteine-rich domains (CRD) 61 , 62 .…”

Nanostructured lipid carriers (NLCs) as drug delivery platform: Advances in formulation and delivery strategies

“…Authors attributed that to larger particle size and un-protonated chitosan at neutral pH leading to reduced interaction with mucin. Sinhmar and coworkers fabricated mannosylated NLCs for active targeting of budesonide to the inflamed bowel tissues ( Sinhmar et al, 2018b ). As the surface of macrophages present at the site of inflammation overexpress C-type lectin receptors which can easily recognize mannose, decoration of mannose group to the NLC surfaces could actively deliver the encapsulated drug to inflamed tissues.…”

Drug Targeting of Inflammatory Bowel Diseases by Biomolecules

“…Additionally, fluorescence imaging analysis confirmed that the optimized NPs were capable of enhancing retention in the colon. With the same purpose of preventing early BUD release in the upper GIT, Sinhmar et al [ 135 ] used Eudragit ® S100 to incorporate mannosylated nanostructured lipid carriers, which enabled the active targeting of BUD to the inflamed tissues. The active targeting relies on the fact that mannose receptors [175-kDa transmembrane protein of the C-type lectin family (CLR)] are exclusively overexpressed on the surface of pro-inflammatory macrophages.…”