title: Renal targeting potential of a polymeric drug carrier, poly-l-glutamic acid, in normal and diabetic rats.
abstract: OBJECTIVE
  Poly-l-glutamic acid (PG) has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier.
  
  
  METHODS
  3H-deoxycytidine-labeled PGs (17 or 41 kDa) and3H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido) fluorescein (fluoresceinyl glycine amide)-labeled PG (PG-AF). To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF).
  
  
  RESULTS
  In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr) presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular tissues at 2 and 6 h after an intravenous administration. In the diabetic (oxidative stress-induced) kidneys, 41 kDa PG-Tr showed the greatest renal accumulation of 8-fold higher than the free compound 24 h post dose. Meanwhile, the synthesized PG-AEBSF was found to inhibit intracellular nicotinamide adenine dinucleotide phosphate oxidase (a reactive oxygen species generator) at an efficiency that is comparable to that of free AEBSF. This indicates the preservation of the anti-oxidative stress properties of AEBSF in the conjugated state.
  
  
  CONCLUSIONS
  The favorable accumulation property of 41 kDa PG in normal and oxidative stress-induced kidneys, along with its capabilities in conserving the pharmacological properties of the conjugated renal protective drugs, supports its role as a potential renal targeting drug carrier.
authors.affiliation: Department of Pharmacology.
authors.forename: Hann-Juang
authors.initials: HJ
authors.lastname: Chai
authors.affiliation: Department of Pharmacology.
authors.forename: Lik-Voon
authors.initials: LV
authors.lastname: Kiew
authors.affiliation: Department of Pharmacology.
authors.forename: Yunni
authors.initials: Y
authors.lastname: Chin
authors.affiliation: Department of Biomedical Science.
authors.forename: Anwar
authors.initials: A
authors.lastname: Norazit
authors.affiliation: Department of Biomedical Science.
authors.forename: Suzita
authors.initials: S
authors.lastname: Mohd Noor
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya; School of Pharmacy, International Medical University, Kuala Lumpur.
authors.forename: Yoke-Lin
authors.initials: YL
authors.lastname: Lo
authors.affiliation: Department of Pharmacology.
authors.forename: Chung-Yeng
authors.initials: CY
authors.lastname: Looi
authors.affiliation: Department of Pharmacology.
authors.forename: Yeh-Siang
authors.initials: YS
authors.lastname: Lau
authors.affiliation: Department of Chemical Science, Faculty of Science, Universiti Tunku Abdul Rahman, Kampar.
authors.forename: Tuck-Meng
authors.initials: TM
authors.lastname: Lim
authors.affiliation: Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur.
authors.forename: Won-Fen
authors.initials: WF
authors.lastname: Wong
authors.affiliation: Department of Pharmacology.
authors.forename: Nor Azizan
authors.initials: NA
authors.lastname: Abdullah
authors.affiliation: School of Pharmaceutical Sciences, Universiti Sains Malaysia, Minden, Malaysia.
authors.forename: Munavvar Zubaid
authors.initials: MZ
authors.lastname: Abdul Sattar
authors.affiliation: Department of Physiology, University College Cork, Cork, Republic of Ireland.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Johns
authors.affiliation: Department of Pharmacology.
authors.forename: Zamri
authors.initials: Z
authors.lastname: Chik
authors.affiliation: Department of Pharmacy, Faculty of Medicine, University of Malaya.
authors.forename: Lip-Yong
authors.initials: LY
authors.lastname: Chung
mesh_terms: D000818:Animals; D001011:Aorta / Q000201:enzymology; D003921:Diabetes Mellitus, Experimental / Q000473:pathology*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004847:Epithelial Cells / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008297:Male; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011099:Polyglutamic Acid / Q000097:blood / Q000737:chemistry*; D011851:Radioactivity; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D004337:Drug Carriers; D013450:Sulfones; D011099:Polyglutamic Acid; C002010:4-(2-aminoethyl)benzenesulfonylfluoride; D019255:NADPH Oxidases
keywords: acute kidney injury; carboxylated polymers; carboxylated polypeptides; carrier; chronic renal failure; diabetes; end-stage renal failure; renal drug delivery