HPMA copolymer-based polymer conjugates for the delivery and controlled release of retinoids

0463658 - ÚMCH 2017 RIV CZ eng J - Článek v odborném periodiku
Lidický, Ondřej - Šírová, Milada - Etrych, Tomáš
HPMA copolymer-based polymer conjugates for the delivery and controlled release of retinoids.
Physiological Research. Roč. 65, Suppl. 2 (2016), S233-S241. ISSN 0862-8408. E-ISSN 1802-9973
Grant CEP: GA MŠk(CZ) LQ1604
Institucionální podpora: RVO:61389013 ; RVO:61388971
Klíčová slova: polymer conjugate * retinoid * HPMA
Kód oboru RIV: EB - Genetika a molekulární biologie; EA - Morfologické obory a cytologie (MBU-M)
Impakt faktor: 1.461, rok: 2016
http://www.biomed.cas.cz/physiolres/pdf/65%20Suppl%202/65_S233.pdf

In this paper, we describe the synthesis, physicochemical characterization, drug release kinetics and preliminary biological evaluation of several N-(2-hydroxypropyl)methacrylamide (HPMA)-based polymer-retinoid conjugates designed for solid tumor immunotherapy. The conjugates are supposed to inhibit the immunosuppressive activity of myeloid-derived suppressor cells (MDSC) accumulated in the solid tumor microenvironment. All-trans retinoic acid (ATRA) was derivatized to hydrazide (AtrHy) and then attached to the polymer backbone via a spacer that is stable at the normal pH of blood (7.4) and hydrolytically degradable in mildly acidic environments (e.g. in endosomes or lysosomes, pH~5.0-6.5). Polymer-AtrHy conjugates were designed to achieve prolonged blood circulation and release of the immunomodulator intracellularly or extracellularly in solid tumor tissue. Three types of polymer precursors, differing in the structure of the keto acid-containing side chains, were synthesized. A linkage susceptible to hydrolytic cleavage was formed by the conjugation reaction of the carbonyl groupterminated side chains of the polymer precursors with the hydrazide group of a drug derivative. In vitro incubation of the conjugates in buffers resulted in much faster release of the drugs or their derivatives from the polymer at pH 5.0 than at pH 7.4, with the rate depending on the detailed structure of the spacer. Both the AtrHy derivative and its polymer conjugates showed the ability to induce the differentiation of retinoid-responsive HL-60 cells, thus demonstrating the required biological activity.
Trvalý link: http://hdl.handle.net/11104/0264460