Improved biological properties and hypouricemic effects of uricase from Candida utilis loaded in novel alkaline enzymosomes.
OBJECTIVE
Previous studies on various enzymosomes (functional lipid vesicles encapsulating an enzyme) have been mostly carried out in vitro and have focused on preserving catalytic activity and improving the stability of the enzyme. Until now, few studies have focused on their in vivo fate. Similarly, although we have previously reported the increased in vitro uricolytic activity (about 2.2 times higher than that of free uricase, or three times higher than that of PEGylated uricase, Puricase(®), under physiological pH and temperature) and improved stability of the novel alkaline enzymosomes (functional lipid vesicles encapsulating uricase from Candida utilis: uricase-containing lipid vesicles, UOXLVs), it is still necessary to study the biological properties and hypouricemic effects of UOXLVs in vivo.


METHODS
The enzyme kinetics, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary safety of UOXLVs were evaluated.


RESULTS
The Michaelis constant (K(m)) value of the UOXLVs was slightly lower than that of the free enzyme. The enzyme release from the UOXLVs lasted over 12 hours and their circulation half-life was about sevenfold longer than that of the free uricase. Meanwhile, the UOXLVs had a 22-fold increase in the area under the curve compared with the free uricase. Furthermore, it took less than 3 hours for the UOXLVs to lower the plasma uric acid concentration from a high to a normal level, compared with 6 hours for the free uricase. In addition, the UOXLVs had much less immunogenicity than free uricase and were well tolerated by all animals throughout the observation period.


CONCLUSIONS
The UOXLVs markedly improved the biological properties and enhanced the hypouricemic effects of uricase in vivo.
Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, People’s Republic of China.
Qun-You
QY
Tan
Jing-Qing
JQ
Zhang
Na
N
Wang
Hong
H
Yang
Xiaoling
X
Li
Hua-Rong
HR
Xiong
Jian-Yong
JY
Wu
Chun-Jing
CJ
Zhao
Hong
H
Wang
Hua-Feng
HF
Yin
D000481:Allantoin / Q000097:blood / Q000378:metabolism; D000818:Animals; D002175:Candida / Q000201:enzymology*; D004337:Drug Carriers / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D004795:Enzyme Stability; D006461:Hemolysis / Q000187:drug effects; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D014503:Urate Oxidase / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014527:Uric Acid / Q000097:blood / Q000378:metabolism*
D004337:Drug Carriers; D014527:Uric Acid; D000481:Allantoin; D014503:Urate Oxidase