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. 2017 Mar 31:12:2607-2620.
doi: 10.2147/IJN.S133078. eCollection 2017.

Photothermal-modulated drug delivery and magnetic relaxation based on collagen/poly(γ-glutamic acid) hydrogel

Sun-Hee Cho  1 , Ahreum Kim  1 , Woojung Shin  2 , Min Beom Heo  1 , Hyun Jong Noh  1 , Kwan Soo Hong  3   4 , Jee-Hyun Cho  3   4 , Yong Taik Lim  1   2
Affiliations

Photothermal-modulated drug delivery and magnetic relaxation based on collagen/poly(γ-glutamic acid) hydrogel

Sun-Hee Cho et al. Int J Nanomedicine. .

Abstract

Injectable and stimuli-responsive hydrogels have attracted attention in molecular imaging and drug delivery because encapsulated diagnostic or therapeutic components in the hydrogel can be used to image or change the microenvironment of the injection site by controlling various stimuli such as enzymes, temperature, pH, and photonic energy. In this study, we developed a novel injectable and photoresponsive composite hydrogel composed of anticancer drugs, imaging contrast agents, bio-derived collagen, and multifaceted anionic polypeptide, poly (γ-glutamic acid) (γ-PGA). By the introduction of γ-PGA, the intrinsic temperature-dependent phase transition behavior of collagen was modified to a low viscous sol state at room temperature and nonflowing gel state around body temperature. The modified temperature-dependent phase transition behavior of collagen/γ-PGA hydrogels was also evaluated after loading of near-infrared (NIR) fluorophore, indocyanine green (ICG), which could transform absorbed NIR photonic energy into thermal energy. By taking advantage of the abundant carboxylate groups in γ-PGA, cationic-charged doxorubicin (Dox) and hydrophobic MnFe2O4 magnetic nanoparticles were also incorporated successfully into the collagen/γ-PGA hydrogels. By illumination of NIR light on the collagen/γ-PGA/Dox/ICG/MnFe2O4 hydrogels, the release kinetics of Dox and magnetic relaxation of MnFe2O4 nanoparticles could be modulated. The experimental results suggest that the novel injectable and NIR-responsive collagen/γ-PGA hydrogels developed in this study can be used as a theranostic platform after loading of various molecular imaging probes and therapeutic components.

Keywords: drug delivery; hydrogel; magnetic nanoparticles; near-infrared; photothermal.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Rheological properties of collagen/γ-PGA hydrogel. Notes: (A) Viscosities and photographs of collagen only and collagen/γ-PGA complex at 25°C. (B) Viscosities and photographs of collagen/γ-PGA complex at 25°C, 37°C, and 42°C. Abbreviation: γ-PGA, poly(γ-glutamic acid).
Figure 2
Figure 2
Effect of different concentrations of urea (hydrogen bonding inhibitor) on stability of collagen/γ-PGA hydrogels. Note: Stability of collagen/γ-PGA hydrogels was measured at ambient temperature. Abbreviations: γ-PGA, poly(γ-glutamic acid); PBS, phosphate-buffered saline.
Figure 3
Figure 3
SEM images of (A) collagen only and (B) collagen/γ-PGA hydrogels after gelation at 37°C for 30 min. Notes: Scale bar represents 100 µm. Magnification ×250. Abbreviations: SEM, scanning electron microscopy; γ-PGA, poly(γ-glutamic acid).
Figure 4
Figure 4
Fluorescence recovery of ICG in collagen/γ-PGA/ICG hydrogels after irradiation with NIR laser. Notes: The inset of the left panel is a photograph of collagen/γ-PGA/ICG (collagen/γ-PGA hydrogels containing ICG) before and after irradiation with an NIR laser. Right panel is schematic illustration of mechanism of fluorescence recovery of ICG in collagen/γ-PGA/ICG hydrogels after irradiation with an NIR laser. Abbreviations: ICG, indocyanine green; γ-PGA, poly(γ-glutamic acid); NIR, near-infrared; T, temperature.
Figure 5
Figure 5
In vivo temperature change in mice injected with collagen/γ-PGA/ICG hydrogel after irradiation with an NIR laser. Notes: Temperature in mice injected with collagen/γ-PGA/ICG hydrogels before and after irradiation with an NIR laser. The concentrations of ICG in the hydrogels were 0, 10, and 100 µg/mL respectively. Abbreviations: γ-PGA, poly(γ-glutamic acid); ICG, indocyanine green; NIR, near-infrared.
Figure 6
Figure 6
Photothermal-modulated release profile of (A) Dox and (B) GM-CSF from collagen/γ-PGA hydrogel. Note: • = release profile at 37°C, = release profile after photothermal treatment. Abbreviations: Dox, doxorubicin; GM-CSF, granulocyte-macrophage colony-stimulating factor; γ-PGA, poly(γ-glutamic acid).
Figure 7
Figure 7
Phase transition and change in MR properties of collagen/γ-PGA/MnFe2O4 hydrogels. Notes: (A) Photographs of phase transition for collagen/γ-PGA/MnFe2O4 hydrogel. Photographs were obtained in vials and NMR tubes. (B) Resonance-selective discrimination of MR images for collagen/γ-PGA and collagen/γ-PGA/MnFe2O4 hydrogels with temperature increase. Inner area indicates collagen/γ-PGA hydrogel without MnFe2O4 and outer area indicates collagen/γ-PGA/MnFe2O4 hydrogel. MR imaging experiment was performed on a 600 MHz NMR spectrometer. (C) Schematic illustration of the change in T2 relaxation time due to phase transition of collagen/γ-PGA/MnFe2O4 hydrogel with temperature increase. Abbreviations: MR, magnetic resonance; γ-PGA, poly(γ-glutamic acid); NMR, nuclear magnetic resonance; TE, echo time.
Figure 8
Figure 8
In vivo T2 brightening effect of collagen/γ-PGA/ICG/MnFe2O4 hydrogels. Notes: (A) In vivo photothermal-modulated change of MR image for mice injected with collagen/γ-PGA/ICG/MnFe2O4 hydrogels. In each image after injection of hydrogel, left circle area indicates part without NIR laser irradiation and right circle area indicates part with NIR laser irradiation. (B) T2 relaxation time of part injected with collagen/γ-PGA/ICG/MnFe2O4 hydrogels with or without irradiation of NIR laser. Abbreviations: γ-PGA, poly(γ-glutamic acid); ICG, indocyanine green; MR, magnetic resonance; NIR, near-infrared; TE, echo time.
Scheme 1
Scheme 1
Schematic illustrations of the fabrication and photothermal-modulating strategy of injectable collagen/γ-PGA/Dox/ICG/MnFe2O4 hydrogels. Notes: Collagen/γ-PGA hydrogels containing MnFe2O4, Dox, and ICG (collagen/γ-PGA/Dox/ICG/MnFe2O4 hydrogels) were fabricated by mixing collagen solution and γ-PGA solution containing γ-PGA-coated MnFe2O4, Dox, and ICG. Collagen/γ-PGA/Dox/ICG/MnFe2O4 complexes were easy to inject using a syringe and formed hydrogels after injection into the body. Following hydrogel formation, collagen/γ-PGA/Dox/ICG/MnFe2O4 hydrogels were disrupted after irradiation with an NIR laser. This resulted in the release of Dox, ICG, and MnFe2O4 from the hydrogels. Abbreviations: γ-PGA, poly(γ-glutamic acid); Dox, doxorubicin; ICG, indocyanine green; NIR, near-infrared; PBS, phosphate-buffered saline; T, temperature.
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