HPMA-based polymer conjugates with drug combination.
Synthesis and physico-chemical behavior of new polymer-drug conjugates intended for the treatment of cancer were investigated. In the polymer conjugate with the expected dual therapeutic activity, two drugs, a cytostatic agent doxorubicin (DOX) and anti-inflammatory drug dexamethason (DEX) were covalently attached to the same polymer backbone via hydrolytically labile pH-sensitive hydrazone bonds. The precursor, a copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) bearing hydrazide groups randomly distributed along the polymer chain, was conjugated with DOX (through its C13 keto group) or with a keto ester (DEX). Two derivatives of DEX, 4-oxopentanoate and 4-(2-oxopropyl)benzoate esters, were synthesized and employed for conjugation reaction. As a control, also a few polymer conjugates containing only a single drug (DOX or DEX) attached to the polymer carrier were synthesized. Physico-chemical properties of the polymer conjugates strongly depend on the attached drug, spacer structure and the drug content. Polymer-drug conjugates incubated in buffers modeling intracellular environment released the drug (DOX) or a drug derivatives (DEX) at the rate significantly exceeding the release rate observed under conditions mimicking situation in the blood stream. Incubation of the DEX conjugates in a buffer containing carboxyesterase resulted in complete ester hydrolysis thus demonstrating susceptibility of the system to release free active drug in the two-step release profile.
Krakovicová
Hana
H
Institute of Macromolecular Chemistry Academy of Sciences of the Czech Republic v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic. krakovicova@imc.cas.cz
Etrych
Tomás
T
Ulbrich
Karel
K
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000737:chemistry; D043182:Carboxylesterase / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage / Q000737:chemistry; D004338:Drug Combinations; D005079:Excipients; D009682:Magnetic Resonance Spectroscopy; D008689:Methacrylates / Q000138:chemical synthesis / Q000737:chemistry*; D011108:Polymers; D013056:Spectrophotometry, Ultraviolet
D000903:Antibiotics, Antineoplastic; D004338:Drug Combinations; D005079:Excipients; D008689:Methacrylates; D011108:Polymers; D004317:Doxorubicin; D043182:Carboxylesterase; C032802:hydroxypropyl methacrylate