Polymer donors of nitric oxide improve the treatment of experimental solid tumours with nanosized polymer therapeutics

0482796 - MBÚ 2018 RIV GB eng J - Journal Article
Šírová, Milada - Horková, Veronika - Etrych, Tomáš - Chytil, Petr - Říhová, Blanka - Studenovský, Martin
Polymer donors of nitric oxide improve the treatment of experimental solid tumours with nanosized polymer therapeutics.
Journal of Drug Targeting. Roč. 25, 9-10 (2017), s. 796-808. ISSN 1061-186X. E-ISSN 1029-2330
R&D Projects: GA ČR(CZ) GA14-12742S; GA MZd(CZ) NV16-28600A
Institutional support: RVO:61388971 ; RVO:61389013
Keywords : Drug delivery * HPMA copolymers * enhanced EPR effect
OECD category: Microbiology; Polymer science (UMCH-V)
Impact factor: 3.408, year: 2017

Polymer carriers based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers with incorporated organic nitrates as nitric oxide (NO) donors were designed with the aim to localise NO generation in solid tumours, thus highly increasing the enhanced permeability and retention (EPR) effect. The NO donors were coupled to the polymer carrier either through a stable bond or through a hydrolytically degradable, pH sensitive, bond. In vivo, the co-administration of the polymer NO donor and HPMA copolymer-bound cytotoxic drug (doxorubicin, Dox) resulted in an improvement in the treatment of murine EL4 T-cell lymphoma. The polymer NO donors neither potentiated the in vitro toxicity of the cytotoxic drug nor exerted any effect on in vivo model without the EPR effect, such as BCL1 leukaemia. Thus, an increase in passive accumulation of the nanomedicine carrying cytotoxic drug via NO-enhanced EPR effect was the operative mechanism of action. The most significant improvement in the therapy was observed in a combination treatment with such a polymer conjugate of Dox, which is characterised by increased circulation in the blood and efficient accumulation in solid tumours. Notably, the combination treatment enabled the development of an anti-tumour immune response, which was previously demonstrated as an important feature of HPMA-based polymer cytotoxic drugs.
Permanent Link: http://hdl.handle.net/11104/0278186