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  • 1
    Keywords: CANCER ; CELLS ; EXPRESSION ; IN-VITRO ; tumor ; CLINICAL-TRIAL ; human ; IN-VIVO ; MODEL ; liver ; PROTEIN ; PROTEINS ; DRUG ; TISSUE ; TUMORS ; MICE ; PATIENT ; SERA ; fibroblasts ; treatment ; MOUSE ; EFFICACY ; drug delivery ; CONJUGATE ; PHARMACOKINETICS ; BEARING RATS ; COLLAGEN-INDUCED ARTHRITIS ; FIBROBLAST-LIKE SYNOVIOCYTES ; LOW- DOSE METHOTREXATE ; SYNOVIAL FIBROBLASTS
    Abstract: We reported recently that albumin is a suitable drug carrier for targeted delivery of methotrexate (MTX) to tumors. Due to pathophysiological conditions in neoplastic tissue, high amounts of albumin accumulate in tumors and are metabolized by malignant cells. MTX, covalently coupled to human serum albumin (MTX-HSA) for cancer treatment, is currently being evaluated in phase II clinical trials. Because synovium of patients with rheumatoid arthritis (RA) shares various features observed also in tumors, albumin-based drug targeting of inflamed joints might be an attractive therapeutic approach. Therefore, the pharmacokinetics of albumin and MTX in a mouse model of arthritis was examined. Additionally, uptake of albumin by synovial fibroblasts of RA patients and the efficacy of MTX and MTX-HSA in arthritic mice were studied. The results show that when compared with MTX, significantly higher amounts of albumin accumulate in inflamed paws, and significantly lower amounts of albumin are found in the liver and the kidneys. The protein is metabolized by human synovial fibroblasts in vitro and in vivo. MTX-HSA was significantly more effective in suppression of the onset of arthritis in mice than was MTX. In conclusion, albumin appears to be a suitable drug carrier in RA, most likely due to effects on synovial fibroblasts, which might increase therapeutic efficacy and reduce side effects of MTX
    Type of Publication: Journal article published
    PubMed ID: 12707361
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  • 2
    Keywords: INVASION ; Germany ; human ; IN-VIVO ; MODEL ; VIVO ; MICE ; GENE-TRANSFER ; REDUCTION ; INDUCTION ; CONTRAST ; fibroblasts ; treatment ; MOUSE ; score ; IMMUNODEFICIENT MICE ; DEGRADATION ; MOUSE MODEL ; METHOTREXATE ; BEARING RATS ; albumin ; fibroblast ; rheumatoid arthritis ; RHEUMATOID-ARTHRITIS ; CYTOKINE INHIBITORS ; DESTRUCTION ; INTERLEUKIN-1
    Abstract: Objective: To investigate the effect of methotrexate (MTX) and albumin coupled with methotrexate (MTX-HSA) on cartilage invasion and induction of perichondrocytic degradation by rheumatoid arthritis synovial fibroblasts ( RA SF) in vivo. Methods: Human cartilage and RA SF were co-transplanted in three groups of severe combined immunodeficient mice ( SCID), which received 1 mg/kg free MTX (n = 9), 1 mg/kg MTX-HSA ( n = 6), or 0.9% NaCl ( n = 5), respectively, intraperitoneally twice a week. After 4 weeks' treatment, the mice were killed and the implants analysed histologically. Results: The control group had a mean (SEM) score for cartilage invasion of RA SF of 2.0 (0.26) and for perichondrocytic cartilage degradation of 1.5 (0.34). In contrast, mice which received MTX showed a significantly reduced invasion (0.78 (0.14), p〈 0.01) and a reduction in perichondrocytic cartilage degradation scores (0.69 (0.2), p〈 0.05) in comparison with the control group. Mice treated with MTX-HSA also had significantly reduced scores for RA SF invasion into the cartilage (0.92 (0.41), p〈 0.05) and for cartilage degradation (0.83 (0.44), p〈 0.05) compared with controls. The effects of MTX and MTX-HSA were not significantly different between these two groups. Conclusion: Treatment with MTX or MTX-HSA significantly ameliorates cartilage destruction in the SCID mouse model for human RA
    Type of Publication: Journal article published
    PubMed ID: 15194591
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