Methoxypoly(ethylene glycol)-conjugated carboxypeptidase A for solid tumor targeting: part II: pharmacokinetics and biodistribution in normal and tumor-bearing rodents.

ABSTRACT

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 4.81. 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.