Targeted Delivery and Improved Therapeutic Potential of Catalase by Chemical Modification: Combination with Superoxide Dismutase Derivatives1
- Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan
Abstract
Four types of bovine liver catalase (CAT) derivatives, succinylated (Suc-CAT), galactosylated (Gal-CAT), mannosylated (Man-CAT), and polyethylene glycol conjugate (PEG-CAT), were synthesized and their pharmacokinetics and therapeutic potential in a hepatic ischemia/reperfusion injury model were studied in mice. About 90% of the CAT enzymatic activity was retained after chemical modification. Biodistribution studies showed that 111indium (111In)-Gal-CAT accumulated selectively in the liver parenchymal cells as 111In-CAT, whereas an increased amount of 111In-Suc-CAT and 111In-Man-CAT was delivered to liver nonparenchymal cells. 111In-PEG-CAT exhibited prolonged retention in plasma. Pharmacokinetic analysis revealed that the hepatic uptake clearances of111In-Suc-CAT, 111In-Gal-CAT, and111In-Man-CAT were much greater than that of111In-CAT, whereas that of 111In-PEG-CAT was very small. In the ischemia/reperfusion injury model, in which hepatic injury was induced by occlusion of the portal vein for 30 min followed by 1 h reperfusion, the elevation of plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase levels was slightly inhibited by treatment with native CAT or Gal-CAT. PEG-CAT was less potent. In contrast, Suc-CAT and Man-CAT effectively suppressed the increase in plasma glutamic pyruvic transaminase and glutamic oxaloacetic transaminase. Coinjection of mannosylated superoxide dismutase marginally improved the inhibitory effects of CAT derivatives. These results demonstrate that targeted CAT delivery to liver nonparenchymal cells via chemical modification is a promising approach to prevent hepatic injuries caused by reactive oxygen species. The potential usefulness of combining of CAT and superoxide dismutase derivatives is also demonstrated.
Footnotes
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Send reprint requests to: Mitsuru Hashida, Ph.D., Department of Drug Delivery Research, Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshidashimoadachi-cho, Sakyo-ku, Kyoto 606 to 8501, Japan. E-mail: hashidam{at}pharm.kyoto-u.ac.jp
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↵1 This work was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan and the grant of “Basic Research on Drug Innovation” by the Japan Health Sciences Foundation.
- Abbreviations:
- CAT
- catalase
- SOD
- superoxide dismutase
- ROS
- reactive oxygen species
- Suc-CAT
- succinylated CAT
- PEG-CAT
- CAT-polyethylene glycol conjugate
- Gal-CAT
- galactosylated CAT, Man-CAT, mannosylated CAT
- Gal-SOD
- galactosylated SOD
- Man-SOD
- mannosylated SOD
- BSA
- bovine serum albumin
- Suc-BSA
- succinylated BSA
- Man-BSA
- mannosylated BSA
- DTPA
- diethylenetriaminepentaacetic acid
- PC
- parenchymal cells
- NPC
- nonparenchymal cells
- AUC
- area under the plasma concentration-time curve
- CLtotal
- total body clearance
- CLorg
- organ uptake clearance
- CLliver
- hepatic uptake clearance
- CLkidney
- renal uptake clearance
- CLurine
- urinary excretion clearance
- GPT
- glutamic pyruvic transaminase
- GOT
- glutamic oxaloacetic transaminase
- TNBS
- trinitrobenzene sulfonic acid
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- Received September 8, 1998.
- Accepted January 7, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
