Methoxypoly(ethylene glycol)-conjugated carboxypeptidase A for solid tumor targeting: part II: pharmacokinetics and biodistribution in normal and tumor-bearing rodents.
We have evaluated effects of mPEG modification on pharmacokinetic properties of carboxypeptidase A (CPA) in normal rats. Attachment of two or three mPEG chains to CPA resulted in the generation of mPEG2-CPA and mPEG3-CPA analogs with significantly enhanced plasma half-lives, especially during the distribution phase. Moreover, the assessment of real-time whole-body kinetics in CT26 tumor-bearing mice showed both mPEG2-CPA and mPEG3-CPA exhibited increased body retention at 48 h post-injection. In addition, tumor localization of mPEG3-CPA at 72 h was visualized and confirmed by fusion of the gamma-scintigraphy and microCT data sets. Results from the imaging studies support our hypothesis of a correlation between tumor uptake and enhanced circulatory half-life. Tissue distribution data indicated the combination of increased tumor extravasation and effective renal elimination observed with mPEG2-CPA at 48 h following administration led to the highest observed tumor-to-blood ratio of 4.8:1. Although the total concentration of mPEG3-CPA accumulated in tumor was higher than that of mPEG2-CPA and CPA at predetermined time intervals, a higher tumor-to-blood ratio was not obtained owing to a higher level of blood activity. Clearly, the attachment of an appropriate number of mPEG chains can facilitate tumor localization as effectively as can the use of a tumor-specific antibody.
Ton
Giangthy N
GN
Department of Radiology, University of Wisconsin, K4/644 Clinical Science Center, 600 Highland Avenue, Madison, WI 53792-3252, USA.
Weichert
Jamey P
JP
Longino
Marc A
MA
Fine
Jason P
JP
Kwon
Glen S
GS
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D043422:Carboxypeptidases A / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D005260:Female; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D004337:Drug Carriers; D007457:Iodine Radioisotopes; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D043422:Carboxypeptidases A