Albumin-based drug delivery as novel therapeutic approach for rheumatoid arthritis.
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.
Wunder
Andreas
A
Department of Radiochemistry and Radiopharmacology, German Cancer Research Center, Heidelberg, Germany.
Müller-Ladner
Ulf
U
Stelzer
Ernst H K
EH
Funk
Jürgen
J
Neumann
Elena
E
Stehle
Gerd
G
Pap
Thomas
T
Sinn
Hannsjörg
H
Gay
Steffen
S
Fiehn
Christoph
C
D000418:Albumins / Q000493:pharmacokinetics; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D004337:Drug Carriers / Q000008:administration & dosage / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation; D006801:Humans; D007834:Lasers; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D055095:Optics and Photonics; D004369:Pentetic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D012709:Serum Albumin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D013583:Synovial Membrane / Q000166:cytology / Q000378:metabolism / Q000637:transplantation
D000418:Albumins; D004337:Drug Carriers; D012709:Serum Albumin; C103803:indium DTPA-albumin; C040811:methotrexate-serum albumin; D004369:Pentetic Acid; D008727:Methotrexate