Stimuli-Responsive Materials for Controlled Release of Theranostic Agents

Abstract

Stimuli-responsive materials are so named because they can alter their physicochemical properties and/or structural conformations in response to specific stimuli. The stimuli can be internal, such as physiological or pathological variations in the target cells/tissues, or external, such as optical and ultrasound radiations. In recent years, these materials have gained increasing interest in biomedical applications due to their potential for spatially and temporally controlled release of theranostic agents in response to the specific stimuli. This article highlights several recent advances in the development of such materials, with a focus on their molecular designs and formulations. The future of stimuli-responsive materials will also be explored, including combination with molecular imaging probes and targeting moieties, which could enable simultaneous diagnosis and treatment of a specific disease, as well as multi-functionality and responsiveness to multiple stimuli, all important in overcoming intrinsic biological barriers and increasing clinical viability.

Keywords: controlled release; smart carriers; stimuli-responsive materials; theranostics.

Figure 1

Schematic illustrations summarizing various stimuli employed for controlled release of therapeutic cargos following systemic administration. The therapeutic cargos can be selectively released in response to internal stimuli, including low pH, redox potential, oxidative stress, enzyme, and temperature, or external stimuli, including temperature (remote heating), light, ultrasound, magnetic field, and electronic field.

Figure 2

Schematic illustrations summarizing the major strategies that have been developed for constructing stimuli-responsive drug release systems.

Figure 3

a) Schematic illustration of the mechanism that uses PLGA HMs containing DOX and NaHCO₃ for pH-responsive drug release. b) SEM micrographs of PLGA HMs (prepared at a NaHCO₃ concentration of 2.5 mg mL⁻¹) after incubation in media with different pH values to mimic the extracellular environment (pH 7.4), early endosomes (pH 6.0), and lysosomes (pH 5.0), respectively. c) CLSM images showing the intracellular release of DOX from PLGA HMs after incubation with cells for 12 h. HMs-w/o-NaHCO₃: HMs containing no NaHCO₃; HMs-low-NaHCO₃: HMs prepared with NaHCO₃ at 1.25 mg mL⁻¹; HMs-high-NaHCO₃: HMs prepared with NaHCO₃ at 2.5 mg mL⁻¹. Reproduced with permission.^[53] Copyright 2011, Wiley-VCH.

Figure 4

a) Schematic illustration showing the performance of a drug-loaded, pH-responsive, charge-switchable PAMA-DMMA nanogel. In the acidic tumor extracellular environment, the nanogel is activated to become positively charged and is thus readily internalized by tumor cells with subsequent intracellular drug release. b, c) CLSM images of MDA-MB-435 cells incubated with the PAMA-DMMA nanogel at (b) pH 6.8 and (c) 7.4 for 2 h, respectively. d, e) CLSM images showing the distributions of (d) PAMA-DMMA and (e) non-pH-responsive PAMA-SA nanogels in the tumor tissue following intratumoral injection. The white arrows indicate the locations of the nanogels. Both nanogels were labeled with fluorescein isothiocyanate (FITC; green). In all CLSM images, the F-actin and nuclei of the cells were stained, respectively, with rhodamine phalloidin (red) and 4′,6-diamidino-2-phenylindole (DAPI; blue) Reproduced with permission.^[54] Copyright 2010, Wiley-VCH.

Figure 5

Schematic illustration showing the intracellular trafficking of redox-responsive nanoparticles for overcoming multidrug resistance of cancer cells.

Figure 6

Efficient Fas inhibition of hMSCs using B-PDA via redox-responsive dis-assembly of Fas siRNA/B-PDA polyplexes. The Fas-inhibited hMSCs can be formulated as enlarged spheroids (≥800 μm in diameter) for enhanced therapeutic angiogenesis. Reproduced with permission.^[64] Copyright 2012, Wiley-VCH.

Figure 7

Schematic illustration of ROS-responsive PATK for facilitated intracellular delivery of plasmid DNA in prostate cancer cells. After DNA/PATK polyplexes are internalized by a prostate cancer cell, DNA is efficiently released from the polyplexes due to ROS-triggered dis-assembly of the polyplexes, leading to efficient gene transfection. Reproduced with permission.^[72] Copyright 2013, Wiley-VCH.

Figure 8

a) Time-lapse fluorescence micrographs showing the melting of a 1-tetradecanol bead and thereby release of FITC-dextran from the gelatin particles as the temperature was gradually increased by adding warm water (60 °C) under gentle stirring. The insets are schematic diagrams showing the three major steps involved in the release of FITC-dextran: melting of 1-tetradecanol beads (30 s), release of gelatin particles (60 s), and release of FITC-dextran as gelatin is being dissolved (120 s). b) Release profiles at 37 and 39 °C for FITC-dextran from gelatin, chitosan, and PLGA microbeads encapsulated in 1-tetradecanol blocks (n=3).^[92] Copyright 2010, Wiley-VCH.

Figure 9

a) Decomposition reaction of ammonium bicarbonate (ABC) upon heating to 40 °C or above, which can quickly generate CO₂ bubbles. b) A schematic illustration showing the composition/structure of the thermo-sensitive, bubble-generating ABC liposomes and how they can be used to eradicate cancer cells by using the mechanical force from transient cavitation. c) Release profiles of calcein from ABC and phosphate buffered saline-containing liposome lacking ABC (PBS liposome) incubated at three different temperatures (n = 6). d) SEM micrographs of HT1080 cells before and after being treated with the ABC liposomes at 42 °C. Reproduced with permission.^[93] Copyright 2012, Wiley-VCH.

Figure 10

a) Schematic illustration of the release mechanism for AuNCs coated with a thermo-responsive copolymer of pNIPAAm-co-pAAm. b) Absorption spectra of alizarin-PEG released from the copolymer-covered AuNCs upon exposure to a pulsed NIR laser (power density = 10 mW/cm²) for 1, 2, 4, 8, and 16 min. The inset shows the accumulated concentrations of alizarin-PEG released from the copolymer-covered AuNCs. c) Cell viability plots for samples after different treatments: (C-1) cells irradiated with a NIR laser for 2 min in the absence of AuNCs; (C-2) cells irradiated with the NIR laser in the presence of DOX-free AuNCs; and (2 min and 5 min) cells irradiated with the NIR laser for 2 and 5 min in the presence of DOX-loaded AuNCs. Reproduced with permission.^[101] Copyright 2009, Nature Publishing Group.

Figure 11

a) Schematic illustration showing how to load the hollow interior of a AuNC with a dye-doped PCM and then have it released from the AuNC through direct or ultrasonic heating. b) Release profiles of rhodamine 6G under direct heating to various temperatures for different periods of time. c) Release profiles of rhodamine 6G via high-intensity focused ultrasound (HIFU) at different powers. Reproduced with permission.^[107] Copyright 2011, American Chemical Society.