Advances in targeting drug delivery to glomerular mesangial cells by long circulating cationic liposomes for the treatment of glomerulonephritis.
OBJECTIVE
Newly designed polyethylene glycol (PEG)-modified cationic liposomes, containing a novel cationic lipid TRX-20 (3,5-dipentadecyloxybenzamidine hydrochloride), bind specifically to cultured human mesangial cells, and not to endothelial cells. In this study, we investigated targeting the delivery of PEG-modified liposomes containing TRX-20 (TRX-liposomes) to mesangial cells and evaluated their pharmacokinetic behavior in a rat experimental glomerulonephritis model, using prednisolone phosphate (PSLP) as a model drug.


METHODS
TRX-liposomes were injected intravenously into experimental glomerulonephritic rats and normal rats to compare its pharmacokinetic behavior with that of non-cationic liposomes (PEG-liposomes). Rhodamine-labeled liposomes were used to evaluate the accumulation in inflamed kidneys. Pharmacological effects of three formulations of PSLP (i.e., a single injection of two liposomal formulations and daily injections of PSLP in saline solution) were estimated in terms of suppressing glomerular cell proliferation in the rat nephritis model.


RESULTS
TRX-liposomes markedly accumulated in the glomeruli of inflamed kidneys, but did not accumulate in the glomeruli of normal kidneys. Although the PEG-liposomes also accumulated in the glomeruli of the inflamed kidneys, their pharmacological behavior was quite different from that of the TRX-liposomes, which were internalized by the target cells. In a comparison among the three formulations of PSLP, the dose of TRX-liposomes required for significant suppression of glomerular cell proliferation was much less (dose of 0.032 mg/kg and above) than that required for the same effect by the PSLP saline solution (3.2 mg/kg daily; 12.8 mg/kg total) and PEG-liposomes (0.32 mg/kg). Interestingly, significant suppression of mesangial cell activation, as assessed by the expression of alpha-smooth muscle actin, was observed in nephritic rats treated with TRX-liposomes, but not in the other two treatment groups.


CONCLUSIONS
The pharmaceutical properties of TRX-liposomes due to their preferential binding to mesangial cells and long circulation time make this a likely candidate system for targeted drug delivery to the inflamed glomeruli of glomerulonephritis.
Morimoto
Katsumi
K
Research and Development Center, Terumo co., 1500 Inokuchi, Ashigarakami-gun, Kanagawa, 259-0151, Japan. Katsumi_Morimoto@terumo.co.jp
Kondo
Masayo
M
Kawahara
Kazuo
K
Ushijima
Hideto
H
Tomino
Yasuhiko
Y
Miyajima
Masaharu
M
Kimura
Junji
J
D000818:Animals; D001550:Benzamidines / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005227:Fatty Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D005921:Glomerulonephritis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007275:Injections, Intravenous; D008081:Liposomes / Q000737:chemistry; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D011239:Prednisolone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
C450860:3,5-dipentadecyloxybenzamidine hydrochloride; D001550:Benzamidines; D005227:Fatty Acids; D008081:Liposomes; C009022:prednisolone phosphate; D011239:Prednisolone