Nanoparticle-based delivery enhances anti-inflammatory effect of low molecular weight heparin in experimental ulcerative colitis

Epithelial administration of low molecular weight heparin (LMWH) has proven its therapeutic efficiency in ulcerative colitis (UC) but still lacks of a sufficiently selective drug delivery system. Polymeric nanoparticles were used here not only to protect LMWH from intestinal degradation but also to provide targeted delivery to inflamed tissue in experimental colitis mice. LMWH was associated with polymethacrylate nanoparticles (NP) type A (PEMT-A) or type B (PEMT-B) of a size: 150 nm resulting in a maximum drug loading: 0.1 mg/mg. In a lipopolysaccharide-stimulated macrophages both, free LMWH and LMWH-NP have significantly reduced the cytokines secretion independently from cellular uptake. The in-vivo therapeutic efficiency was dose dependent as at low doses (100 IU/kg) only minor differences between free LMWH and LMWH-NP were found and the superiority of LMWH-NP became prominent with dose increase (500 IU/kg). Administration of LMWH-NP at 500 IU/kg has markedly improved the clinical activity as compared to LMWH while similarly pathophysiological indicators revealed increased therapeutic outcome in presence of NP compared to LMWH alone: Myeloperoxidase (Colitis control: 10 480 ± 5335, LMWH-PEMT-A NP: 1507 ± 2165, LMWH-PEMT-B NP: 382 ± 143, LMWH: 8549 ± 5021 units/g) and tumor necrosis factor: (Colitis control: 1636 ± 544, LMWH-PEMT-A NP: 511 ± 506, LMWH-PEMT-B NP: 435 ± 473, LMWH: 1110 ± 309 pg/g). Associating LMWH with NP is improving the anti-inflammatory efficiency of LMWH in-vivo by its protection against degradation in luminal environment and selective drug delivery. Such a combination holds promise for a highly specific therapy by its double selectivity towards the inflamed intestinal tissue. LMWH-PEMT NP have significantly improved the clinical activity in-vivo in comparison to free LMWH.