The structure-dependent toxicity, pharmacokinetics and anti-tumour activity of HPMA copolymer conjugates in the treatment of solid tumours and leukaemia

0463915 - MBÚ 2017 RIV NL eng J - Článek v odborném periodiku
Tomalová, Barbora - Šírová, Milada - Rossmann, Pavel - Pola, Robert - Strohalm, Jiří - Chytil, Petr - Černý, Viktor - Tomala, Jakub - Kabešová, Martina - Říhová, Blanka - Ulbrich, Karel - Etrych, Tomáš - Kovář, Marek
The structure-dependent toxicity, pharmacokinetics and anti-tumour activity of HPMA copolymer conjugates in the treatment of solid tumours and leukaemia.
Journal of Controlled Release. Roč. 223, 10 February (2016), s. 1-10. ISSN 0168-3659. E-ISSN 1873-4995
Grant CEP: GA ČR(CZ) GAP301/11/0325; GA MŠMT(CZ) ED1.1.00/02.0109
Institucionální podpora: RVO:61388971 ; RVO:61389013
Klíčová slova: HPMA * Doxorubicin * Structure
Kód oboru RIV: EE - Mikrobiologie, virologie; CD - Makromolekulární chemie (UMCH-V)
Impakt faktor: 7.786, rok: 2016

Polymer drug carriers that are based on N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers have been widely used in the development and synthesis of high-molecular-weight (HMW) drug delivery systems for cancer therapy. In this study, we compared linear (M-w similar to 27 kDa, Rh similar to 4 nm) and non-degradable star (M-w similar to 250 kDa, R-h similar to 13 nm) HPMA copolymer conjugates bearing anthracycline antibiotic doxorubicin (DOX) bound via pH-sensitive hydrazone bond. We determined the in vitro and in vivo toxicity of both conjugates and their maximum tolerated dose (MTD). We also compared their anti-tumour activity in mouse B-cell leukaemia (BCL1) and a mouse T-cell lymphoma (EL4) model. We found that MTD was higher for the linear conjugate (85 mg DOX/kg) and lower for the star conjugate (22.5 mg DOX/kg). An evaluation of the intestinal barrier integrity using FITC-dextran as a gut permeability tracer proved that no pathology was caused by the MTD of either conjugate. However, free DOX showed some damage to the gut barrier. The therapy of BCL1 leukaemia by both of the polymeric conjugates using the MTD or its fraction (i.e., equitoxic dosage) showed better results in the case of the star conjugate.
Trvalý link: http://hdl.handle.net/11104/0263061