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.
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Authors | Milada Šírová, Veronika Horková, Tomáš Etrych, Petr Chytil, Blanka Říhová, Martin Studenovský |
Journal | Journal of drug targeting
(J Drug Target)
2017 Nov - Dec
Vol. 25
Issue 9-10
Pg. 796-808
ISSN: 1029-2330 [Electronic] England |
PMID | 28726521
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents
- Drug Carriers
- Nitric Oxide Donors
- Polymers
- Nitric Oxide
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Topics |
- Animals
- Antineoplastic Agents
(administration & dosage, metabolism)
- Cell Line, Tumor
- Drug Carriers
(administration & dosage, metabolism)
- Female
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Nanoparticles
(administration & dosage, metabolism)
- Neoplasms, Experimental
(drug therapy, metabolism, pathology)
- Nitric Oxide
(metabolism)
- Nitric Oxide Donors
(administration & dosage, metabolism)
- Polymers
(administration & dosage, metabolism)
- Treatment Outcome
- Tumor Burden
(drug effects, physiology)
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