HPMA copolymers containing doxorubicin bound by a proteolytically or hydrolytically cleavable bond: comparison of biological properties in vitro
Language English Country Netherlands Media print
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
PubMed
15380639
DOI
10.1016/j.jconrel.2004.07.015
PII: S0168-3659(04)00328-1
Knihovny.cz E-resources
- MeSH
- Acrylamides chemical synthesis metabolism pharmacology MeSH
- Apoptosis drug effects MeSH
- Cell Membrane drug effects pathology MeSH
- Cell Cycle genetics MeSH
- DNA antagonists & inhibitors genetics metabolism MeSH
- Doxorubicin chemical synthesis metabolism pharmacology MeSH
- Gene Expression drug effects genetics MeSH
- Genes, myc drug effects genetics MeSH
- Hydrazones chemical synthesis metabolism pharmacology MeSH
- Hydrolysis MeSH
- Inhibitory Concentration 50 MeSH
- Cyclin-Dependent Kinase Inhibitor p21 MeSH
- Caspase 3 MeSH
- Caspases adverse effects drug effects metabolism MeSH
- Ligands * MeSH
- RNA, Messenger genetics MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Drug Evaluation, Preclinical methods MeSH
- Cell Proliferation drug effects MeSH
- bcl-Associated Death Protein MeSH
- bcl-2-Associated X Protein MeSH
- Cell Cycle Proteins genetics metabolism MeSH
- Proto-Oncogene Proteins c-bcl-2 genetics metabolism MeSH
- Receptors, Transferrin drug effects genetics MeSH
- Thymidine metabolism MeSH
- Carrier Proteins genetics metabolism MeSH
- Tritium MeSH
- Animals MeSH
- Check Tag
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- Acrylamides MeSH
- Bad protein, mouse MeSH Browser
- Bax protein, mouse MeSH Browser
- Casp3 protein, mouse MeSH Browser
- Cdkn1a protein, mouse MeSH Browser
- DNA MeSH
- Doxorubicin MeSH
- Hydrazones MeSH
- Cyclin-Dependent Kinase Inhibitor p21 MeSH
- Caspase 3 MeSH
- Caspases MeSH
- Ligands * MeSH
- RNA, Messenger MeSH
- N-(2-hydroxypropyl)methacrylamide co-polymer-doxorubicin conjugate MeSH Browser
- bcl-Associated Death Protein MeSH
- bcl-2-Associated X Protein MeSH
- Cell Cycle Proteins MeSH
- Proto-Oncogene Proteins c-bcl-2 MeSH
- Receptors, Transferrin MeSH
- Thymidine MeSH
- Carrier Proteins MeSH
- Tritium MeSH
N-(2-Hydroxypropyl)methacrylamide (HPMA) copolymer carrier containing the anticancer drug doxorubicin bound either by a proteolytically degradable bond (non-targeted PK1 or targeted with alpha-CD71 mAb) or by a hydrolytically degradable bond were synthesised and tested in vivo for various biological properties. Mouse 38C13 B-cell lympoma was used as a well established and defined cell line for this study. 38C13 cells are sensitive to free doxorubicin and IC50 was very low, about 0.014 microM. PK1 showed a strongly decreased cytostatic effect, IC50 being 12.6 microM. alpha-CD71 targeted conjugate, which can be considered as an antibody-targeted form of PK1, had IC50 0.358 microM. HPMA copolymer with doxorubicin bound via a hydrolytically sensitive bond (HYD conjugate) showed a high cytostatic effect with IC50 about 0.052 microM. We demonstrated that HYD conjugate inhibited DNA synthesis and induced p21(Waf1/Cip1) protein expression (p21(Waf1/Cip1) is cyclin-dependent kinase inhibitor which blocks cell cycle progression) as quickly as free doxorubicin, whereas PK1 acted much more slowly. Similarly, apoptosis induction measured by Annexin V binding and Caspase 3 activity was detected later after incubation of cells with PK1 or alpha-CD71 targeted conjugate. Apoptosis was manifested by elevation of bax and bad mRNA levels, which was much more rapid and intense in the case of free doxorubicin and HYD conjugate. Expression of antiapoptotic genes as well as cyclin-dependent kinases was surprisingly not affected.
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