New HPMA copolymers containing doxorubicin bound via pH-sensitive linkage: synthesis and preliminary in vitro and in vivo biological properties
Language English Country Netherlands Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
11337062
DOI
10.1016/s0168-3659(01)00281-4
PII: S0168365901002814
Knihovny.cz E-resources
- MeSH
- Doxorubicin administration & dosage chemistry therapeutic use MeSH
- Globulins analysis immunology MeSH
- Hydrogen-Ion Concentration MeSH
- Lymphoma, T-Cell drug therapy MeSH
- Methacrylates chemical synthesis chemistry MeSH
- Molecular Weight MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Drug Carriers chemical synthesis chemistry MeSH
- Oxidation-Reduction MeSH
- Antibiotics, Antineoplastic administration & dosage chemistry therapeutic use MeSH
- Drug Screening Assays, Antitumor MeSH
- T-Lymphocytes drug effects immunology MeSH
- Neoplasm Transplantation MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Doxorubicin MeSH
- Globulins MeSH
- hydroxypropyl methacrylate MeSH Browser
- Methacrylates MeSH
- Drug Carriers MeSH
- Antibiotics, Antineoplastic MeSH
In this paper we describe the synthesis, physico-chemical characteristics and results of tests of biological activity of polymer drugs based on conjugates of anti-cancer drug doxorubicin (Dox) with water-soluble polymer drug carriers, N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. In the conjugates the drug is attached to the polymer backbone via a spacer stable under physiological conditions (pH 7.4) and hydrolytically degradable in mild acidic environment (e.g., endosomes, pH approximately 5). This enables designing polymer drugs with long blood circulation and release and specific activation of the active compound in endosomes of target cells. Two types of Dox conjugates differing in the length and structure of the oligopeptide spacer were synthesised (GG and GFLG). In both types, the linkage susceptible to hydrolytic cleavage was formed by the reaction of the carbonyl group of Dox with the hydrazide group terminating the oligopeptide side chains of the polymer. In vitro incubation of conjugates in buffers resulted in much faster release of Dox from the polymer at pH 5 than at pH 7.4 (more than 10 times) the rate being higher for the conjugate containing GG spacer. The presence of cathepsin B in incubation media increased the rate of Dox release from the conjugate with GFLG spacer, Dox release from conjugate with GG spacer remained unchanged. Cytotoxicity of conjugates for T-splenocytes and mouse EL-4 T cell lymphoma cells was much higher compared with the effect of similar 'classic' conjugates bearing Dox attached via amide bond. In vivo anti-tumor activity of conjugates containing hydrolytically sensitive linkage was also significantly improved in mouse EL4 T cell lymphoma.
References provided by Crossref.org
Water-Soluble, Biocompatible Polyphosphazenes with Controllable and pH-Promoted Degradation Behavior
