Injectable Thermoresponsive Microparticle/Hydrogel System with Superparamagnetic Nanoparticles for Drug Release and Magnetic Hyperthermia Applications

Abstract

Cancer is a disease that continues to greatly impact our society. Developing new and more personalized treatment options is crucial to decreasing the cancer burden. In this study, we combined magnetic polysaccharide microparticles with a Pluronic thermoresponsive hydrogel to develop a multifunctional, injectable drug delivery system (DDS) for magnetic hyperthermia applications. Gellan gum and alginate microparticles were loaded with superparamagnetic iron oxide nanoparticles (SPIONs) with and without coating. The magnetic microparticles' registered temperature increases up to 4 °C upon the application of an alternating magnetic field. These magnetic microparticles were mixed with drug-loaded microparticles, and, subsequently, this mixture was embedded within a Pluronic thermoresponsive hydrogel that is capable of being in the gel state at 37 °C. The proposed DDS was capable of slowly releasing methylene blue, used as a model drug, for up to 9 days. The developed hydrogel/microparticle system had a smaller rate of drug release compared with microparticles alone. This system proved to be a potential thermoresponsive DDS suitable for magnetic hyperthermia applications, thus enabling a synergistic treatment for cancer.

Keywords: Pluronic; hydrogels; microparticles; rheology.

Figure 1

TEM analysis of (a) SPIONs and (b) SPIAPTS and their respective distribution in (c,d).

Figure 2

Adsorption efficiency (a) and adsorption capacity of SPIONs (b) in microparticles with and without APTES coating and at different nanoparticle concentrations (1, 2.5, and 5 mg/mL). Levels with statistically significant differences are presented by *, ** and *** above the bars (ANOVA, p < 0.05).

Figure 3

SEM analysis (a) and EDX analysis (b) of the surface of a microparticle loaded with SPIONs. In Figure (b), the reddish zones depict the presence of iron, and the green zones represent the presence of calcium. Microscopy analysis of (c) microparticles loaded with SPIONs and (d) microparticles loaded with SPIAPTS.

Figure 3

SEM analysis (a) and EDX analysis (b) of the surface of a microparticle loaded with SPIONs. In Figure (b), the reddish zones depict the presence of iron, and the green zones represent the presence of calcium. Microscopy analysis of (c) microparticles loaded with SPIONs and (d) microparticles loaded with SPIAPTS.

Figure 4

(a) Thermal gravimetry analysis of GG:Alg microparticles with and without mNPs with different concentrations; (b) Fourier-transform infrared spectroscopy of the microparticles with and without mNPs (SPIONs and SPIAPTS made with 5 mg/mL); (c) DRX of microparticle-loaded mNPs (SPIONs and SPIAPTS made with 5 mg/mL).

Figure 5

(a) Swelling ratio in PBS (pH 6.5) with and without mNPs (microparticles submerged in suspensions of 5 mg/mL of mNPs); (b) Degradation (mass loss) of microparticles with and without mNPs.

Figure 6

Vero cell viability (%) after 48 h of indirect exposure to the developed microparticles with and without mNPs (GG:Alg). Microparticles that were submerged in different concentrations of mNPs (1, 2.5, and 5 mg/mL) were analyzed. Data are expressed as the mean ± standard deviation of at least four experiments. C− is the negative control (no medium alterations), and C+ is the positive control (medium with 10 μL of DMSO). Levels with statistically significant differences are presented by *; ** and *** above the bars (ANOVA, p < 0.05).

Figure 7

(a) Temperature ramp in oscillation for Pluronic systems (F127:F68—17:3) with and without microparticles. The samples with just GG:Alg refer to samples without mNPs, and the samples with GG:Alg/SPIONs and GG:Alg/SPIAPTS refer to systems with mNPs (a ratio of 1:1 of GG:Alg and GG:Alg/mNPs); (b) frequency sweep tests at 37 °C for similar systems (with 5 w/v% of microparticles with and without mNPs); (c) tg(δ) of the analyzed systems in (b), where a line on 0.2 was put to mark the threshold between soft gel and non-soft gel; (d) flow curves at 21 °C of a similar system with 5 w/v% of microparticles within the Pluronic with and without mNPs).

Figure 8

Pluronic hydrogel with GG:Alg microparticles (2 wt.%) loaded with SPIONs (GG:Alg/SPIONs) at (a) 21 °C and (b) 37 °C.

Figure 9

Magnetic hyperthermia study: temperature variation with the application of an alternating magnetic field (300 Gauss and 388.5 kHz) (microparticle/hydrogel system with 5 w/v%).

Figure 10

Release profiles of GG:Alg microparticles loaded with MB within a Pluronic hydrogel and with GG:Alg microparticles loaded with mNPs (the ratio of microparticles with MB and microparticles with mNPs is 1:1).

Figure 11

Scheme of the production of the DDS. The iron oxides used were Fe²⁺ and F³⁺.