New HPMA copolymers containing doxorubicin bound via pH-sensitive linkage: synthesis and preliminary in vitro and in vivo biological properties.
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.
Etrych
T
T
Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, Heyrovský Sq. 2, 162 06 6, Prague, Czech Republic. etrych@imc.cas.cz
Jelínková
M
M
Ríhová
B
B
Ulbrich
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D005916:Globulins / Q000032:analysis / Q000276:immunology; D006863:Hydrogen-Ion Concentration; D016399:Lymphoma, T-Cell / Q000188:drug therapy; D008297:Male; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D008970:Molecular Weight; D009368:Neoplasm Transplantation; D010084:Oxidation-Reduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D005916:Globulins; D008689:Methacrylates; D004317:Doxorubicin; C032802:hydroxypropyl methacrylate