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Effect of Molecular Size of Pegylated Peptide on the Pharmacokinetics and Tumor Targeting in Lymphoma-Bearing Mice¹

Department of Internal Medicine, Division of Hematology/Oncology, Section of Radiodiagnosis and Therapy, University of California Davis Medical Center, Sacramento, California 95816 [S. J. D., Z. Y., P. A. B., G. R. M., R. T. O., G. L. D.]; Department of Internal Medicine, Division of Hematology/Oncology, University of California, Davis Medical Center, Sacramento, California 95817 [K. S. L., A. S.]; and Brain Tumor Research Center, University of California San Francisco, San Francisco, California 94143 [K. R. L.]

Purpose: Rapid blood and body clearances have hampered effective tumor targeting by small molecules. We used branched poly(ethylene glycol) (pegylated) polymers (M_r 40,000, M_r 70,000, M_r 100,000, and M_r 150,000) conjugated to tumor-specific and control peptides to assess the effect of both molecular weight and tumor specificity on pharmacokinetics and biodistribution.

Experimental Design: Pegylated specific lymphoma-binding peptide and control peptide (containing stereoisomers of proline and aspartate) were synthesized, radiolabeled with ¹¹¹In, fractionated by size, and injected into Raji lymphoma-bearing athymic mice (4–6 mice/group). Pharmacokinetics were followed for 2 days to evaluate effects of specificity and molecular size on blood clearance, body clearance, and biodistribution.

Results: As molecular size increased, blood and body clearances decreased (P < 0.001). The effect of molecular size on blood clearance was not altered by ligand binding specificity (P = 0.21), with t_1/2 ranging from 5.4 h (M_r 40,000) to 17.7 h (M_r 150,000). However, ligand specificity did alter body clearance, with pegylated control peptides clearing the body more slowly than pegylated specific peptides [P = 0.03; range, 19.1–91.3 h (specific peptides) versus 23.6–115.7 h (control peptides)]. At 24 h, there was more uptake of specific versus control pegylated peptides in tumor, liver, and marrow, but there was less uptake in kidneys, with a more pronounced difference for the higher molecular weight peptides (P < 0.01).

Conclusions: These results demonstrate that the pharmacokinetics and biodistribution of peptides and resultant uptake in tumor and normal tissues can be altered by both molecular size and ligand specificity, with molecular size affecting pharmacokinetics and organ uptake in a predictable manner.