Smart Magnetic Nanocarriers for Multi-Stimuli On-Demand Drug Delivery

Abstract

In this study, we report the realization of drug-loaded smart magnetic nanocarriers constituted by superparamagnetic iron oxide nanoparticles encapsulated in a dual pH- and temperature-responsive poly (N-vinylcaprolactam-co-acrylic acid) copolymer to achieve highly controlled drug release and localized magnetic hyperthermia. The magnetic core was constituted by flower-like magnetite nanoparticles with a size of 16.4 nm prepared by the polyol approach, with good saturation magnetization and a high specific absorption rate. The core was encapsulated in poly (N-vinylcaprolactam-co-acrylic acid) obtaining magnetic nanocarriers that revealed reversible hydration/dehydration transition at the acidic condition and/or at temperatures above physiological body temperature, which can be triggered by magnetic hyperthermia. The efficacy of the system was proved by loading doxorubicin with very high encapsulation efficiency (>96.0%) at neutral pH. The double pH- and temperature-responsive nature of the magnetic nanocarriers facilitated a burst, almost complete release of the drug at acidic pH under hyperthermia conditions, while a negligible amount of doxorubicin was released at physiological body temperature at neutral pH, confirming that in addition to pH variation, drug release can be improved by hyperthermia treatment. These results suggest this multi-stimuli-sensitive nanoplatform is a promising candidate for remote-controlled drug release in combination with magnetic hyperthermia for cancer treatment.

Keywords: controlled drug release; drug delivery; magnetic hyperthermia; magnetite nanoparticles; pH-responsive nanocarriers; thermo-responsive nanocarriers.

Figure 1

Schematic description of the smart magnetic nanocarriers, which offer drug loading capability and spatial and temporal control over the release of the drug.

Figure 2

X-ray diffraction pattern of Fe₃O₄ MNPs prepared by polyol method compared to the reference pattern of magnetite (red bars; PDF 65-3107) (a); TEM image of Fe₃O₄ MNPs (b) together with the size distribution (c) obtained from a statistical analysis over ca. 280 MNPs. The continuous red line represents the best-fit curve to a log-normal distribution.

Figure 3

TEM images of Fe₃O₄@ PVCL-co-PAA (sample A) at low (a) and higher magnification (b); TEM image of polymer before MNPs’ inclusion (c) (the scale is the same as (b)); Hydrodynamic diameter of MNPs and MNCs determined by DLS (d); FT-IR spectra of Fe₃O₄@PVCL-co-PAA (blue line), PVCL-co-PAA (red line), and uncoated Fe₃O₄ (green line) (e); TG curve of MNCs made up of Fe₃O₄ coated PVCL-co-PAA (f). For comparison, the TG curves of uncoated MNPs and polymer alone are also shown.

Figure 4

Room temperature field dependence of the magnetization of copolymer coated and uncoated MNPs measured in the field range ± 50 kOe (a) and enlargement of the low field region of the low temperature loop (b).

Figure 5

Hydrodynamic size variation of MNCs as a function of temperature, evaluated by DLS (a); zeta potential of MNCs as a function of pH measured by the dispersion of stimuli-responsive MNCs in buffer phosphate 10 mM; starting pH was 7.4 and was then adjusted with NaOH 0.1 M or HCl 0.1 M (b).

Figure 6

Release of DOX from DOX-MNCs at different pH values (7.4, 5.5, and 4.5) and temperatures (25 °C, 37 °C, and 48 °C); Standard deviation of triplicate drug release tests (n = 3) (a); Scheme of the drug release mechanisms operating in MNCs: gentle release caused by shrinkage of the temperature-responsive polymer under heating at neutral pH and intense release at pH 4.5 and 5.5 due to additional ruptures of the nanocarrier (b).

Figure 7

Cumulative DOX release of A^DOX_7.4 and A^DOX_5.5 for different exposure times to the AMF. Standard deviation of triplicate drug release tests (n = 3) (a); on–off switching cycles of AMF and DOX release profile corresponding to reversible swell–shrink property of samples B^DOX_7.4 and B^DOX_5.5 when applying an intermittent AMF (b).

Figure 8

Relative cell viabilities of A375 human melanoma cells incubated with different concentrations of MNCs (a), free DOX and DOX-MNCs (b) during 6 h incubation.

Figure 9

Confocal microscopy images of A375 melanoma (a) and MCF7 breast cancer cells (b) treated with vehicle (Control), MNCs, or DOX-MNCs for 6 h. The first row represents DOX fluorescent images, the second row the phase contrast microscopy images, and third row represent DOX overlay and merged images.

Figure 10

Relative cell viability and optical images of (a,b) A375 and (c,d) MCF7 cancer cells treated with vehicle (Control), MNC, or MNC@DOX for 24 h before and after AMF exposure. Error bars: mean ± SD. Statistical analysis was performed using one-way ANOVA followed by Newman–Keuls multiple comparison test. * p ≤ 0.05.