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

ABSTRACT: 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.

SUBMITTER: Yazeji T

PROVIDER: S-EPMC8240985 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Evodiamine (Evo) is an alkaloid that can be extracted from the berry fruit Evodia rutaecarpa and has been reported to exert various pharmacological effects, such as antidiarrheal, antiemetic and antiulcer effects. In vivo, the potential effects of Evo were investigated in a mouse model of dextran sodium sulfate (DSS)‑induced ulcerative colitis (UC) and in adenomatous polyposis coli (Apc)MinC/Gpt C57BL/6 mice with colorectal cancer (CRC), where the latter harbours a point‑mutation in the Apc gene. Evo suppressed the degree of weight loss and colon shortening induced by DSS, decreased the disease activity index value and ameliorated the pathological alterations in the colon of mice with UC as examined via H&E staining of colon tissues. In addition, Evo decreased the number and size of colonic tumors in ApcMinC/Gpt mice. Proteomics (colon tissues), ELISA (colon tissues and serum) and western blotting (colon tissues) results revealed that Evo inhibited NF‑κB to mediate the levels of various cytokines, including, in the DSS‑induced UC model, IL‑1β, IL‑2, IL‑6, IL‑8, TNF‑α, IFN‑γ (ELISA of colon tissues and serum), NF‑κB, IKKα+β, IκBα, S100a9, TLR4 and MyD88 (western blotting of colon tissues), and, in the colorectal cancer model, IL‑1β, IL‑2, IL‑6, IL‑15, IL‑17, IL‑22, TNF‑α (ELISA of colon tissues and serum), NF‑κB, IKKα+β, IκBα and S100a9 (western blotting of colon tissues), to achieve its anti‑inflammatory and antitumor effects. In vitro, Evo also reduced the viability of the colon cancer cell line SW480, inhibited mitochondrial membrane potential (MMP detection), caused G2/M‑phase arrest (cell cycle detection) and suppressed the translocation of phosphorylated‑NF‑κB from the cytoplasm into the nucleus (immunofluorescence of p‑NF‑κB). Theoretical evidence (MD simulations) suggest that Evo may bind to the ordered domain (α‑helix) of NF‑κB to influence this protein. The protein secondary structure changes were analyzed by the cpptraj module in Amber. In addition, these data provide experimental evidence that Evo may be an effective agent for treating UC and CRC.

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

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