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Polyion-complex-coated biodegradable polymeric micelles exhibiting cell-specific uptake and dual-stimuli-responsive degradation

Yuichi Ohya1, 2, Yoshinori Morimoto1, Akihiro Takahashi2, Akinori Kuzuya1, 2 and Atsushi Maruyama3
  • 1 Kansai University, Department of Chemistry and Materials Engineering, Japan
  • 2 Kansai University, ORDIST, Japan
  • 3 Tokyo Institute of Technology, Graduate School of Bioscience and Biotechnology, Japan

Self-assembled block copolymer micelles have attracted great attention as nanometer scale drug delivery vehicles. Previously, we reported on the coating of positively charged micelles prepared from AB-type diblock copolymers poly(L-lysine) and PLLA, PLys+-b-PLLAs, with anionic hyaluronic acid (HA) by polyion complex (PIC) formation. The obtained HA-coated micelles showed extremely high stability against dilution in aqueous solution[1], and sustained release of drugs[2]. In this study, we tried to further functionalization of the micelle system by PIC coating. By repeating PIC coating of positively charged PLys+-b-PLLA micelles with anionic HA and cationic PLys to give multi-layer-coated micelles to provide drug delivery vehicles exhibiting dual-stimuli(two enzymes)-responsive drug release. On the other hand, galactose(Gal)-immobilized micelles were also prepared by coating PLys+-b-PLLA micelles with Gal-HA conjugate to exhibit cell-specific recognition. The potential utility of these obtained micelles as drug delivery vehicles were evaluated.

PLys+-b-PLLA micelle having positive charges on the surface was prepared by the methods previously reported[1]. Multilayer-coated micelles (MC-micelles) were obtained by repeating PIC formation of PLys+-b-PLLA micelle with HA and PLys (Figure1). HA-immobilized galactose (Gal-HA) was synthesized by the coupling reaction of HA with galactosyl-triethylenglycolamine (Gal-TEG-NH2).Gal-immobilized micelles (Gal-HA micelles) were prepared by drop-wise addition of aqueous PLys+-b-PLLA micelle solution into Gal-HA aqueous solution with vigorous stirring.

Dual-stimuli responsive degradation behavior of MC-micelles was investigated using hyaluronidase and trypsin. The MC-micelles showed significant degradation only in the presence of both hyaluronidase and trypsin. The cellular uptake of Gal-HA-coated micelles into HepG2 cells was investigated by confocal laser scanning microscopic (CLSM) analysis. The CLMS study revealed that Gal-HA-coated micelle could be specifically uptaken into HepG2 cells. So, the Gal-HA-coated micelle is expected to be applied as drug carriers having specific affinity to hepatoma cells.

These all results suggest that functionalization of biodegradable polymeric micelles can be achieved by coating various functional polymers via PIC formation. Such PIC-coated micelles system should be useful to prepare functional drug delivery vehicles.

References:
[1] Ohya, Y.; Takeda, S.; Shibata, Y.; Ouchi, T.; Maruyama, A.; Macromol. Chem. Phys., 2010,211, 1750-1756.
[2] Ohya, Y.; Takeda, S.; Shibata, Y.; Ouchi, T.; Kano, A.; Iwata, T.; Mochizuki, S.; Taniwaki, A.; Maruyama, A.; 2011, 155, 104-110.

Keywords: nanoparticle, Micelle, Polymeric material, targeting delivery

Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.

Presentation Type: Poster

Topic: Self-assembling micellar systems

Citation: Ohya Y, Morimoto Y, Takahashi A, Kuzuya A and Maruyama A (2016). Polyion-complex-coated biodegradable polymeric micelles exhibiting cell-specific uptake and dual-stimuli-responsive degradation. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.01123

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Received: 27 Mar 2016; Published Online: 30 Mar 2016.