title: Polymer conjugates of doxorubicin bound through an amide and hydrazone bond: Impact of the carrier structure onto synergistic action in the treatment of solid tumours.
abstract: In this study, we describe the synthesis, physico-chemical characterisation and results of the in vitro and in vivo evaluation of the biological behaviour of N-(2-hydroxypropyl)methacrylamide-based (HPMA) copolymer conjugates bearing doxorubicin (DOX) partly bound via a pH-sensitive hydrazone and partly via enzymatically degradable amide bonds, each contributing to a different anti-tumour mechanism of action of the polymer-doxorubicin conjugate. The following two types of HPMA copolymer drug carriers designed for passive tumour targeting were synthesised and compared: the linear non-degradable copolymer and the biodegradable high-molecular-weight (HMW) diblock copolymer. The HMW diblock copolymer carrier containing a degradable disulphide bond between the polymer blocks showed a rapid degradation in a buffer containing glutathione within the first few hours of incubation. In contrast to the conjugate with the amide bond-bound DOX requiring the presence of lysosomal enzymes to release DOX, the polymer-drug conjugate with the DOX bound via a hydrazone bond released DOX by pH-sensitive hydrolysis, which was significantly faster in a buffer of pH 5.0 (intracellular pH) than pH 7.4, mimicking the conditions in the bloodstream. The significant and comparable in vivo anti-tumour activity of the diblock HMW conjugate and an equimolar mixture of the conjugates differing in the DOX attachment method along with the development of cancer resistance during treatment with these conjugates demonstrated the high potential of these compounds in the development of new nanomedicines suitable for the treatment of solid tumours.
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic. Electronic address: etrych@imc.cas.cz.
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., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Vladimír
authors.initials: V
authors.lastname: Subr
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Richard
authors.initials: R
authors.lastname: Laga
authors.affiliation: Institute of Microbiology, Academy of Sciences of the Czech Republic v.v.i, Vídeňská 1083, 142 20 Prague 4, Czech Republic.
authors.forename: Blanka
authors.initials: B
authors.lastname: Ríhová
authors.affiliation: Institute of Macromolecular Chemistry, Academy of Sciences of the Czech Republic v.v.i., Heyrovsky Sq. 2, 162 06 Prague 6, Czech Republic.
authors.forename: Karel
authors.initials: K
authors.lastname: Ulbrich
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry* / Q000494:pharmacology; D004355:Drug Stability; D005260:Female; D006835:Hydrazones / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000178:Acrylamides; D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D006835:Hydrazones; D004317:Doxorubicin; C032976:N-(2-hydroxypropyl)methacrylamide
keywords: Doxorubicin; Drug delivery; HPMA copolymer; In vivo efficacy; Synergistic effect