title: Thermoresponsive Polymer Micelles as Potential Nanosized Cancerostatics.
abstract: An effective chemotherapy for neoplastic diseases requires the use of drugs that can reach the site of action at a therapeutically efficacious concentration and maintain it at a constant level over a sufficient period of time with minimal side effects. Currently, conjugates of high-molecular-weight hydrophilic polymers or biocompatible nanoparticles with stimuli-releasable anticancer drugs are considered to be some of the most promising systems capable of fulfilling these criteria. In this work, conjugates of thermoresponsive diblock copolymers with the covalently bound cancerostatic drug pirarubicin (PIR) were synthesized as a reversible micelle-forming drug delivery system combining the benefits of the above-mentioned carriers. The diblock copolymer carriers were composed of hydrophilic poly[N-(2-hydroxypropyl)methacrylamide]-based block containing a small amount (∼ 5 mol %) of comonomer units with reactive hydrazide groups and a thermoresponsive poly[2-(2-methoxyethoxy)ethyl methacrylate] block. PIR was attached to the hydrophilic block of the copolymer through the pH-sensitive hydrazone bond designed to be stable in the bloodstream at pH 7.4 but to be degraded in an intratumoral/intracellular environment at pH 5-6. The temperature-induced conformation change of the thermoresponsive block (coil-globule transition), followed by self-assembly of the copolymer into a micellar structure, was controlled by the thermoresponsive block length and PIR content. The cytotoxicity and intracellular transport of the conjugates as well as the release of PIR from the conjugates inside the cells, followed by its accumulation in the cell nuclei, were evaluated in vitro using human colon adenocarcinoma (DLD-1) cell lines. It was demonstrated that the studied conjugates have a great potential to become efficacious in vivo pharmaceuticals.
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Department of Biomedical Polymers, Heyrovský square 2, 162 06 Prague, Czech Republic.
authors.forename: Richard
authors.initials: R
authors.lastname: Laga
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Department of Biomedical Polymers, Heyrovský square 2, 162 06 Prague, Czech Republic.
authors.forename: Olga
authors.initials: O
authors.lastname: Janoušková
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Department of Biomedical Polymers, Heyrovský square 2, 162 06 Prague, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Department of Biomedical Polymers, Heyrovský square 2, 162 06 Prague, Czech Republic.
authors.forename: Robert
authors.initials: R
authors.lastname: Pola
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Department of Biomedical Polymers, Heyrovský square 2, 162 06 Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Blažková
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Department of Biomedical Polymers, Heyrovský square 2, 162 06 Prague, Czech Republic.
authors.forename: Sergey K
authors.initials: SK
authors.lastname: Filippov
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Department of Biomedical Polymers, Heyrovský square 2, 162 06 Prague, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Etrych
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic, v.v.i., Department of Biomedical Polymers, Heyrovský square 2, 162 06 Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Pechar
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D016503:Drug Delivery Systems; D006801:Humans; D006863:Hydrogen-Ion Concentration; D057927:Hydrophobic and Hydrophilic Interactions; D008823:Micelles; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy*; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D008823:Micelles; D011108:Polymers; D004317:Doxorubicin; C027260:pirarubicin