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

Milada Šírová*, Veronika Horková, Tomáš Etrych, Petr Chytil, Blanka Říhová, Martin Studenovský

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)796-808
Number of pages13
JournalJournal of Drug Targeting
Volume25
Issue number9-10
DOIs
Publication statusPublished - 26 Nov 2017
Externally publishedYes

Keywords

  • Drug delivery
  • EL4 lymphoma
  • HPMA copolymers
  • anti-tumour immune response
  • enhanced EPR effect
  • polymer NO donor
  • polymer cytotoxic drugs
  • solid tumour treatment

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