Double stimuli-responsive polymer systems: How to use crosstalk between pH- and thermosensitivity for drug depots. (November 2016)

• Record Type: Journal Article
• Authors: Bogomolova, A.; Kaberov, L.; Sedlacek, O.; Filippov, S.K.; Stepanek, P.; Král, V.; Wang, X.Y.; Liu, S.L.; Ye, X.D.; Hruby, M.
• Is Part Of: European polymer journal. Volume 84(2016:Nov.)
• Page Start: 54
• Page End: 64
• Publication Date: 2016-11
• Subjects: Drug depot formulation -- Double responsive system -- pH-responsive polymer -- Thermoresponsive polymer; Polymers -- Periodicals; Polymerization -- Periodicals; Polymères -- Périodiques; Polymérisation -- Périodiques; Polymerization; Polymers; Periodicals; Electronic journals; 547.705
• DOI: 10.1016/j.eurpolymj.2016.09.010
• Languages: English
• ISSNs: 0014-3057

Abstract

Graphical abstract: Strategy for a depot drug delivery application using a simultaneous response to changes in temperature and pH. Highlights: The described acrylamide-type copolymers show double pH- and thermoresponsivity. Crosstalk between thermo- and pH-responsivity efficiently helps forming drug depot. Thermoresponsive copolymer efficiently controls drug release rate in vivo. Abstract: We describe a new approach to depot drug delivery in which a copolymer poly[ N -isopropyl acrylamide- co - N -(3-imidazolylpropyl)methacrylamide] (PNIPAM- co -ImPM) is considered as the main object and matrix for a new formulation strategy that provides the controlled and sustained release of an incorporated drug. The relatively low content of ImPM groups (1.6 mol%) was determined to be sufficient to introduce pH-sensitive behavior to the polymer. Together with NIPAM units, which possess a thermo-sensitive behavior, a dual sensitivity was imparted to the polymer that was investigated by means of turbidimetry and dynamic light scattering. A change in pH from 9 down to 4 was observed to result in the increase of the polymer transition temperature from 32 to 70 °C. The separation process is also accompanied with the formation of ca. 150–300 nm particles while above the transition temperature. The pH value of approximately 6.5 was defined as a boundary value, where certain properties of the system significantly change. This observation assumes a potential attractiveness of the system for biological applications in which injection is possible using a liquid form at pH ca. 5 without the risk of injection needle obstruction. In this way, a depot is formed at the application site upon simultaneously heating to body temperature and increasing the pH to the physiological value of 7.4. An in vivo experiment using the polymer in PBS (pH = 5.0) with paliperidone as a model drug showed excellent results regarding the release of the drug from a depot. The putative mechanism of action for our depot system is thoroughly described in the article.