Drug Implants of Hydrogels via Collective Behavior of Microgel

Article Cite This: ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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Drug Implants of Hydrogels via Collective Behavior of Microgel Colloids for On-Demand Cancer Therapy Yitong Wang,† Ling Wang,† Miaomiao Yan,‡ Lei Feng,† Shuli Dong,† and Jingcheng Hao*,† †

Key Laboratory of Colloid and Interface Chemistry (Shandong University), Ministry of Education, Jinan 250100, P. R. China Department of Pharmacy, Binzhou Medical College, Yantai 264003, P. R. China

ACS Appl. Bio Mater. Downloaded from pubs.acs.org by UNIV AT BUFFALO STATE UNIV NEW YORK on 03/18/19. For personal use only.

‡

S Supporting Information *

ABSTRACT: In nature, the collective behaviors such as the growth of bacteria and the cooperation of insects possess great superiority and can create functional materials through diversified interactions for accomplishing complex tasks that cannot be performed by a single unit. Here we develop a new protocol for fabricating drug implants of hydrogels via the collective behavior of jagged magnetic microgels constructed by further coating Au nanorod@SiO2 with the thermo- and magnetic-responsive polymer shells, poly(N-isopropylacrylamide-co-magnetic ionic liquids). The magnetism of resultant macroscale hydrogels was enhanced nearly 5-fold because of the selforganization process, presenting new evidence for the essence of magnetism generation at a molecular level. By virtue of using a near-IR laser excitation stimulus, minimal cytotoxicity, and high biocompatibility, the implants of hydrogels not only have the potential to be local drug implants for sustaining drug release over 30 days but also achieve on-demand release for the enhanced therapeutic effect. The formation of microgel colloids provides an unprecedented strategy to rearrange molecular magnets and a unique potential and possibility for magnetism enhancement. This enhancement motivates an improvement of solid tumor therapy and also supplies a force for the real implementation of the on-demand drug treatment. KEYWORDS: drug implant, magnetic-ionic-liquid microgel colloid, self-organization, near-IR laser excitation, biocompatibility

1. INTRODUCTION It is well-known that collective behavior in nature is ubiquitous, including the growth of bacterial colonies, the collective cooperation of insects, the migration of birds in a queue, and the withdrawal of fish schools. These organisms act collectively, care for and help each other, regardless of whether they forage, rest, or migrate.1 Such collective intelligence is also presented by biological agents, typically in bacterial communities and the teamwork of kinesins. Collective behavior can create more complex entities through local interactions in order to complete complicated tasks that an individual unit cannot complete.2,3 Inspired by the bio-organization in the natural world, how to realize the clustering and dispersion of artificially synthesized colloids, especially for microgel particles,4 has attracted widespread attention.5−8 In 2004, thermosensitive poly(N-isopropylacrylamide) (PNIPAm) microgel particles were synthesized with N,N-methylenebis (acrylamide) and a sulfate initiator. These microgels displayed collective behavior. They flocculated together into large-scale structures when the ionic strength and temperature reached to thresholds.9 McDonald and his co-workers10 extended this viewpoint in 2017. They reported a dual-stimuli responsive microgel. They found that the physiological environment can be driven, i.e., salts at physiological concentration and the temperature above the lower critical solution temperature of the microgels. These responsive microgels can organize into © XXXX American Chemical Society

more a complex shape (i.e., persistent bulk aggregates), serving as drug implants through hypodermic needles and sustained drug release for at least 120 days. These works indicated that large-scale structures may appear through the collective behavior of microgels, which can self-assemble into bulk hydrogels via a rational design. In this present work, a new type of hydrogel implants was constructed by physiological environment-induced self-assembly of dual-stimuli responsive magnetic microgels. This kind of hydrogel implant exhibits excellent collective effects driven by both magnetic field and near-infrared (near-IR) laser. As shown in Figure 1a, we fabricated a jagged magnetic microgel by further coating Au nanorod@SiO2 with the thermo- and magnetic-responsive polymer shells, poly(N-isopropylacrylamide-co-magnetic ionic liquids) (the construction process was shown in Figure 1a). These magnetic microgel particles respond to the physiological environment at the salt concentration of 0.137 M and the temperature of 37 °C (both sides of Figure 1a are a thermometer and a salimeter, representing the responsiveness of magnetic microgels to salt concentration and temperature). They can cooperatively selfassemble into hydrogel implants. This strategy that uses Received: December 21, 2018 Accepted: February 25, 2019 Published: February 25, 2019 A

DOI: 10.1021/acsabm.8b00823 ACS Appl. Bio Mater. XXXX, XXX, XXX−XXX

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ACS Applied Bio Materials

Figure 1. (a) Schematic illustration of magnetic hydrogels for near-IR regulated on-demand cancer therapy. (b and c) TEM images of magnetic microgels. (d) Z-average diameter in either water or PBS buffer solution and zeta potential of magnetic microgel water solution (2.0 wt %) as a function of the temperature. (e and f) SEM images of hydrogel implants. (g) Elastic modulus (G′) and viscous modulus (G′′) as a function of the applied stress. (h) Frequency sweep of the hydrogel implants.

magnetic microgels. Previous works in our group have proved that the magnetic ionic liquids, readily achieved by coordinating iron trihalide with conventional ionic liquids in methanol, serve as the monomers of polymerization reaction for magnetic microgels.13 Compared with iron oxide magnetic nanoparticles-loaded magnetic materials,14 the magnetism testing results of the type of the microgels containing magnetic ionic liquids was barely satisfactory, which limited their applications in the field of nanomaterials and biomedicine. In this work, we expect that enhanced magnetism can be realized through the self-assembly process. Our results may broaden

thermosensitive nanoscale assembly of magnetic microgels into a platform of hydrogel implants is expected to solve several practical issues: (i) Because of their excellent nature, magnetic microgels have attracted much attention with the good performance not only by inducing cell apoptosis caused by hyperthermia11 but also by acting as the magnetic resonance imaging agents for guiding cancer therapy.12 The reported magnetic microgels were primarily constructed by magnetic nanoparticles. Their stability was greatly influenced by the external environment, and the synthetic conditions were always very harsh. We hope to find alternative materials to form B


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for 4 h. The resultant magnetic microgels were centrifuged and washed with water. 2.2. Characterizations. About 10 μL of sample solution was dropped onto a carbon-supported membrane and dried naturally. Then the morphologies were observed on a JEOL JEM-1400 TEM through a Gatanmultiscan CCD for collecting images. Zeta potential and dynamic light scattering (DLS) data were detected with a Zeta PALS potential analyzer instrument (Brookhaven, U.S.A.). The sample solutions were put into a folded capillary cell for zeta potential measurement and a rectangular plastic glass cell for DLS measurement. 2.3. Tissue Injection Simulation. Agarose powder (0.5% (w/w) was dissolved in PBS buffer solution (pH 7.4) while it was stirred. The bottle and the mixture were weighed, and then the bottle was covered with parafilm with a hole. The mixture was heated to 95 °C for 10 min and weighed the bottle and the mixture again. Hot water was replenished to ensure the weight keep as the original level. Then the mixture was cooled to 55 °C, poured into a preheated bottle, and left for 12 h at 37 °C before use. The magnetic microgel solution was injected through an 18G hypodermic needle into the above agarose gel at 37 °C. 2.4. Drug Loading and Release. Dox was loaded into magnetic microgels through stirring magnetic microgel solution with Dox solution in PBS buffer for at least 12 h. The unencapsulated Dox was removed via several centrifugation and washing steps with water. The amount of Dox loaded was calculated by UV−vis analysis. Afterward, the required amount of freeze-dried microgels, 10.3% (w/w), was dispersed into PBS buffer solution (pH 7.4, 137 mM NaCl and 2.7 mM KCl) and heated to 37 °C to form a hydrogel implant. Then the hydrogel implant was put into a dialysis tube. This dialysis tube was transferred to a clean beaker with 50 mL of fresh PBS buffer solution. The release profile of Dox was constructed without or with 808 nm near-IR laser irradiation at different power density. In order to avoid solvent saturation, subsequent release samples were taken at different time intervals by collecting 3 mL from the beaker and replacing with the same volume of fresh PBS buffer solution at 37 °C. The amount of Dox released from the hydrogel implant was quantified by UV−vis analysis based on the standard curve of Dox at 480 nm. 2.5. In Vitro Cytotoxicity Study. In this work, we adopted two methods to represent the cytotoxicity of this self-supporting hydrogel. One method is that the cells were seeded above the hydrogel implants in the well plates, and this method is called the “gel method”. The other method is that the cells were seeded into the well plates beforehand to make contact with the extracts of the hydrogel implants, and this method is called the “extracts method”. MTT assay was carried out to evaluate the biocompatibility and therapeutic effect of hydrogel implants. In the first step, cells were seeded in 96-well plates at a density 2000 HepG2 cells dispersed in 100 μL of Dulbecco’s Modified Eagle Medium (DMEM) per well and incubated at cell incubator for 24 h. For the first gel method, a 10.3% (w/w) freeze-dried magnetic microgel or a Dox-loaded magnetic microgel was dispersed into PBS buffer solution and spread in the 96well plates. When the hydrogel implant was formed, 2000 HepG2 cells per well were seeded onto the hydrogel. After they were incubated for 24 or 48 or 72 h, MTT solution (0.5 mg/mL) was added into the wells, and after 4 h, the cell culture medium was carefully removed. Then 150 μL of DMSO solution was added to dissolve the formazan crystals. After they were blended in a shaker for 15 min, absorbance of the DMSO solution was detected at 570 nm by using a multidetection microplate reader (Synergy TMHT, BioTek Instruments Inc., U.S.A.). Then for the second extract method, 20 g of swollen hydrogel implant was dissolved into 20 mL of DMEM, and it was then incubated and immersed at 37 °C for 24 h. The residual hydrogels were discarded, and the DMEM solution was regarded as the 100% extract. The other concentrations of extract were obtained by diluting the 100% extract with DMEM. When the extracts were used in cell culture, 10% (v/v) fetal bovine serum (FBS, Fanbo) was added to guarantee adequate nutrients for cells. When the HepG2 cells were growth in 96-well plates for 24 h, different concentrations of

the applications of magnetic ionic liquids, providing the intellectual thought for design and construction of smart functional magnetic materials. (ii) Although tremendous and continuous efforts have been made to fight cancer and improve the overall survival among patients, the solid tumor malignancy still threatens our life because of the incidental occurrence of postoperative complications.15−18 In order to avoid the local recurrence or metastasis of the primary tumor, chemotherapy is by far the most adopted and effective approach for the adjuvant therapy after the surgical resection of the primary tumor.19,20 On the basis of the fact that diffusion pattern of free chemotherapeutic drugs results in the poor drug penetration through cell membranes or into tissues, as well as rapid drug clearance,21,22 building a local delivery system acting as a drug depot for on-demand drug release is highly desired for solid tumor malignancy treatment.23,24 The microgels in this work could first be administered directly at the tumor site in the form of a fluid, and then they selfassemble into a hydrogel implant driven by the body physiological conditions and being immobilized at the tumor site (hydrogel implant and magnet at the bottom of Figure 1a, demonstrating the magnet promotes the hydrogel implant to accumulate in the subcutaneous solid tumor tissue). Subsequently, the sustained and controlled drug release can be directly achieved in the tumor tissues, which prompts the cancer cells to absorb the adequate chemotherapeutic drugs during each cycle of tumor cell division. More importantly, the side effect induced by the systemic circulation of the chemotherapeutic agents was effectively diminished through such protocol. In an attempt to truly achieve the on-demand drug delivery,25−27 Au nanorods (Au NRs) are skillfully equipped as a switch to adjust the diffusion rate and the final release amount of agents with high controllability. Taking advantage of that controllability, Au NRs could produce different amounts of heat under a near-IR laser with different power density, and hence, drug release could be regulated from the hydrogels by demand (at the top of Figure 1a, the number of lightning symbols express different power density of near-IR laser, resulting in different amounts drug release). Thus, from a fundamental perspective, combining collective behavior of microgel colloids and macroscale drug-delivery systems, the unique hydrogel implant system can not only offer a distinctive design principle for macro drug-delivery systems composed of nanosubunits but also act as an on-demand drug release reservoir to enhance and control antitumor efficacy by subcutaneous or peri-tissue administration.

2. EXPERIMENTAL SECTION 2.1. Preparation of the Magnetic Core−Shell Microgels. The tetraethyl orthosilicate and (3-(methacryloxy)-propyl)triethoxysilane (MPS)-modified Au@SiO2 and the magnetic ionic liquids, 3-n-butyl1-vinylimidazolium trichloromono-bromoferrate ([VBIM]FeCl3Br) were obtained according to our previous work.13 In a typical procedure, 0.034 g of N-isopropylacrylamide (NIPAM) was added into 6 mL of water, and then 0.6 mL of 50 mM N,N′methylenebis(acrylamide) (MBA), 0.3 mL of 100 mM [VBIM]FeCl3Br, and 0.1 mL of 100 mM sodium dodecyl sulfate (SDS) were added to above mixture. After the mixture was stirrred adequately, 2.5 mL of MPS-modified Au@SiO2 was added into the mixture and passed through a filter with a pore diameter of 800 nm. After the mixture was heated to 70 °C, nitrogen was bubbled through the mixture for 30 min to remove oxygen. Subsequently, 1.0 mL of 10 mM potassium persulfate (KPS) solution was rapidly injected into the above mixture, and the reaction was under the protection of nitrogen C


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ACS Applied Bio Materials extract were added into the 96-well plates and incubated for another 24 or 48 or 72 h. Then the same steps were taken as the first method. The gel method was taken to investigate cellular uptake of Dox by using a laser confocal microscope (Leica TCS SPE, Germany). Additionally, in order to understand the influence of the hydrogel implant on cells, a live cell imaging system (DV ELITE, America) was used to observe the cell morphology over the incubation. The extract method was used for detecting the Dox concentration in the cells via flow cytometry (FACS AriaIII, America) analysis, and the concentration of extract is 100%. The HepG2 cells were seeded onto the hydrogel in a 96-well plate, and after 6 h, the laser irradiation without or with different power density was applied for 10 min. After another 6 h, the supernatants were collected. Cells were then detached by trypsinization, collected through centrifugation, and washed three times with PBS. Cell suspension was measured by flow cytometry analysis. 2.6. Data Availability. The data that support the findings of this study are available from the corresponding author (J.H.) upon request. Readers interested in the detailed information on the hardware and software implementation should please contact author J.H.

negative charges of the chain ends providing by KPS. Above the VPTT, the zeta potential shows a slight corresponding increase with the increase in charge density due to the reduction in size, and the chains ends collapse onto the surface. Pelton et al.31 and Vincent et al.10 have shown that attributing to the electrostatic shielding at higher NaCl concentrations, one kind of PNIPAM-based microgels incorporated with MBA and a sulfate initiator could aggregate in the presence of salts at physiological concentrations (0.137 M) when reaching the VPTT. In our case, as Mmgels were dispersed in PBS buffer, Zaverage diameters present a sudden increase at 33 °C (the red line in Figure 1d), clearly indicating the aggregation behavior of Mmgels. This kind of microgel aggregation character triggered by both temperature and salt concentration provides basis for the thermosensitive nanoscale self-assembly of Mmgels into hydrogel implants, which is ideal for a smart drug-delivery system. In addition to magnetism, another notable feature of MPILs is that their chemical and physical properties are influenced strongly by the nature of the counterions. It is particularly significant when the MPILs are incorporated into microgels.32 To confirm this point, we fabricated normal nonmagnetic microgels (Nmgels) by PNIPAM and P[VBIM]Br under the same conditions, where the counterion is [Br−]. As shown in Figure S2a in the SI, in place of those jagged shapes in magnetic microgels, a disordered morphology was rendered for the normal small counterion [Br−] microgels. Although the Zaverage diameter and zeta potential for Nmgels reveal similar results to the Mmgels (Figure S2b in the SI), the VPTT of Nmgels (45 °C) is much higher than the one in Mmgels, which is well above normal body temperature, hence restricting the practical application in biomedicine. We believe that the significant difference in VPTT is contributed to the magnetic counterions [FeCl3Br]−. According to the classical colloid particle models,33,34 counterions are enriched around the microgel when the polymeric ionic liquid monomer is introduced into a microgel. Compared to halide counterions, Br−, magnetic counterions [FeCl3Br]− are more hydrophobic, hence, stronger hydrophobic interaction with the alkyl chains of the polymer monomers exists in the microgel network, leading to a lower VPTT. In summary, magnetic counterions, [FeCl3Br]− are of the utmost importance not only for the magnetism but also for the VPTT closed to body temperature. Collective effects triggered by both temperature and salt concentration may facilitate the thermosensitive nanoscale selfassembly of Mmgels into hydrogel implants. Thus, an inverted test tube method was used to confirm whether the formation of hydrogel implants was possible via increasing high enough concentration of Mmgels. By continuously increasing the concentration (%, w/w) of Mmgels in PBS solution at 37 °C, a self-supporting hydrogel implant was formed at 10.3%, and the macroscopic sample appeared to have a state of immobility even when the sample vials were inverted, as shown in Figure S2c in the SI. The SEM images in Figure 1e,f show that typical three-dimensional network structures with some breakage and pores about 200 nm to 1 μm in size, verifying the hydrogel character. In Figure 1f, one can clearly identify some particles embedded into networks, exhibiting that the hydrogel implant was self-assembled from microgel particles. Furthermore, the sizes of embedded microgel particles (about 150 nm) were consistent with the results of the average dynamic diameters of completely wrinkled microgels (about 140 nm shown in Figure 1d), which further proved that the hydrogel implant was

3. RESULTS AND DISCUSSION 3.1. Thermosensitive Nanoscale Collective Behavior of Magnetic Microgels into Hydrogel Implants. The fabrication procedure of magnetic microgels (Mmgels) via precipitation polymerization is illustrated in Figure 1a. First, to couple abundant CC bonds onto the surface of silicondioxide-coated gold nanorods (Au@SiO2), a silane-coupling agent, 3-methacryloxypropyl-triethoxysilane (CH2C(CH3)COO-C3H6Si(OCH3)3, MPS), was used to modified Au@SiO2 according to our previous work.13 On behalf of integration of thermo- and magnetic-responsive properties into microgels, a polymer layer consisting of N-isopropylacrylamide (PNIPAm) and the magnetic polymeric ionic liquids, poly(3-n-butyl-1vinylimidazolium trichloromonobromoferrate) (P[VBIM]+[FeCl3Br]−) were coated onto the surface of Au@ SiO2. PNIPAm molecules have been regarded as the most heavily studied polymer for forming thermoresponsive microgels, which is known to undergo a reversible, temperatureinduced phase separation from a coil polymer to a condensed globule when the temperature reaches to 32 °C.28 Magnetic polymeric ionic liquids (MPILs) can be readily synthesized by monomer polymerization of magnetic ionic liquids, whose magnetism was endowed by magnetic counterions. The investigation on these ionic liquids with magnetic counterions was pioneered by Eastoe et al.29,30 We extended the applications of magnetic ionic liquids to magnetic polymeric ionic liquids and introduced it to microgel field.13 Figure 1b,c shows the typical transmission electron microscopy (TEM) images of Mmgels with a well-defined core−shell jagged structure of ∼295 nm diameter (Figure S1 in the Supporting Information (SI)). A large amount of studies have reported that the thermosensitive microgels can shrink by expelling water over a narrow temperature range upon heating. One usually calls this temperature to be the “volume phase transition temperature” (VPTT). The Z-average diameter and zeta potential were measured by a Zeta PALS potential analyzer instrument. As shown in Figure 1d, the Mmgels shrink in water as a function of temperature, but they remain colloidally stable, resulting in the dramatic decrease in Zaverage diameter at the VPTT (33 °C). The zeta potential of Mmgels was positive, demonstrating successful incorporation of the P[VBIM]+[FeCl3Br]− magnetic comonomer. P[VBIM]+[FeCl3Br]− possess positive charges that counter the D


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Figure 2. (a) Near-IR-induced temperature increase curves of hydrogel implants under different power density irradiation. (b) The final temperature of hydrogel implants as a function of different depths of hog skin under different power density irradiation. (c) SQUID magnetometry results of hydrogel implants powder and Mmgel powder at 300 K. (d) Mimic process of the formation of hydrogel implants under physiological conditions by injecting magnetic microgel solutions into 37 °C agarose gel through 18G hypodermic needle for tissue mimic.

composed of the microgel particles. Then we studied the rheological properties of the hydrogel implants. The strength of the network structures can be reflected via the yield stress (τ*) value. The storage modulus (elastic modulus, G′) and loss modulus (viscous modulus, G′′) were analyzed. G′ and G′′ will be decreased suddenly above a critical value τ*, indicating the broken of three-dimensional networks. Stress sweep (Figure 1g) shows a broad linear viscoelastic region and G′ exceeds G′′ over the investigated frequency range, indicating the typical hydrogel rheological property and the excellent antishear ability. From the oscillatory measurement (Figure 1h), G′ and G′′ of the hydrogel are about 18 and 6 kPa, respectively, which is in agreement with the stress sweep results. All the results confirmed that a hydrogel implant can be formed through a physiological condition-triggered nanoscale self-assembly process of Mmgels, which is potential to act as a depot for sustained drug release. It is worth mentioning that premature aggregation is averted thanks to the aggregation behavior of microgels only under circumstance of both the adequate temperature and salt. 3.2. Photothermal Conversion and Enhanced Magnetic Property of Hydrogel Implants. In view of its deep tissue penetration and diminutive diffusion property, near-IR laser has been regarded as a prospective tool for photothermal cancer therapy.35 However, the safety concerns relevant to the injuring side effect of high energy laser have drawn much attention, considering that a high-energy laser not only kills cancer cells but also damages normal tissues and cells, which greatly restrict its practical application. Therefore, to achieve a safety treatment, developing good agents that can convert lowpower energy into thermal energy in a pico-time domain are urgent. To meet this requirement, Au NRs remain a good choice for being actively studied as promising and versatile

photothermal conversion materials. The relationship between temperature increase and the irradiation power of resultant hydrogel implants was shown in Figure 2a, in which an irradiation at a power density of 1.0 W/cm2 could bring a rush rise in the surface temperature of the hydrogel implants rapidly close to the boiling temperature only for 7 min. Even when an irradiation with lower power density of at 0.4 W/cm2 was applied, the surface temperature of the hydrogel implants still increased to ∼60 °C after 7 min. It is clearly demonstrated that thermal efficiency could be increased monotonically with the radiant energy. To verify the photothermal penetration effect of hydrogel implants on biological tissues using near-IR laser, the hydrogel implants were implanted on the internal surface of a piece of pork at different depths, followed by irradiation with laser on the external surface of the pork, as shown in Figure S3 in the SI. The final surface temperature of the hydrogel implants at corresponding depth was monitored using an IR thermography, as shown in Figure 2b. Even when the depth of the white fat is as thick as 10 mm, the surface temperature of the hydrogel implants still reached to ∼55 °C, indicating the strong penetration photothermal effect of the hydrogel implants. More importantly, the therapy depth can be simply adjusted by the laser power density and irradiation time; this is ideal for the rapid and localized ablation of solid tumor malignancy in future applications. Particularly, strong interparticle plasmonic coupling that arises by narrow gaps between the Au NRs produces enhanced electromagnetic field, leading to increased photothermal conversion efficiency.36 Thus, we expected the self-assembly process could induce a strong the plasmonic coupling effect of Au NRs and result in enhanced photothermal conversion efficiency. According to a reported method,37 the heat conversion efficiency (η) of macroscale E


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Figure 3. (a) Dox release profiles from hydrogel implants over 30 days with or without near-IR laser at different power density. (b) The amplifying release profiles of blue and pink lines in Figure 3a. Application of the Higuchi model (c) and zero-order release pattern (d) to the Dox release over 30 days.

external magnet (1 T), the hydrogel implant powder could be manipulated to overcome the gravity and migrated a distance, indicating that the paramagnetic counterions, [FeCl3Br]−, are the original source for magnetic property of the hydrogel sample. The superconducting quantum interference device (SQUID) results in Figure 2c show both Mmgels and hydrogel implants possess the paramagnetism. The Mmgel particles display weak paramagnetic with a very small superparamagnetism behavior as well as magnetic moment zenith was about 0.2044 emu·g−1 (the magnetic field is 6000 Oe). Interestingly, the self-assembly of Mmgels results in the enhanced paramagnetic property of hydrogel implants. The magnetic moment zenith was increased to 0.9854 emu·g−1 (the magnetic field is 6000 Oe), namely the magnetism of the hydrogel implants was tremendously improved 4.89-fold. The question remained to solve is why the magnetism can be improved. On the one hand, it is because of the hydrophobic interaction between counterions, [FeCl3Br]− and the alkyl chains of ionic liquids, the relatively hydrophobic anions [FeCl3Br]− can be enriched around the hydrophobic portion of the hydrogels. On the other hand, according to the molecular packing theory, the self-assembly of microgels into hydrogel implants with stronger long-range structural ordering and long-range interactions may result in the enrichment of [FeCl3Br]− and hence the magnetism enhancement. For the first time, colloidal microgel particles self-assembled into a hydrogel implant, providing an unprecedented platform to arrange molecular magnets and offering a unique potential and possibility for magnetism enhancement.

hydrogels at 808 nm laser can be calculated to be 29.54%, which is higher than that of pure Mmgels (22.76%) (Figure S4 in the SI). It is confirmed that the self-process reduces the distance between the Mmgels, inducing a plasmonic coupling effect and mildly improve the photothermal conversion efficiency. From the other perspective, it proved that hydrogel implants are not formed by being stacked together, but rather, they are self-assembled together as an individual unit through weak interaction. The excellent photothermal properties lay a firm foundation for controlled release of the anticancer drugs from the hydrogel implants. Currently, magnetic materials have attracted extensive research interest especially for their extensive applications in functional nanomaterials and biomedicine, in which blending or in situ precipitation of Fe3O4 nanoparticles was the main protocol for the construction of magnetic materials. For both the blending or in situ precipitation methods, noncovalent forces are the main interaction between the networks and the Fe3O4 nanoparticles, and therefore, Fe3O4 nanoparticles cannot be guaranteed to distribute equally and stably within the networks. In the current study, transition-metal-based polymeric ionic liquids with halide anions, [VBIM]FeCl3Br, was used for the monomers of microgels, which display simple paramagnetic behavior over a very broad temperature range from 50 to 350 K.38 In such a magnetic polymeric ionic liquids strategy, once the microgel particles assembled into hydrogel implants, the uniform magnetism distribution within the hydrogel matrix could be realized and also ensure the stability of the as-prepared hydrogel implants. As intuitively shown in Figure S5 and Movie S1 in the SI, by vertically applying a weak F


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ACS Applied Bio Materials 3.3. Injection of Microgels into Tissue Mimic. Serving as a depot for sustained drug release, the state of existence of hydrogel implants is a key nature to explore.39−41 We next simulated the injection process of Mmgels into tissue. In view of the rheological properties, the composition , and the water content, agarose gel has been considered as an artificial tissue for understanding the biological process, because of the typical gel property that is similar to the biological tissues.42 Hence, we chose agarose gels as the subcutaneous tissue mimic at 37 °C. The Mmgel solution at room temperature was injected through an 18G hypodermic needle into the above agarose gel at 37 °C. The microgel particles aggregated rapidly into a depot (Figure 2d and the Movie S2 in the SI). The most likely reason is that microgel particles filled the void of the agarose gel broken by the hypodermic needle. More importantly, the hydrogel implant depot can remain steady over 40 days, and no dispersal behavior was observed. The ability of microgel solution to achieve depot formation is a prerequisite for the solid tumor cancer therapy system. 3.4. Drug Loading and Laser-Controlled Release Study. Dox is the most studied anticancer drug, which can be readily loaded into the Mmgels with a loading content up to 19.8%. Increasing the concentration (w/w%) of Dox-loaded Mmgels in PBS solution at 37 °C to 10.3% (w/w), a hydrogel implant complex formed (abbreviated as Dox-implants). The release of Dox from Dox-implants into the surrounding PBS was then measured over time using an ultraviolet spectrophotometer. In order to avoid the saturation of the drug concentration, the release media was removed partially and replaced with the same volume of fresh PBS during the release experiment.43 The release profiles of Dox-implants with or without the laser irradiation are collected in Figure 3a. The amplifying release profiles of blue and pink lines in Figure 3a are magnified in Figure 3b. One can be seen that the release rate of the gel depots is enhanced as exposure to a higher powder density laser, leading to a larger total cumulative release after 30 days. These high maneuverability and controllability properties provide a chance to tune the release rate from the implants according to the practical requirement. It is reported that Fickian diffusion is the main driving force for the release of polymeric drug systems.44,45 The drug release can be divided into three types, including sustained release, controlled release, and delayed release, which can be distinguished through different curve fitting of release profiles. For sustained release drug carriers, the release rate presents a trend that increases first and then decreases over the experimental time; while as the controlled release drug carriers, the release rate remains constant over the experimental time, following the zero-order release pattern. As presented in Table 1, which was calculated from Figure 3c,d, there is almost no

burst release from the Dox-implants without illumination or with a lower power density at 0.2 W/cm2. Both of them display a similar release behavior, which follows the pattern of zeroorder release. The Dox was released in a constant amount every day, maintaining the stable blood concentration and guaranteeing the complete absorption of body, which is very meaningful for long-term medication patients. When being irradiated with the 0.4 or 0.8 W/cm2 power density of laser for Dox-implants, noteworthily, there are two phases or release trends (I and II) (in Table 1). The release curves show an appreciable burst release of 55% and 80% within 5 h, respectively (Figure 3b). The simplified Higuchi model46 of drug release could be applied to describe the release data. In phase I, the introduced laser with the power density of 0.8 W/ cm2 could allow Dox to be released from the Dox-implants (diffusion constant is 219.865), presenting a much larger dissolution constant than the other formulations. This is followed by phase II where it appears that the phase II diffusion constant of the Dox-implants irradiated by a laser with the power density of 0.8 W/cm2 (diffusion constant is 3.515) is parallel to the diffusion constant of Dox-implants without irradiation (diffusion constant is 3.033). This result proved that in phase II, the laser was not the main driving force to induce the Dox diffuse out of the hydrogel matrix, and instead, the Dox was released with a free dissolution pattern. Relative to the situation of applying 0.8 W/cm2 power density, it exerted a slower release rate for the 0.4 W/cm2 power density. Additionally, Figure S6 in the SI shows the excellent mechanical stability of hydrogel implants, remaining in its original three-dimensional network over the complete release period. These behaviors potentially offer hydrogel implants an opportunity for achieving the on-demand drug delivery. 3.5. Biocompatibility Study of Hydrogel Implants. Currently, with tunable physicochemical properties and excellent biocompatibility, hydrogel implants have emerged as a novel biomaterial, and different protocols have been applied for the cell experiments.47 Much focus has been paid on the gel method and extract method, which are described in detail in the Experimental Section. The former one aims at assessing the surface of the hydrogel with the cells, and the process is more realistic close to the injection environment; however, the latter one pays more attention to the final equilibrium process. Both of them have their own strengths and weaknesses; thus, in this work, two methods were used to evaluate the hydrogel implants at the cellular level. The human hepatoma cell lines, HepG2 cells, were chosen as the model cells. The cytotoxicity of the hydrogel implants was first assessed using a live cell station, which can real-time monitor the cellular morphology and cellular growth. A live video in the SI (Movie S3) recorded the whole process of the cells incubated with the hydrogel implants for 48 h though a live cell station. The cell division process occurred in the first 24 h, and the apoptosis of cells was accomplished at 40 h. However, because the live cell station is not an enclosed environment like the cell incubator, it can only simulate the cell culture environment. Hence, cell proliferation was not the same because of the discrepant tolerance ability of different cancer cells. In this case, a control experiment should be carried out with the cells being incubated in culture medium for 48 h by the same cell proliferation as the cells incubated with the magnetic hydrogels in Movie S4 in the SI. As expected, the comparative results reveal that the magnetic hydrogels have no influence on the cell growth because of the low cytotoxicity

Table 1. Correlation Coefficient (Rc), Higuchi Dissolution Constant (κH), and Zero-Order Dissolution Constant (κ0) phase I 2

power density (W/cm ) 0 0.2

Rc

κ0 (days)

0.999 3.033 0.999 3.087 phase I

phase II Rc

κ0 (days)

0.981 0.471 0.981 0.731 phase II

power density (W/cm2)

Rc

κH (days0.5)

Rc

κH (days0.5)

0.4 0.8

0.979 0.991

159.203 219.865

0.976 0.931

14.772 3.515 G


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Figure 4. Cytotoxicity of free hydrogel implants toward cells adopting gel method (a) or extract method (b). (c) The cells incubated with the Doximplants with 808 nm laser at different power density with gel method. (d) Cells incubated with different concentrations of Dox-implant extracts by illuminating an 808 nm laser with a power density of 0.2, 0.4, or 0.8 W cm−2, respectively (extract method).

Figure 5. CLSM images of HepG2 cells after laser irradiation for 6 h with a power density of 0 (A, a), 0.2 (B, b), 0.4 (C, c) or 0.8 (D, d) W/cm2, respectively. Particularly, A−D are the superimposed field CLSM images, and a−d are fluorescence field CLSM images.

methods, the cell viability, as shown in Figure 4a,b, was all above 90% even after 72 h cell culture for pure hydrogel implants, further indicating that the HepG2 cells could live well after incubated with the hydrogel implants.

and high biocompatibility of all the components of the hydrogel implants including Au NRs, SiO2 nanoparticles, and P(NIPAM-[VBIM]FeCl3Br) polymers, which have been proved in previous literatures.13,48,49 Meanwhile, for both H


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Figure 6. Dox concentration in the HepG2 cells after laser irradiation for 6 h with a power density of 0 (b), 0.2 (c), 0.4 (d), or 0.8 W/cm2 (e), respectively. The concentration of extract is 100% and (a) is negative control group.

3.6. Cellular Internalization with High Controllability by Hydrogel Implants. Although Dox-implants have shown high maneuverability and controllability as near-IR-responsive drug implants in the PBS buffer solution, what about in live cells? The cellular uptake of Dox encapsulated into the hydrogel implants was monitored by confocal laser scanning microscopy (CLSM). Figure 5 shows that the near-IR laser is a switch to control the Dox release. After laser irradiation for 6 h with different power densities, the Dox amounts entered into the cells show significant distinction. For the Dox-implants without irradiation or with irradiated by a laser with the power density of 0.2 W/cm2, the cellular uptake was minimal. In contrast, a much higher uptake in cellular nuclei of Dox (red) was observed for cells treated with Dox-implants irradiated by a laser with the power density of 0.4 and 0.8 W/cm2, which can be observed more clearly in the Figure 5a−d. In Figure 5A,B, the HepG2 cells presented a good growth condition with uniform morphology; nevertheless, the cells in Figure 5C,D were not in good condition. The cell morphology turned twisty and rounded, and much substance dissolved out from cells. This may be because the near-IR induced the more Dox release from the hydrogel implants, which is consistent with the results of drug release in the PBS buffer solution, and results in high Dox concentration in the cells. Therefore, the state of cells was worse. Flow cytometry results also corroborated this point. As shown in Figure 6, the cells were separated into two groups: cells with fluorescent signal (P3) and cells without fluorescent signal. Encouragingly, with the laser power density increasing, the cells demonstrated significantly higher cell population with fluorescent signal, such as, when the power density is 0.4 or 0.8 W/cm2, the percentages of the cells with fluorescent signal are 4.7% and 18.4%, respectively. When the power density is 0 or 0.2 W/ cm2, the cells show almost no fluorescent signal. In order to investigate whether the extended time promotes the cell

uptake, the CLSM images of HepG2 cells without laser irradiation were shot at different time points. As shown in Figure S7 in the SI, the percentage of cells with fluorescent signal was almost unchanged with the time extending. That may be because of the lower Dox release amount without laser irradiation (the Dox release amount in PBS buffer is 7.4% at 72 h, as shown in Figure 3a). These results confirm that the present hydrogel implants can effectively release the drugs with high controllability, which is potential for the achievement of on-demand drug delivery. 3.7. In Vitro Antitumor Assay. We further evaluated the cell viability of HepG2 cells treated with Dox-implants. Also two methods were used to assess the therapeutic effect. For the gel method, it could be observed from Figure 4c that the Doximplants show time-independent cell proliferation inhibition behaviors and the near-IR laser illumination led to enhanced cell proliferation inhibition. The laser enhancement effect of Dox-implant system was obvious for the cell viability, and it is as low as 16.84% illumination with a power density of 0.8 W/ cm2 after 24 h incubation compared with illumination with a power density of 0.4 W/cm2 (25.91%) and illumination with a power density of 0.2 W/cm2 (96.53%). For the extract method (as shown in Figure 4d), interestingly, the cell viability displays time-independent behaviors when incubated with the different extract concentrations, which is different from previous work. It is thought that the Dox release was in an equilibrium state for the extracts method; thus, Dox concentration is high enough to induce apoptosis even with a dilution of 5×. This deduction is also supported by the cell viability difference between two methods (the viability of cells incubated with the Dox-implants with 808 nm laser at power density of 0.2 W/ cm2 for 72 h in gels method is 91.71%, while the viability in extracts method is as low as 51.56%). We expect that the two methods used in the cell culture not only assess our hydrogel depot system but also provide a reference for researchers to I



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choose suitable methods. These results exhibit that the present hydrogel implants have great potential as an injectable implant for sustained drug release and subsequently as an effective drug carrier through near-IR laser as a switch.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsabm.8b00823. Hydrodynamic diameters, TEM images, and photographs of microgels; setup diagram of the final temperature curves of hydrogel implants as a function of different depths of hog skin under different power density irradiation; photothermal effect of the irradiation of magnetic microgels in aqueous dispersion with the NIR laser, time constant for heat transfer; photographs of the hydrogel implant powder; TEM images of the hydrogel implants after the Dox release; and Dox concentration in the HepG2 cells without irradiation (PDF) Movies S1−S4 (ZIP)

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REFERENCES

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4. CONCLUSIONS In summary, a thermosensitive nanoscale self-assembly of magnetic microgels fabricated by coating an Au@SiO2 with a thermo- and magnetic-responsive polymer shell consisting of PNIPAM and [VBIM]FeCl3Br into hydrogel implants was realized. The activation stimulus was the physiological environment (both the salt and the temperature), which could be used to control the self-assembly process as well as magnetic enhancement. The hydrogel implants showed excellent mechanical strength and high stability, which can form a depot for sustained drug release over 30 days. MTT assay displayed the minimal cytotoxicity and high biocompatibility of hydrogel implants. Since the near-IR laser can be manipulated precisely and flexibly, the hydrogel implant provides an ideally versatile platform to deliver anticancer drugs in a laser-activation mechanism with facile control of the area, time, and dosage, which actually achieved the on-demand drug delivery. We anticipate that the present hydrogel implant system could be a local delivery system for the treatment of solid tumor malignancy. The prolonged drug release could ensure that cancer cells take in adequate chemotherapeutic drugs during each cycle of tumor cell division and thoroughly avoid the local recurrence or metastasis of primary tumor.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +86-531-88363768. Fax: (+86) 531-8856-4750. ORCID

Shuli Dong: 0000-0003-3961-7238 Jingcheng Hao: 0000-0002-9760-9677 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was funded by the National Natural Science Foundation of China (Grant Nos. 21773144 and 21420102006) and the Natural Science Foundation of Shandong Province (ZR2018ZA0547). J


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Drug Implants of Hydrogels via Collective Behavior of Microgel

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