Polymer nitric oxide donors potentiate the treatment of experimental solid tumours by increasing drug accumulation in the tumour tissue

Studenovský, Martin; Sivák, Ladislav; Sedláček, Ondřej; Konefal, Rafal; Horková, Veronika; Etrych, Tomáš; Kovář, Marek; Říhová, Blanka; Šírová, Milada

doi:https://dx.doi.org/10.1016/j.jconrel.2017.11.017

Number of the records: 1

Polymer nitric oxide donors potentiate the treatment of experimental solid tumours by increasing drug accumulation in the tumour tissue

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SYSNO ASEP	0481666
Document Type	J - Journal Article
R&D Document Type	Journal Article
Subsidiary J	Článek ve WOS
Title	Polymer nitric oxide donors potentiate the treatment of experimental solid tumours by increasing drug accumulation in the tumour tissue
Author(s)	Studenovský, Martin (UMCH-V)_{RID, ORCID} Sivák, Ladislav (MBU-M)_RID Sedláček, Ondřej (UMCH-V)_{RID, ORCID} Konefal, Rafal (UMCH-V)_{RID, ORCID} Horková, Veronika (MBU-M) Etrych, Tomáš (UMCH-V)_{RID, ORCID} Kovář, Marek (MBU-M)_{RID, ORCID} Říhová, Blanka (MBU-M)_RID Šírová, Milada (MBU-M)_{RID, ORCID}
Source Title	Journal of Controlled Release. - : Elsevier - ISSN 0168-3659 Roč. 269, 10 January (2018), s. 214-224
Number of pages	11 s.
Language	eng - English
Country	NL - Netherlands
Keywords	enhanced permeability and retention effect ; nitric oxide donor ; polymer-based cytotoxic drugs
Subject RIV	CD - Macromolecular Chemistry
OECD category	Polymer science
Subject RIV - cooperation	Institute of Microbiology - Microbiology, Virology
R&D Projects	GA14-12742S GA ČR - Czech Science Foundation (CSF)
	NV16-28600A GA MZd - Ministry of Health (MZ)
	LQ1604 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
	ED1.1.00/02.0109 GA MŠMT - Ministry of Education, Youth and Sports (MEYS)
Institutional support	UMCH-V - RVO:61389013 ; MBU-M - RVO:61388971
UT WOS	000423760400019
EID SCOPUS	85034437726
DOI	10.1016/j.jconrel.2017.11.017
Annotation	The delivery of nitric oxide (NO) specifically to solid tumours was explored in this study as a strategy to augment the passive accumulation of nanomedicines in tumours induced by the Enhanced Permeability and Retention (EPR) effect. An increase in accumulation was achieved by the binding of the chemical precursor of NO, based on an organic nitrate, to a water-soluble synthetic polymer drug carrier. Four structurally different N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer NO donors were synthesized. Depending on their chemical structure, two of these donors were hydrolytically stable, while two rapidly released the parent nitrate under acidic conditions, mimicking the intracellular environment. The polymer NO donors were shown to overcome the drawbacks related to low-molecular-weight NO releasing compounds, namely systemic toxicity, lack of site specificity, and fast blood clearance. The NO donors showed intracellular NO release upon incubation with tumour cells. In vivo, they potentiated the EPR effect, resulting in an increased accumulation of polymer-bound cytotoxic drug doxorubicin (Dox) in EL4 T-cell lymphoma inoculated in mice. This led to a better therapeutic outcome in the treatment of lymphoma with the high-molecular-weight polymer conjugates carrying Dox but not in the treatment with the free Dox. The localized augmentation of the EPR effect via the tumour-specific NO delivery system can be viewed as a promising strategy to potentiate polymer-based tumour therapy without increasing systemic toxicity.
Workplace	Institute of Macromolecular Chemistry
Contact	Eva Čechová, cechova@imc.cas.cz ; Tel.: 296 809 358
Year of Publishing	2019

Number of the records: 1