Acute renal toxicity of doxorubicin (adriamycin)-loaded cyanoacrylate nanoparticles.
Acute doxorubicin-loaded nanoparticle (DXNP) renal toxicity was explored in both normal rats and rats with experimental glomerulonephritis. In normal rats, 2/6 rats given free doxorubicin (DX) (5 mg/kg) died within one week, whereas all control animals and all rats having received free NP or DXNP survived. A 3 times higher proteinuria appeared in animals treated with DXNP than in those treated with DX. Free NP did not provoke any proteinuria. Two hr post-injection, DXNP was 2.7 times more concentrated in kidneys than free DX (p < 0.025). In rats with immune experimental glomerulonephritis, 5/6 rats given DX died within 7 days, in contrast to animals treated by DXNP, NP, or untreated, which all survived. Proteinuria appeared in all series, but was 2-5 times more intense (p > 0.001) and prolonged after doxorubicin treatment (400-700 mg/day), without significant difference between DXNP and DX. Rats treated by unloaded NP behaved as controls. These results demonstrate that, in these experimental conditions, DXNP killed less animals than free DX, despite of an enhanced renal toxicity of the former. Both effects (better survival and nephrosis) are most probably related to an enhanced capture of DXNP by cells of the mononuclear phagocyte system, including mesangial cells.
Manil
L
L
Internal Medicine Department, University of LIEGE, Sart-Tilman, Belgium.
Couvreur
P
P
Mahieu
P
P
D000208:Acute Disease; D000818:Animals; D003487:Cyanoacrylates / Q000008:administration & dosage* / Q000633:toxicity*; D004317:Doxorubicin / Q000008:administration & dosage* / Q000633:toxicity*; D004337:Drug Carriers; D005921:Glomerulonephritis / Q000139:chemically induced / Q000503:physiopathology / Q000652:urine; D007674:Kidney Diseases / Q000139:chemically induced* / Q000652:urine; D010316:Particle Size; D011507:Proteinuria / Q000139:chemically induced; D051381:Rats; D017207:Rats, Sprague-Dawley
D003487:Cyanoacrylates; D004337:Drug Carriers; D004317:Doxorubicin