Smart microcapsules for direction-specific burst release of hydrophobic drugs

Abstract

A novel type of monodisperse dual magnetic and thermo-responsive microcapsule, which is composed of a thermo-responsive microgel shell and an eccentric magnetic core as well as an eccentric oil core, is developed for site-specific targeted delivery and direction-specific controlled release of hydrophobic substances. The microcapsules are fabricated with microfluidic-prepared quadruple-component (oil 1 + oil 2)-in-water-in-oil ((O1 + O2)/W/O) double emulsions as templates. The poly(N-isopropylacrylamide) (PNIPAM) microgel shell of the microcapsule can protect the encapsulated hydrophobic drugs at temperatures lower than the lower critical solution temperature (LCST), and achieve the burst release of drugs when the environmental temperature is increased higher than the LCST. The eccentric oil core provides a large inner volume for encapsulation of hydrophobic drug molecules, while the eccentric magnetic core makes the microcapsule able to achieve not only magnetically-guided translational movement for site-specific targeting but also magnetically-guided rotational motion for direction-specific controlled release. The results show that the microcapsules are efficient carriers for site-specific targeted delivery and direction-specific burst release of hydrophobic substances. For the first time our novel microcapsules enable precise “aiming” before “firing”, which is highly desired but was unavailable before.

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Introduction

Recently, significant progress has been made in the field of multi-functional microcapsules. Because of their controllable features, such as size, shape, morphology, or reliable response to various external or internal stimuli, multi-functional microcapsules have numerous applications in a wide range of fields including encapsulation and controlled release of drugs, protection of active species, environmental sensors, microreactors, etc.^1–7 In these applications, microencapsulation of drugs has attracted great attention because of its capability of masking unpleasant drug tastes and odors, in controlled release of drugs, in protecting drugs from undesirable degradation, and in increasing therapeutic efficiency and decreasing side effects.^2,6,8 Ideal microcapsules used for encapsulation and controlled release of drugs should have a membrane that effectively captures and retains drugs within the core and possesses excellent specificity for triggered release at the right moment and right place by the target stimulus, such as temperature,^9–32 pH,^{8,10,11,33–36} light,^12,37–40 magnetic field,^13–15,17 and metal ions.³² As temperature is an important factor that can be easily controlled, and certain temperature change can be used as the trigger stimulus for drug release since the normal temperature in human body is always constant.⁹ Targeted drug delivery system, which is preferred to increase the efficiency of drug delivery to specific tissues as well as to decrease side effects, can be achieved easily by magnetic targeting.^10,31 Therefore, design and development of microcapsules with dual thermo- and magnetic-responsive properties for controlled release of drugs are of great significance.

In the last decade, a series of dual thermo- and magnetic-responsive microcapsules have been developed by incorporation of superparamagnetic Fe₃O₄ nanoparticles (MNPs) into thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) based materials for controlled release of drugs.^16–31 According to the hydrophilic and hydrophobic nature of encapsulated drugs, the thermo- and magnetic-responsive microcapsules can be classified into the following two categories. One is used for encapsulation and controlled release of hydrophilic drugs, and the other one is used for encapsulation and controlled release of hydrophobic drugs. For encapsulation and controlled release of hydrophilic drugs, the thermo- and magnetic-responsive microcapsule can be classified into two main types further. One type is prepared by incorporating MNPs into non-responsive porous microcapsule membrane first, and then by grafting PNIPAM chains into the membrane pores as thermo-responsive gates for controlled release.¹⁶ The other type is fabricated by incorporating MNPs into thermo-responsive PNIPAM microgel directly or by coating PNIPAM microgel onto the MNPs.^17–30 The release mechanisms of these microcapsules mainly rely on the deswelling/swelling properties of the PNIPAM chains or membranes themselves induced by temperature increase/decrease, which make it nearly impossible for these microcapsules to achieve controlled release of drug in a specific direction. It is worth noting that, currently available anticancer drugs such as paclitaxel and carmustine are usually hydrophobic molecules. Therefore, design of carriers for hydrophobic drugs is of great importance. The thermo- and magnetic-responsive microcapsules for encapsulation and controlled release of hydrophobic drugs are usually fabricated by using O/W/O double emulsions as templates.³¹ Such microcapsules can be site- and/or route-specifically delivered to a desired site with the help of an external magnetic field at temperatures below the lower critical solution temperature (LCST). At desired site, the inner oil cores can be burst-released from the microcapsules at a high speed by increasing the environmental temperature above the LCST. Nevertheless, the uniformly dispersed MNPs in the microcapsule membrane can only achieve targeted delivery while cannot achieve controllable rotational motion of the microcapsules themselves, which restricts their application in direction-specific release of drugs. Actually, direction-specific release of drug can effectively decrease side effects and increase bioavailability in a maximum extent.^39,40 Therefore, development of thermo- and magnetic-responsive microcapsules for targeted delivery and direction-specific release of hydrophobic drugs is of both scientific and technological importance.

In this study, we report on a dual thermo- and magnetic-responsive microcapsule with multi-functional property of encapsulation, targeted delivery and controllable direction-specific burst release of hydrophobic drugs. The proposed microcapsule is a magnetic PNIPAM core–shell microcapsule, which is composed of a thermo-responsive PNIPAM microgel shell, an oil core and an eccentric magnetic core. The microcapsule is fabricated by solvent evaporation and UV-initiated polymerization of microfluidic-prepared (O1 + O2)/W/O quadruple-component double emulsion template.^41,42 The PNIPAM shell can protect the encapsulated drugs at lower temperature, and achieve the controllable release of hydrophobic drug when the environmental temperature is higher than the LCST. The oil core provides large inner volume for encapsulation of hydrophobic drugs. The eccentric magnetic core makes it possible for the microcapsule to not only achieve the targeted delivery but also achieve the direction-specific controlled release of encapsulated drugs with proper magnetic operation.^42–44 That is, once the magnetic PNIPAM core–shell microcapsules are delivered to a desired site, the encapsulated hydrophobic drugs can be burst-released from the microcapsule in a controllable specific direction under dual thermal and magnetic stimuli. The proposed magnetic PNIPAM core–shell microcapsule is a very efficient and promising carrier for controllably targeted delivery as well as direction-specific burst release of hydrophobic substances.

Experimental section

Materials

Monomer N-isopropylacrylamide (NIPAM, TCI) is purified by recrystallization with a hexane–acetone mixture (v/v, 50/50). N,N′-Methylenebisacrylamide (MBA) is used as the cross-linker. 2,2′-Azobis(2-amidi-nopropanedihydrochloride) (V50) and 2,2-dimethoxy-2-phenylacetophenone (BDK) are respectively used as the initiators dissolved in aqueous phase and oil phase. Pluronic F-127 (Sigma-Aldrich) and polyglycerol polyricinoleate (PGPR 90) (Danisco, Denmark) are respectively used as the emulsifiers for aqueous phase and oil phase. Lumogen® F Red 300 (LR300, BASF) is used as the hydrophobic model drug. Oleic acid (OA) is used to modify the MNPs. All other reagents are of analytical grade and used as received. De-ionized (DI) water from a Milli-Q Plus water purification system (Millipore) is used throughout the experiments.

Microfluidic device

Capillary microfluidic device is fabricated by assembling glass capillary tubes on glass slides, as illustrated in Fig. 1a. The cylindrical capillaries of the injection tube 1, injection tube 2, transition tube 1, transition tube 2, transition tube 3, and collection tube have inner diameters of 550, 550, 150, 150, 250, and 450 μm, respectively. The outer diameters of all cylindrical capillaries are 1.0 mm, which is the same as the inner dimension of the square capillary tubes. The front-ends of injection tube 1, injection tube 2, and transition tube 3 are tapered by a micropuller (Narishige) and then adjusted by a microforge (Narishige) with inner diameters at 50, 50, and 180 μm, respectively. Briefly, the tapered ends of the injection tubes 1 and 2 are inserted into the transition tubes 1 and 2 respectively, which are then linked with the transition tube 3 to form a Y-shaped connector. Then, the outlet of the transition tube 3 is inserted into the collection tube. All cylindrical capillaries are coaxially aligned within the square capillary tubes by matching the outer diameters of the cylindrical tubes to the inner dimensions of the square ones. Finally, transparent epoxy resin is used to seal the tubes where required to fabricate the microfluidic device.

Fig. 1 Schematic illustration of the fabrication process of magnetic PNIPAM core–shell microcapsules. (a) Microfluidic device for generating (O1 + O2)/W/O double emulsions, where fluid O1 is an oil that contains emulsifier, initiator and model drug LR300, fluid O2 is a mixture of hexane and butyl acetate containing dispersed Fe₃O₄ magnetic nanoparticles (MNPs), fluids W1 and W2 are aqueous phases that contain the emulsifier, monomer, initiator and crosslinker, fluid O is an oil that contains a surfactant and initiator. Illustrations A–A, B–B, C–C, D–D and E–E are cross-section images of the capillary microfluidic device in relevant positions, which clearly show how the square capillary tubes and cylindrical tubes are assembled in the device. (b and c) Solvent evaporation process for constructing the eccentric solid magnetic core. (d) UV-initiated polymerization of the emulsion template for fabricating magnetic PNIAPM core–shell microcapsules.

Preparation of oleic acid modified magnetic nanoparticles (OA–MNPs)

To be well dispersed in cyclohexane and butyl acetate to form the solid magnetic core in each microcapsule, Fe₃O₄ MNPs are modified by OA.^31,42 Briefly, after obtaining Fe₃O₄ MNPs, OA (6 g), which is preheated at 60 °C for 5–10 min, is added into the MNPs drop by drop and mixed at 60 °C for another 20 min. The obtained OA–MNPs are washed with ethanol (100 mL) to remove the excess OA, and then separated by a magnet. By adding cyclohexane into the OA–MNPs dropwise under stirring, ferrofluid is obtained. The obtained ferrofluid is preserved for further use.

Preparation of magnetic PNIPAM core–shell microcapsules

The magnetic PNIPAM core–shell microcapsules are prepared from quadruple-component (O1 + O2)/W/O double emulsions. Typically, soybean oil containing PGPR 90 (2% (w/v)), BDK (0.25% (w/v)) and LR300 (0.5% (w/v)) is used as the inner oil phase 1 (O1). Ferrofluid (1 mL) dispersed in a mixed solvent of cyclohexane and butyl acetate (4 mL) with the volume ratio of 1 : 1 is used as the oil phase 2 (O2). NIPAM (1 mol L⁻¹), MBA (0.05 mol L⁻¹), Pluronic F-127 (1 wt%) and V50 (0.5 wt%) are dissolved in deionized water as the middle aqueous phases (W1 and W2). PGPR 90 (10% (w/v)) and BDK (0.25% (w/v)) dispersed in soybean oil is used as the outer oil phase (O). All solutions are supplied to the device through polyethylene tubing attached to syringes operated by syringe pumps (LSP01-1A, Baoding Longer Precision Pump), with the flow rates of O1, O2, W1, W2 and O being 150, 200, 450, 600, and 5000 μL h⁻¹, respectively (Fig. 1a). The generated monodisperse (O1 + O2)/W/O double emulsions are collected in a collection solution of soybean oil containing PGPR 90 (10% (w/v)) and BDK (0.25% (w/v)) (Fig. 1b). Then, the double emulsions are kept for about 2 h to allow evaporation of ethyl acetate and cyclohexane in the magnetic oil droplets (O2) for constructing the solid magnetic core (Fig. 1c). The middle aqueous phase of the double emulsions is converted into hydrogel networks by UV-initiated polymerization for 10 min in an ice-water bath. A 250 W UV lamp with an illuminance spectrum of 250–450 nm is employed to produce UV light. The solid magnetic core and soybean oil core loading with LR300 are encapsulated inside the magnetic PNIPAM core–shell microcapsule after polymerization (Fig. 1d).

Characterization

The morphology and size of OA–MNPs are characterized by transmission electron microscopy (TEM, JEM-100CX, JEOL). The componential analyses of samples are carried out by using Fourier transform infrared spectroscope (FTIR, IR prestige-21, Shimadzu) in the range of 4000–400 cm⁻¹ with KBr disc technique. A vibrating-sample magnetometer (7400, Lakeshore) is used to study the magnetic property of the OA–MNPs and the magnetic PNIPAM microcapsules. The (O1 + O2)/W/O double emulsion templates and the resultant magnetic PNIPAM core–shell microcapsules are observed by an optical microscope (BX61, Olympus) and a confocal laser scanning microscope (CLSM, Leica SP5-II) with excitation at approximately 488 nm. Magnetic-induced movement of the magnetic PNIPAM core–shell microcapsules is performed with a cylindrical NdFeB magnet (size: Ø 4 mm × 10 mm). Thermogravimetric analysis measurement (TGA, TG209F1, Netzsch) is performed with a heating rate of 10 °C min⁻¹ from 30 to 800 °C under a nitrogen atmosphere. Temperature-responsive volume change of the magnetic PNIPAM microcapsules and thermo-triggered release of hydrophobic drugs in deionized water are observed and recorded by an optical microscope equipped with a thermostatic stage system (TS 62, Instec) and a CCD camera.

Results and discussion

Characterization of OA–MNPs

The morphology and distribution of OA–MNPs are observed by TEM. The prepared OA–MNPs disperse quite well in cyclohexane due to the modification of OA, which is essential for fabrication of magnetic oil droplets in microfluidic device. The mean diameter of OA–MNPs is about 12 nm (Fig. 2a). FT-IR analyses are performed to determine the chemical compositions of OA, MNPs and OA–MNPs (Fig. 2b). The characteristic absorption peaks of OA (b1), which include peaks at 2926.01 cm⁻¹ and 2854.65 cm⁻¹ for CH₂ asymmetric and symmetric stretch, also appear in the spectra of OA–MNPs (b3). It is worth noting that the C=O stretch band of the carboxyl group, which is presented at 1710.86 cm⁻¹ in the FT-IR spectrum of pure OA (b1), is absent in the spectrum of OA–MNPs (b3). Instead, two new bands at 1525.69 cm⁻¹ and 1423.47 cm⁻¹ appear in b3 (Fig. 2b), which are characteristic peaks of COO⁻ asymmetric and symmetric stretch. The characteristic absorption band of Fe₃O₄ at 582.50 cm⁻¹ (b2) also appears in the spectra of OA–MNPs (b3). The results confirm that OA is chemisorbed as a carboxylate onto the surface of Fe₃O₄ nanoparticles. The magnetization hysteresis loop of OA–MNPs at room temperature is shown in Fig. 2c. The saturation magnetization (M_s) of OA–MNPs is 63.49 emu g⁻¹. The hysteresis and coercivity are almost undetectable, which suggests that the superparamagnetic property of OA–MNPs is satisfactory.

Fig. 2 Characterization of magnetic nanoparticles (MNPs). (a) TEM image of oleic acid modified magnetic nanoparticles (OA–MNPs). (b) FT-IR spectra of OA (b1), MNPs (b2), and OA–MNPs (b3). (c) Magnetization hysteresis loop of OA–MNPs at room temperature.

Fabrication of monodisperse (O1 + O2)/W/O emulsions and magnetic PNIPAM core–shell microcapsules

Template synthesis results of magnetic PNIPAM core–shell microcapsules from (O1 + O2)/W/O double emulsions are shown in Fig. 3. The optical micrograph of the prepared (O1 + O2)/W/O quadruple-component double emulsions collected in a vessel at about 11 min after formation is shown in Fig. 3a. The emulsions are highly monodisperse and quite stable, and the number of red oil droplet and black magnetic droplet in each double emulsion is strictly limited to one. The generated emulsions are kept for about 1.8 h to allow solvent evaporation of the butyl acetate and cyclohexane in the magnetic droplet, resulting in a decrease of size and an increase of density of the magnetic droplet (Fig. S1†). Because the density increases with solvent evaporating, the magnetic droplet sinks in the middle aqueous phase (Fig. S1f†). After solvent evaporation, the heavier solid magnetic core sink to the bottom of the double emulsion, and the lighter red oil droplet float to the top of the double emulsion. Then, UV light is used to initiate the polymerization in the middle aqueous solution of the emulsions to fabricate the PNIPAM microgel shell. After the solvent evaporation and UV-initiated polymerization, the solid magnetic core and oil droplet encapsulated in the PNIPAM microgel shell is always on the opposite direction because of density difference in the emulsion template (Fig. 3b). The polymerized magnetic PNIPAM core–shell microcapsules are then separated from the oil phase and redispersed in deionized water.

Fig. 3 Template synthesis of magnetic PNIPAM core–shell microcapsules from (O1 + O2)/W/O double emulsions. (a–c) Optical micrographs of the emulsion templates used for synthesis of magnetic PNIPAM core–shell microcapsules at about 11 min after formation (a), and the resultant magnetic PNIPAM core–shell microcapsules in soybean oil (b) and in deionized water with an external magnet guiding (c) at room temperature. (d) CLSM image of the resultant magnetic PNIPAM core–shell microcapsules in deionized water at 25 °C. Scale bars are 200 μm.

The optical micrograph of the resultant magnetic PNIPAM core–shell microcapsules in deionized water at room temperature is shown in Fig. 3c. Because of density difference, the solid magnetic core is always down and the soybean oil core is always up in deionized water. To visualize the structure of the microcapsules in deionized water clearly, an external magnet is used to guide the rearrangement of the magnetic PNIPAM core–shell microcapsules (Fig. 3c). All the microcapsules are highly monodisperse. Actually, the thickness of microcapsule membrane is not uniform along the circumference as clearly shown in Fig. 3b and c. The thickness of the polymerized hydrogel membrane is much thicker on one side but much thinner on the other side of the core–shell microcapsule, and the thinnest membrane is always on the opposite direction of the solid magnetic core (Fig. 3c) because of density difference in the emulsion template. The CLSM image of the resultant magnetic PNIPAM core–shell microcapsules in deionized water at 25 °C (Fig. 3d) illustrates that no leakage of hydrophobic drug from the prepared microgel capsule is observed. Because the encapsulated hydrophobic drugs trapped in the oil phase inside the microcapsule are immiscible with or insoluble in aqueous solutions, there is no way for them to pass through the hydrophilic PNIPAM shell via solution/diffusion when the temperature is below the LCST, although the concentration gradient exists between inside and outside of the microcapsule. Therefore, when the microcapsules are stored, transported, or delivered at temperatures below the LCST, there is no leakage of encapsulated hydrophobic drugs from the microcapsules.

Magnetic-responsive characteristics of the magnetic PNIPAM core–shell microcapsules

The movement of the magnetic PNIPAM core–shell microcapsules carried out in a homemade glass holder can be controlled remotely due to the magnetic core (Fig. 4a and Movie S1 in the ESI†). A magnet is placed on the right near the glass holder and moved manually to guide the movement of the microcapsule. When the microcapsule with an eccentric magnetic core is placed in an external magnetic field, it aligns in such a way that the magnetic hemisphere faces toward the magnetic field.⁴⁴ Therefore, under magnetic-guide, the magnetic PNIPAM core–shell microcapsule placed at the left of the channel move to the right via first rotational and then translational movement as shown in Fig. 4a. Because the magnetic hemisphere orients toward the magnetic field direction, it is available to rotate the microcapsule by rotating the magnet. Therefore, with this eccentric magnetic core, the magnetic PNIPAM core–shell microcapsules can not only achieve magnetic-guided translational movement for site-specific targeting, but also achieve magnetic-guided rotational motion for direction-specific controlled release.

Fig. 4 Magnetic properties of the magnetic PNIPAM core–shell microcapsule. (a) Schematic illustration of the experimental setup (a1, a3, a5) and optical micrographs (a2, a4, a6) of the magnetic-guided movement of the magnetic PNIPAM core–shell microcapsule in deionized water at 20 °C, scale bar is 200 μm. (b) Magnetization hysteresis loop of the magnetic PNIPAM microcapsules at room temperature.

The magnetization hysteresis loop of the magnetic PNIPAM microcapsules at room temperature is displayed in Fig. 4b. The sample for VSM characterization is prepared by washing with isopropanol and water to remove the oil phases and then freeze-drying. The hysteresis and coercivity are almost undetectable, which suggests that the magnetic PNIPAM core–shell microcapsules remain satisfactory superparamagnetic property as a result of the OA–MNPs. The superparamagnetic property of the magnetic PNIPAM core–shell microcapsules is critical for their practical application, which enables them to redisperse rapidly when the magnetic field is removed. The M_s of the magnetic PNIPAM microcapsules is 6.715 emu g⁻¹, which is much lower than that of OA–MNPs (63.49 emu g⁻¹). This significant reduction of M_s is mainly attributed to the presence of nonmagnetic organic components in the microcapsules.

The content of Fe₃O₄ MNPs in the magnetic PNIPAM microcapsules can be determined by TGA. The thermogravimetric curves of MNPs, OA–MNPs and magnetic PNIPAM microcapsules characterized in a nitrogen environment with a heating rate of 10 °C min⁻¹ are shown in Fig. 5. The weight loss of Fe₃O₄ MNPs is attributed to the gasification of water, and the residual mass percentage is 95.74 wt% at 800 °C (curve a). The weight loss of OA–MNPs is attributed to the gasification of water and decomposition of OA, and its residual mass percentage is 85.29 wt% at 800 °C (curve b). For magnetic PNIPAM microcapsules, the weight loss is attributed to the gasification of water and decomposition of OA and PNIPAM networks, and the residual mass percentage is 7.96 wt% at 800 °C (curve c). The evidence for the decrease in magnetic content on the basis of magnetization curves is confirmed by the TGA measurement. It can be estimated that the content of Fe₃O₄ MNPs in the magnetic PNIPAM microcapsules is about 7.96 wt%.

Fig. 5 Thermogravimetric curves of MNPs (a), OA–MNPs (b), and magnetic PNIPAM microcapsules (c).

Thermo-responsive characteristics of the magnetic PNIPAM core–shell microcapsules

The prepared magnetic PNIPAM core–shell microcapsules exhibit an excellent thermo-sensitivity and fast response to environmental temperature (Fig. 6). The temperature-dependent equilibrium volume change of the resultant magnetic PNIPAM microcapsules in deionized water is shown in Fig. 6a. The volume of the magnetic microcapsules decreases significantly with increasing temperature across the LCST. The equilibrium volume of the magnetic microcapsules at 21 °C is about 17 times larger than that at 40 °C.

Fig. 6 Thermo-responsive characteristics of magnetic PNIPAM core–shell microcapsules in deionized water. (a) Volume phase transition behaviour of the magnetic PNIPAM microcapsule, in which “IV” means the volume determined by the inner core at temperature T to that at 21 °C, and “OV” means the volume determined by the outer diameter at temperature T to that at 21 °C. (b) Thermo-triggered release of hydrophobic drugs from the magnetic PNIPAM core–shell microcapsule by increasing the environmental temperature from 20 °C to 60 °C. Scale bar is 200 μm.

The dynamic shrinking behaviour of the magnetic PNIPAM core–shell microcapsules in deionized water by increasing the environmental temperature from 20 °C to 60 °C is shown in Fig. 6b (please see Movie S2 in the ESI†). Because of the density differences in O1, O2 and W in (O1 + O2)/W/O emulsions, the membrane thicknesses of the polymerized microcapsules are always not even (Fig. 3 and 6). Such uneven membrane thickness is beneficial to the squirting release mechanism of the capsule, because the thinnest point of the microcapsule membrane is usually the point where pressure induces breakage. The thinnest point of the membrane is always on the opposite direction of the magnetic core because the encapsulated magnetic core and the oil droplet are always on the opposite direction (Fig. 3c and 6b). With increasing environmental temperature, thermo-responsive PNIPAM shell of the microcapsule shrinks dramatically. Since the inner oil core is incompressible but the internal pressure in oil core keeps increasing due to the shell shrinkage, the PNIPAM shell finally ruptures because of the limited mechanical strength, which results in burst release of the inner oil core from the membrane in a direction opposite to the magnetic hemisphere (Fig. 6b).

Direction-specific burst release of hydrophobic drugs under magnetic and thermal stimuli

The application of the magnetic PNIPAM core–shell microcapsules for direction-specific burst release of hydrophobic drugs under dual magnetic and thermal stimuli is shown in Fig. 7 (please see Movie S3 in the ESI†). Due to the oil reservoir inside the magnetic PNIPAM core–shell microcapsule, this kind of microcapsules has great potential in delivery and control release of substances such as paclitaxel,⁴⁵ all-trans-retinoic acid,⁴⁶ nanoparticles,⁴⁷ contrast agent,⁴⁸ ibuprofen,⁴⁹ and so on.⁵⁰ In previously published literatures, pharmacokinetics of drug release from oil phase have been investigated and discussed carefully.^45–50 Therefore, in this study we just choose the fluorochrome LR300 rather than actual drug as the lipophilic model drug to demonstrate the site-specific targeted delivery and direction-specific burst release property. This experiment is carried out in a homemade glass holder with a “funnel”-shaped channel by assembling patterned glass slides. The “neck” of the “funnel” is covered by a cover slip, as illustrated in Fig. 7a. The eccentric magnetic core in the microcapsule not only enable the magnetic-guided targeting transport of the microcapsule from the top of the channel to the left place (Fig. 7a1–a3 and b1–b3), but also make the microcapsule able to be manipulated and rotated on micro-scale using an external magnet to control the direction of the thinnest point on microgel membrane (Fig. 7a3–a4 and b3–b4). Then, by increasing the environmental temperature to above the LCST (Fig. 7a4 and b4), because the oil core is incompressible and cannot pass through the membrane via diffusion, the liquid pressure inside the microcapsule increases rapidly due to the membrane shrinkage (Fig. 7b5). When the internal pressure increases to a critical value, the membrane ruptures suddenly and the encapsulated oil core squirts out from the opposite direction of the magnetic hemisphere (Fig. 7a5 and b6). Because of the capillarity induced by the small channel and the cover slip as illustrated in Fig. 7a, the squirted inner oil droplet at the entrance of “neck” is inhaled into the “neck” (Fig. 7b7). The magnetic microcapsule carrier can then be removed from the targeted site by using an external magnet (Fig. 7a6 and b8–b9). The results show that, the proposed microcapsules with hydrophobic substances trapped in the oil cores can be site- and/or route-specifically delivered to a desired site with the help of an external magnetic field, and the encapsulated hydrophobic substances can be burst-released from the microcapsules in a controllable specific direction with proper dual magnetic and thermal manipulation.

Fig. 7 Direction-specific burst release of hydrophobic drugs from magnetic PNIPAM core–shell microcapsule under dual magnetic and thermal stimuli. (a) Scheme illustration of the experimental setup. (b) Optical micrographs showing the magnetic-guided movement (b1, b2) and rotation (b3, b4) of the magnetic PNIPAM core–shell microcapsules under an external magnetic field, the thermo-triggered release of hydrophobic drugs from the magnetic PNIPAM core–shell microcapsule by increasing the environmental temperature from 20 °C to 60 °C (b4–b7), and the removal of the carrier by a magnet (b8, b9). Scale bar is 200 μm.

Conclusion

In summary, we have developed a novel type of monodisperse dual magnetic and thermo-responsive microcapsules with both eccentric magnetic core and eccentric oil core, which is an efficient type of carriers for targeted delivery and direction-specific burst release of hydrophobic substances. That is, our novel microcapsules enable precise “aiming” before “firing”, which is highly desired but unavailable before. Besides site-specific targeted drug delivery and direction-specific controlled release, such magnetic microcapsules have great potential in a wide range of microcapsule-based biomedical systems, including high-throughput immunoassays and biological probes as well as microfluidic pumps and mixers.

Acknowledgements

The authors gratefully acknowledge support from the National Natural Science Foundation of China (21136006, 21322605) and the Program for Changjiang Scholars and Innovative Research Team in University (IRT1163).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Fig. S1 showing optical micrographs of the (O1 + O2)/W/O quadruple-component double emulsions at different time after formation; Movies S1–S3 showing the magnetic-guided movement of the magnetic PNIPAM core–shell microcapsules, the thermal-triggered release of hydrophobic drugs from magnetic PNIPAM core–shell microcapsules, and the direction-specific burst release of hydrophobic drugs from magnetic PNIPAM core–shell microcapsules. See DOI: 10.1039/c4ra09174d

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