Introduction: Stimuli-responsive polymer particles are promising as smart carriers for self-regulated drug delivery because they undergo changes in the size in response to environmental stimuli such as pH and temperature. However few biologically stimuli-responsive particles that exhibit size changes in response to a target biomolecule have been prepared because of difficulties in converting molecular recognition events to responsive size changes. Using biomolecular complexes as dynamic crosslinks, we designed biologically stimuli-responsive hydrogels that were sensitive to target biomolecules such as antigens and tumor markers[1]-[4]. This paper describes synthetic methods to design biologically stimuli-responsive polymeric particles that undergo changes in the size in response to a target biomolecule or a pH/reducing environmental change.
Materials and Methods: Glucose-responsive polymeric particles were synthesized using complex formation between lectin concanavalin A (ConA) and glycopolymers as follows[3]. Acryloyl-modified ConA was mixed with 2-glucosyloxyethyl methacrylate (GEMA) to form a GEMA-ConA complex with polymerizable groups. The GEMA-ConA complexes were copolymerized with N, N-diethylaminoethyl methacrylate (DEAEMA) and poly(ethylene glycol) dimethacrylate (PEGDMA) by surfactant-free emulsion polymerization to obtain GEMA-ConA particles.
Dual stimuli-responsive polymeric particles that have both DEAEMA as a pH-sensitive moiety and a disulfide bond as a reductant-responsive crosslink were prepared by surfactant-free emulsion polymerization. Using cystamine bisacrylamide (CBA) as a reductant-responsive crosslinker, the CBA-DEAEMA particles were prepared by surfactant-free emulsion polymerization of DEAEMA, PEGDMA and CBA.
Results and Discussion: Swelling ratio of the GEMA-ConA particles gradually increased with an increase in glucose concentration, but the particles remained unchanged in the presence of galactose. Furthermore, the GEMA-ConA particles showed reversible swelling/shrinking behavior in response to stepwise changes in glucose concentration (Fig. 1). The reversibly glucose-sensitive swelling/shrinking behavior is attributed to the dissociation of GEMA-ConA complex crosslinks by complex exchanges between GEMA and free glucose.
The CBA-DEAEMA particles swelled drastically under acidic and reducing environment owing to both protonation of tertiary amino groups in DEAEMA and cleavage of disulfide bonds in CBA as a crosslink. Doxorubicin (Dox) as a hydrophobic anticancer drug was successfully loaded into the CBA-DEAEMA particles. The Dox release from Dox-loaded CBA-DEAEMA particles was inhibited at pH 7.4 without dithiothreitol (DTT) as a reductant. However, the Dox release was significantly enhanced by a decrease in pH and an addition of DTT (Fig. 2). These results indicate that the CBA-DEAEMA gel particles are promising as smart carriers for intracellular delivery.
Conclusion: Biologically stimuli-responsive polymer particles with dynamic crosslinks were designed by surfactant-free emulsion polymerization. The GEMA-ConA and CBA-DEAEMA particles underwent rapid changes in the size in response to glucose and reductant, respectively. The biologically stimuli-responsive particles are promising smart biomaterials for self-regulated DDS and sensor systems.
References:
[1] T. Miyata, N. Asami, T. Uragami, Nature, 399, 766 (1999).
[2] T. Miyata, M. Jige, T. Nakaminami, T. Uragami, Proc. Natl. Acad. Sci. USA, 103, 1190 (2006).
[3] A. Kawamura, Y. Hata, T. Miyata, T. Uragami, Colloids Surf. B: Biointerfaces, 99, 74 (2012).
[4] A. Kawamura, T. Kiguchi, T. Nishihata, T. Uragami, T. Miyata, Chem. Commun., 50, 11101 (2014).