Treatment of murine EL4 T cell lymphoma with N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer conjugates of doxorubicin (Dox) leads to complete tumor regression and to the development of therapy-dependent longlasting cancer resistance. This phenomenon occurs with two types of Dox conjugates tested, despite differences in the covalent linkage of Dox to the polymer carrier. Such a cancer resistance cannot fully express in conventional treatment with free Dox, due to substantial immunotoxicity of the treatment, which was not observed in the polymer conjugates. In this study, calreticulin (CRT) translocation and high mobility group box-1 protein (HMGB1) release was observed in EL4 cells treated with a conjugate releasing Dox by a pH-dependent manner. As a result, the treated tumor cells were engulfed by dendritic cells (DC) in vitro, and induced their expression of CD80, CD86, and MHC II maturation markers. Conjugates with Dox bound via an amide bond only increased translocation of HSPs to the membrane, which led to an elevated phagocytosis but was not sufficient to induce increase of the maturation markers on DCs in vitro. Both types of conjugates induced engulfment of the target tumor cells in vivo, that was more intense than that seen with free Dox. It means that the induction of anti-tumor immunity documented upon treatment of EL4 lymphoma with HPMA-bound Dox conjugates does not rely solely on CRT-mediated cell death, but involves multiple mechanisms.
- MeSH
- antigeny CD80 metabolismus MeSH
- antigeny CD86 metabolismus MeSH
- antitumorózní látky aplikace a dávkování chemie toxicita MeSH
- apoptóza účinky léků MeSH
- chemorezistence účinky léků MeSH
- dendritické buňky cytologie imunologie MeSH
- doxorubicin aplikace a dávkování analogy a deriváty chemie toxicita MeSH
- fagocytóza MeSH
- kalretikulin metabolismus MeSH
- koncentrace vodíkových iontů MeSH
- kyseliny polymethakrylové aplikace a dávkování chemie toxicita MeSH
- lymfom T-buněčný farmakoterapie imunologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- nosiče léků chemie MeSH
- protein HMGB1 metabolismus MeSH
- proteiny tepelného šoku metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The cytostatic effects of polymeric conjugates based on N-(2-hydroxypropyl)methacrylamide copolymers (PHPMA) and containing doxorubicin bound through amide and hydrazone bonds (mixed conjugates) were compared with the cytostatic effects of monoconjugates containing drug bound through an amide or hydrazone bond. One group of mixed conjugates was formed from two comonomers containing doxorubicin bound to the methacryloyl group through a spacer and an amide (DOX(AM)) or hydrazone (DOX(HYD)) bond via copolymerization with HPMA. A second group of mixed conjugates was formed from two different interconnected HPMA copolymers, one containing DOX(AM) and the other DOX(HYD), forming a high-molecular-weight branched structure. The third mixed polymeric system was a simple mixture of monoconjugates DOX(AM)-PHPMA and DOX(HYD)-PHPMA. Simultaneous treatment with all mixed forms of the polymeric derivatives of doxorubicin significantly increased antitumor efficacy after application of monoconjugates, suggesting a synergizing effect that could be used in designing new doxorubicin-containing therapeutic systems.
- MeSH
- akrylamidy chemie MeSH
- amidy chemie MeSH
- antibiotika antitumorózní chemie farmakologie MeSH
- buněčné linie MeSH
- doxorubicin chemie farmakologie MeSH
- fluorescenční mikroskopie MeSH
- hydrazony chemie MeSH
- lidé MeSH
- lymfom T-buněčný farmakoterapie MeSH
- molekulární struktura MeSH
- myši inbrední C57BL MeSH
- myši nahé MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- polymery chemická syntéza chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- MeSH
- akrylamidy farmakologie chemická syntéza MeSH
- doxorubicin farmakologie chemická syntéza metabolismus MeSH
- finanční podpora výzkumu jako téma MeSH
- ligandy MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
- MeSH
- biomechanika MeSH
- externí fixátory trendy využití MeSH
- otevřené fraktury terapie MeSH
- počítačová simulace využití MeSH
- Publikační typ
- přehledy MeSH