Investigation of Targeting Mechanism of New Dextran-Peptide-Methotrexate Conjugates Using Biodistribution Study in Matrix-Metalloproteinase-Overexpressing Tumor Xenograft Model

• Published in: Journal of pharmaceutical sciences Vol. 95; no. 3; pp. 542 - 551
• Main Authors: Chau, Ying, Dang, Natalie M., Tan, Frederick E., Langer, Robert
• Format: Journal Article
• Language: English
• Published: Hoboken Elsevier Inc 01.03.2006; Wiley Subscription Services, Inc., A Wiley Company; Wiley; American Pharmaceutical Association
• Subjects: Animals; Antimetabolites, Antineoplastic - administration & dosage; Antimetabolites, Antineoplastic - blood; Antimetabolites, Antineoplastic - pharmacokinetics; Biological and medical sciences; cancer; cancer chemotherapy; Cell Line, Tumor; clearance; conjugation; Dextrans - administration & dosage; Dextrans - blood; Dextrans - pharmacokinetics; distribution; Drug Delivery Systems; drug targeting; Fibrosarcoma - drug therapy; Fibrosarcoma - pathology; General pharmacology; Humans; Injections, Intraperitoneal; Intestine, Small - metabolism; Matrix Metalloproteinases - biosynthesis; Matrix Metalloproteinases - genetics; matrix-metalloproteinase; Medical sciences; Methotrexate - administration & dosage; Methotrexate - blood; Methotrexate - pharmacokinetics; Mice; Oligopeptides - administration & dosage; Oligopeptides - blood; Oligopeptides - pharmacokinetics; Pharmaceutical technology. Pharmaceutical industry; pharmacokinetics; Pharmacology. Drug treatments; polymeric drugs; site-specific delivery; Tissue Distribution; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; drug targeting; matrix-metalloproteinase; cancer chemotherapy; pharmacokinetics; site-specific delivery; clearance; cancer; polymeric drugs; distribution; conjugation; Antineoplastic agent; Targeting; Peptides; Metalloendopeptidases; Heterograft; Antifolate; Target; Blood substitute; Mechanism of action; Methotrexate; Pharmaceutical technology; Enzyme; Malignant tumor; Dextran; Peptidases; Antimetabolic; Distribution; Hydrolases; Pharmacokinetics; Conjugated compound
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.20548

We conducted a biodistribution study in HT-1080 bearing mice to investigate the drug targeting mechanism and the cause of side effects of the new dextran-peptide-methotrexate conjugates. HT-1080 is a human fibrosarcoma cell line that is known to overexpress matrix-metalloproteinases (MMPs). The experiments compared conjugates carrying MMP sensitive peptide linkers, conjugates carrying MMP insensitive linkers, and free methotrexate. Passive targeting was evidenced by the prolonged plasma circulation and higher tissue accumulations of both types of the conjugates compared to free methotrexate. Independent of the peptide sequence of the linker, the ratio of drug accumulation at the tumor versus drug accumulation at the major site of side effects (small intestine) for either conjugate was increased by the effect of enhance permeation and retention (EPR). The conjugate released a sufficient amount of peptidyl methotrexate to cause inhibition of tumor growth. There was no significant difference in drug accumulation at the tumor site between the MMP-sensitive and the MMP-insensitive conjugates. We concluded that the tumor targeting effect of the dextran-peptide-methotrexate conjugate was dominantly due to passive targeting and EPR. The difference in the systemic side effects observed for conjugates with different linkers could probably be attributed to their varying susceptibility towards enzymes in normal tissues. © 2006 Wiley-Liss, Inc. and the American Pharmacists Association.