Doxorubicin bound to a HPMA copolymer carrier through hydrazone bond is effective also in a cancer cell line with a limited content of lysosomes.

Abstract

We have synthesized conjugates containing doxorubicin (DOX) bound to oligopeptide side chains (GlyGly or GlyPheLeuGly) of a water-soluble copolymer carrier based on poly[N-(2-hydroxypropyl)methacrylamide] (PHPMA) either through proteolytically (PK1 conjugates) [Synthetic polymeric drugs. U.S. Patent 5,037,883 (1991)] or hydrolytically cleavable bond (HC conjugates). Pharmacological efficacy of PK1 and HC conjugates was compared in vitro on murine: T-cell lymphoma EL4, B-cell leukemia BCL1, B-cell lymphoma 38C13, leukemia P388 and Con A-stimulated A/Ph splenocytes and on human: primary (SW480) and metastatic (SW620) colorectal cancer cell lines parent and transfected with Thy 1.2 gene [2] and on erythromyeloid leukemia cell line K 562. Inhibition of proliferation determined by 3[H]-thymidine incorporation revealed that the cytostatic effect of HC conjugates is up to two orders of magnitude higher compared to PK1 conjugates. In some cancer cell lines (SW 620/T, SW 480) the pharmacological activity of HC conjugates is in vitro comparable with the activity of the free drug. Unlike PK1 conjugates, HC conjugates with a lysosomally degradable spacer (GlyPheLeuGly) are less effective compared to HC conjugates containing lysosomally non-degradable spacer (GlyGly). Moreover, HC conjugates exert pronounced anti-proliferative activity also in erythroblastoid leukemia cell line K 562 with a limited content of lysosomes.

• Authors: B Ríhová, T Etrych, M Pechar, M Jelínková, M Stastný, O Hovorka, M Kovár, K Ulbrich
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 74 Issue 1-3 Pg. 225-32 (Jul 06 2001) ISSN: 0168-3659 [Print] Netherlands
• PMID: 11489498 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Drug Carriers
• Hydrazones
• Methacrylates
• Oligopeptides
• Polymethacrylic Acids
• Duxon
• Doxorubicin
• hydroxypropyl methacrylate

Topics

• Animals
• Antibiotics, Antineoplastic (administration & dosage, chemistry)
• Doxorubicin (administration & dosage, chemistry)
• Drug Carriers
• Hydrazones (chemistry)
• Lysosomes (chemistry)
• Methacrylates
• Mice
• Molecular Weight
• Neoplasms (drug therapy)
• Oligopeptides (administration & dosage, chemistry)
• Polymethacrylic Acids
• Spleen (cytology, drug effects)
• Tumor Cells, Cultured