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
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
24632485
DOI
10.1016/j.ejps.2014.02.016
PII: S0928-0987(14)00090-6
Knihovny.cz E-resources
- Keywords
- Doxorubicin, Drug delivery, HPMA copolymer, In vivo efficacy, Synergistic effect,
- MeSH
- Acrylamides chemistry MeSH
- Doxorubicin chemistry pharmacokinetics pharmacology therapeutic use MeSH
- Hydrazones chemistry MeSH
- Hydrogen-Ion Concentration MeSH
- Mice, Inbred C57BL MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Neoplasms drug therapy metabolism MeSH
- Drug Carriers chemistry pharmacology MeSH
- Antibiotics, Antineoplastic chemistry pharmacokinetics pharmacology therapeutic use MeSH
- Drug Stability MeSH
- Cell Survival drug effects MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Acrylamides MeSH
- Doxorubicin MeSH
- Hydrazones MeSH
- N-(2-hydroxypropyl)methacrylamide MeSH Browser
- Drug Carriers MeSH
- Antibiotics, Antineoplastic MeSH
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.
References provided by Crossref.org
HPMA Copolymer-Based Nanomedicines in Controlled Drug Delivery
