Near-Infrared Light-Responsive Composite Microneedles for On

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Near-Infrared Light-Responsive Composite Microneedles for On-demand Transdermal Drug Delivery Mei-Chin Chen, Ming-Hung Ling, Kuan-Wen Wang, Zhi-Wei Lin, Bo-Hung Lai, and Dong-Hwang Chen Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.5b00185 • Publication Date (Web): 03 Apr 2015 Downloaded from http://pubs.acs.org on April 7, 2015

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Near-infrared Light-responsive Composite Microneedles for On-demand Transdermal Drug Delivery

Mei-Chin Chen*, Ming-Hung Ling, Kuan-Wen Wang, Zhi-Wei Lin, Bo-Hung Lai, and Dong-Hwang Chen*

Department of Chemical Engineering, National Cheng Kung University, Tainan, Taiwan (ROC)

*

Correspondence to:

Mei-Chin Chen, PhD

Dong-Hwang Chen, PhD

Associate Professor

Distinguished Professor

Department of Chemical Engineering

Department of Chemical Engineering

National Cheng Kung University

National Cheng Kung University

Tainan, Taiwan 70101

Tainan, Taiwan 70101

Tel: +886-6-275-7575 # 62696

Tel: +886-6-275-7575 # 62680

Fax: +886-6-234-4496

Fax: +886-6-234-4496

E-mail: [email protected]

E-mail: [email protected]

*To whom correspondence should be addressed: [email protected] (Dr. M.C. Chen) and [email protected] (Dr. D.H. Chen).

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Abstract This study presents near-infrared (NIR)-light-responsive polymer-nanostructure composite microneedles used for on-demand transdermal drug delivery. Silica-coated lanthanum

hexaboride

(LaB6@SiO2)

nanostructures

were

incorporated

into

polycaprolactone microneedles, serving as an NIR absorber. When the microneedles were irradiated with NIR light, light-to-heat transduction mediated by the LaB6@SiO2 nanostructures caused the microneedle melting at 50 °C. This increased the mobility of the polymer chains, enabling drug release from the matrix. Drug release from the microneedles was evaluated for 4 laser on/off cycles. In each cycle, the samples were irradiated until the temperature reached 50 °C for 3 min (laser on); the laser was then turned off for 30 min (laser off). The results showed that light-induced phase transition in the polymer triggered drug release from the melted microneedles. A stepwise drug-release behavior was observed after multiple cycles of NIR light exposure. No notable drug leakage was found in the off state. This NIR-light-triggerable device exhibits excellent reproducibility, low off-state leakage, and noninvasive triggerability and, thus, represents an advance in transdermal delivery technology.

Keywords: controlled drug release; composite; NIR absorber; stimuli-responsive; polycaprolactone.

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Introduction Microneedle technology has been introduced recently as an efficient, easily applied, and minimally invasive means of transdermal drug delivery.1−3 This technology involves creating micropores in the stratum corneum, thereby enabling the delivery of a broad range of therapeutics that cannot permeate intact skin. Compared with microneedles composed of metal and silicon materials, microneedles composed of dissolving or biodegradable polymers have received more attention because of their biocompatibility, safety, low cost, and high loading capacity, and because they are easy to fabricate. Typically, microneedles rapidly dissolve in the interstitial fluid of the skin and then release their encapsulated payload within minutes, often resulting in a bolus release of drugs.4,5 Biodegradable microneedles can provide extended drug release; however, their release rate depends mainly on the hydrolytic or enzymatic degradation behavior of the polymer matrix.6−8. However, conventional polymer microneedles cannot provide controllable or programmable drug delivery according to patient needs or changing physiological circumstances. Triggerable delivery systems enable on-demand drug delivery that is adaptable to patient regimens as well as the delivery of multiple dosages through a single administration.9−11 Such delivery systems are particularly useful for treating people with addiction problems12 and those who experience pain.13 For example, cancer patients often experience pain of various levels that may be a side effect of the treatment or a symptom of the cancer. Breakthrough pain, a sudden increase in intensity despite ongoing control of chronic pain, is a common symptom of cancer that markedly reduces patients’ quality of life.14,15 Appropriate treatment of breakthrough pain remains a clinical challenge. Therefore, a self-administered drug delivery device that enables patients to receive on-demand pain relief is attractive. Using such a device, patients can personally modulate the timing and dosage of the medication they receive to alleviate withdrawal symptoms or pain. Recent studies have reported that bolus, pulsatile or responsive drug administration can be achieved when microneedle-iontophoresis combinations were used.16−20 This technology has the potential to overcome the limitations of conventional microneedle design and could

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easily be employed for dosing-on-demand. Moreover, a combination of microneedles and ultrasound has been shown to provide a higher and controllable drug delivery rate.21,22 This paper presents a near-infrared (NIR)-light-triggerable microneedle patch that can respond to NIR light irradiation to release encapsulated contents and deliver doses through multiple triggering cycles. This patch was composed of polycaprolactone (PCL) microneedles containing photosensitive nanomaterials, specifically, silica-coated lanthanum hexaboride (LaB6@SiO2) nanostructures (Fig. 1). The microneedles were composed of PCL, a bioresorbable polyester, because of its well-known biocompatibility and low melting point. Numerous PCL-based drug delivery and medical devices have secured U.S. Food and Drug Administration approval and Communauté Européennes mark registration.23

Figure 1. Schematic illustrations of on-demand transdermal drug delivery using near-infrared (NIR) light-responsive microneedles (MNs), composed of polycaprolactone and NIR absorbers, silica-coated lanthanum hexaboride (LaB6@SiO2) nanostructures.

Previous studies have demonstrated that LaB6 nanoparticles exhibit strong light

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absorption in the NIR region.24−26 We incorporated LaB6 nanostructures into PCL microneedles; these nanostructures act as NIR light absorbers, enabling the polymer matrix to be heated and resulting in drug release. When the microneedles are exposed to an NIR laser, the light is absorbed by the LaB6 nanostructures and converted into heat, causing the PCL microneedles to melt (approximately 50 °C) and, thus, triggering the release of encapsulated agents (Fig. 1). Numerous stimuli, including the pH value,27,28 electric or magnetic fields,29 ultrasound,30,31 and light,32−34 have been used to trigger drug release. NIR light is particularly attractive for transdermal drug delivery because it can penetrate up to several centimeters of tissue and can be applied remotely with high spatial and temporal precision.35,36 In addition, NIR light is safe and causes minimal photodamage to the tissue involved. In this study, we assumed that, when microneedles are irradiated with NIR light (laser on), LaB6 nanostructures can be used as localized heat sources for raising the temperature to the melting point of the microneedles. This increases the mobility of the polymer chains, enabling drug release from the matrix.37 When the laser is turned off, heating immediately ceases and release is terminated. This triggerable delivery system enables on-demand drug delivery in which a small amount or none of the drug is released in the off state; moreover, this system is repeatedly switchable to the on state and can be noninvasively triggered to release a consistent dosage demanded by a patient or prescribed by a doctor.38 To test the NIR-light-responsive property, the microneedles were irradiated with NIR light, and the morphology and temperature changes were recorded using a high-resolution thermal imager. A fluorescent dye, Rhodamine 6G (R6G), was used as a model drug for evaluating the feasibility of using NIR light to repetitively trigger drug release from the microneedles. Moreover, the in vivo controlled release of an anticancer drug, doxorubicin hydrochloride (DOX), from microneedles was studied in a rat model.

Experimental Section Preparation of Silica-coated Lanthanum Hexaboride Nanostructures

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LaB6@SiO2 nanostructures were prepared according to our previous study.39 The mean hydrodynamic diameter was measured using a dynamic light scattering spectrometer (Zetasizer Nano-ZS, Malvern, Herrenberg, Germany). The morphology and the chemical composition of the LaB6@SiO2 nanostructures were characterized using a transmission electron microscope (TEM; JEM-2100F, JEOL, Tokyo, Japan) equipped with an energy-dispersive X-ray (EDX) spectrometer. The TEM sample was prepared by placing a drop of a colloid solution onto a Formvar-covered copper grid and allowing the solution to evaporate in air at room temperature. The absorption spectra of the LaB6 nanostructures were measured before and after silica coating (Model V-570, UV/VIS/NIR spectrophotometer, JASCO, Tokyo, Japan).

Fabrication of Composite Microneedles A pyramidal microneedle master structure was created using an electrodischarge machining process (Micropoint Technologies Pte, Ltd., Singapore). Microneedle molds were composed of PDMS to inverse-replicate the stainless steel master structure according to a published procedure.7 The obtained PDMS molds were repeatedly used to fabricate polymer microneedles. 4 g of PCL (MW = 70−90 kDa) was dissolved in 16 mL of acetone and stirred at 60 °C for 5 h to obtain a 25% (w/v) PCL solution. A LaB6@SiO2 solution (10 mg/mL) and R6G (16 mg) or DOX (160 mg) were added into the PCL solution to form a drug/LaB6@SiO2/PCL mixture solution. For fabrication of drug-loaded microneedle patches, a 2-step process that involved combining centrifugation with vacuum molding was used. First, a filter paper was placed on the PDMS mold surface. Two milliliters of the drug/LaB6@SiO2/PCL solution was applied to the filter paper as the first layer and then centrifuged in a swinging bucket rotor at 5000 rpm at 30 °C for 2 h. The filter paper was peeled from the mold for removal of excess solution. The filled mold was then dried in an oven at 37 °C for 2 h to form drug-loaded microneedles containing LaB6@SiO2 nanostructures.

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A vacuum molding process was then used to form a PCL patch. The PDMS mold was covered with a PCL flake and placed into a vacuum oven in a vacuum of −70 kPa for 1 h at 70 °C. After being cooled to room temperature, the fabricated microneedle patch was gently peeled from the mold and examined using a stereomicroscope (SZ−61, Olympus, Olympus Corporation, Tokyo, Japan) and a scanning electron microscope (Hitachi S−4000, Tokyo, Japan).

In Vitro Skin Insertion Test To confirm the skin insertion capability, microneedles were inserted into a porcine cadaver skin by using a homemade applicator. The insertion site was then exposed to blue tissue-marking dye (Shandon, Richard-Allan Scientific, Kalamazoo, MI, USA) for 1 min to mark the sites of stratum corneum perforation. To prepare histological specimens, insertion sites were collected by using a scalpel. The isolated skin section was embedded in an OCT compound in a cryostat mold and frozen in liquid nitrogen. The frozen OCT-skin samples were then sliced into 5-µm-thick sections by using a cryotome (Shandon Cryotome E, Thermo Electron Corporation, USA).

Near-infrared-light-responsive Property of Composite Microneedles To evaluate the NIR-light-responsive property of the composite microneedles, samples were irradiated with 808-nm NIR laser light (830 mW, Power Technology, Inc., Alexander, AR, USA) continuously or intermittently at a power density of 7 or 5 W/cm2. For intermittent irradiation, the microneedles were repeatedly exposed to the laser and the highest temperature was maintained at approximately 50 °C for 3 min (laser on); subsequently, the laser was turned off for 2 min (laser off). This cycle was repeated 4 times to assess the repeatability of the NIR-responsive property. For the continuous irradiation, the temperature of the microneedles was not controlled intentionally. During NIR exposure, thermographic images of microneedles were captured using an infrared thermography system (Advanced Thermo TVS-500EX, NEC Avio Infrared Technologies, Tokyo, Japan) equipped with a microscopic lens (18.5 µm, TVM-7025U, NEC Avio Infrared Technologies).

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The maximal temperature of the microneedles was recorded and plotted as a function of the exposure time.

Repeated Near-infrared-light-triggered Release of Rhodamine 6G to Porcine Cadaver Skins To assess the on-demand triggered release capability of the composite microneedles, the release of R6G from microneedles that were and were not exposed to NIR light for 4 laser on/laser off cycles was evaluated. R6G-loaded microneedles were inserted into porcine cadaver skin and secured to the skin by using a dermal tape. The applied skin was then exposed to the NIR laser and the highest temperature was maintained at approximately 50 °C for 3 min (laser on); subsequently, the laser was turned off for 30 min (laser off). The control samples were only inserted into the skin, but not exposed to the NIR throughout the experiment. At a specified time interval, the laser irradiated samples were removed from the skin and then examined using a stereomicroscope. The amount of released drug was calculated by subtracting the amount remaining in the samples after insertion and that remaining on the skin surface from the amount initially loaded within the samples at each sampling point. To measure the loading amount and residual amount in the samples, the microneedles before and after skin insertion were separately dissolved in ethanol and stirred overnight to extract the drug. The microneedle puncture sites were tape-stripped 3 times consecutively with 3M TransporeTM tapes to collect the drug on the skin surface.7 The stripped tapes were also extracted in ethanol to determine the drug on the tapes. The amount of drug extracted from the samples or the tapes was determined based on the fluorescence intensity in the extract by using a microplate spectrofluorometer (Infinite M200, Tecan Group Ltd., Männedorf, Switzerland) at 526 nm excitation and 555 nm emission.

Animal Studies The Institutional Animal Care and Use Committee of National Cheng Kung University approved all animal protocols, and experiments were conducted according to the guidelines

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of the Laboratory Animal Center of National Cheng Kung University. Four-week-old male Sprague Dawley (SD) rats weighing 200 ± 25 g were used. The rats were anesthetized with an intramuscular injection of Zoletil 50 (35 mg/kg) and Rompun (2 mg/kg), and their back hair was removed using an electric shaver.40 The application site on the bare rat skin was gently swabbed with 70% ethanol and allowed to dry.

In Vivo Triggered Release of Doxorubicin to Rat Skin DOX-loaded samples were inserted into the rat dorsal skin and then fixed with a dermal tape. The sample was then exposed to NIR light for 4 laser on/off cycles. The sample not irradiated with NIR was used as a control (no NIR light). After treatment, the rats were imaged using an in vivo imaging system (IVIS; Xenogen 200, Caliper Life Sciences, Alameda, CA). This IVIS was used to non-invasively obtain fluorescent images and analyze fluorescence data, which are expressed as photon flux (photons/s/cm2/steradian).4 The insertion sites were collected for confocal laser scanning microscopy (CLSM; FluoView FV1000, Olympus Corporation, Tokyo, Japan).

Acute Toxicity and Biodistribution in Rat SD rats were randomly divided into two groups: the microneedle group was treated with microneedles (without drug loading) and then irradiated with NIR light for 3 laser on/off cycles. The control group was not given any treatment. All animals were fed with normal chows and water ad libitum. Animals were observed carefully for the onset of any signs of toxicity and monitored for changes in body weight. The rats were sacrificed after designated time periods to analyze the tissue distribution of LaB6@SiO2 nanostructures and perform histological analysis. For histological examinations, specimens of liver, kidney, and spleen were embedded in an OCT compound, sectioned, and stained with hematoxylin and eosin (H&E). To determine the lanthanum content in the tissue, samples from the skin, liver, kidney, and spleen were harvested for inductively coupled plasma-mass spectrometry (ICP-MS;

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ELAN 6000, Perkin-Elmer Sciex, Ontario, Canada), according to a published procedure.41 Final values were normalized to the total amount of delivered LaB6@SiO2 nanostructures.

Statistical Analysis The differences between the two groups were analyzed using a one-tailed Student’s t test using statistical software (SPSS, Chicago, Ill, USA). Data are presented as mean ± SD. A difference of P < 0.05 was considered statistically significant.

Results and Discussion Characterization of Silica-coated Lanthanum Hexaboride Nanostructures LaB6 nanomaterials have been considered a potential alternative to gold-based nanoparticles because they feature high photothermal conversion efficiency and low cost, and are easily fabricated.24,25,42 In this study, LaB6 nanostructures were prepared using a bead milling process and then coated with silica to improve their dispersibility and chemical stability. A TEM image (Fig. 2A) and an EDX line scan (Fig. 2B) of the LaB6@SiO2 nanostructures showed that the dark LaB6 were coated with a uniform grey silica shell. The mean hydrodynamic diameters of the LaB6 nanostructures before and after silica coating were 99.0 ± 1.8 and 154.2 ± 3.1 nm (n = 5), indicating that the silica shell thickness was approximately 20−30 nm. This was consistent with the TEM observation (Fig. 2A, 2B). The LaB6 nanostructures exhibited an irregular shape because of the collisions between the LaB6 powders and the grinding beads during the mechanical milling process.25 Figure 2C shows the absorption spectra of the LaB6 nanostructures before and after silica coating, illustrating that both samples exhibited strong optical absorption in the NIR region because of the localized surface plasmon resonance of their free electrons.25,26,43 This indicated that the silica layers did not affect the NIR-light absorption property of the LaB6 nanostructures.

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Figure 2. Characterization of LaB6@SiO2 nanostructures. TEM image (A) and EDX line-scan profile (B). Absorption spectra of LaB6 nanostructures before and after silica coating (C).

Characterization of Composite Microneedles To evaluate the feasibility of on-demand drug delivery by using composite microneedles, a lipophilic fluorescent dye, R6G, was used as a model drug and encapsulated within the microneedles. We used a 2-step molding process that involved combining centrifugation with vacuum molding to localize drugs and NIR absorbers in the microneedles to prevent waste in the patch. Using this method, we successfully replicated solid and robust R6G-loaded microneedles from the master structure. The fabricated patch consisted of 225 (15 × 15) pyramidal needles with a tip-to-tip distance of 500 µm. Each microneedle had a base width of 300 µm, a height of 600 µm, and a tip radius of 5 µm (Figs. 3A− −3C).

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Figure 3. Relative height of Rhodamine 6G (R6G)-loaded microneedle patch next to a Taiwan one-dollar coin (A). Bright-field micrograph (B) and SEM image (C) of R6G-loaded microneedles. Porcine cadaver skin after microneedle insertion and staining with blue tissue marking dye (D) and its corresponding histological sections (E). The arrows in (E) point to the microneedle insertion sites.

In Vitro Skin Insertion Capability of Composite Microneedles An appropriate force is required to help the microneedles overcome the skin resistance during puncture. The force applied to the patch determines the insertion behavior and performance of microneedles.44,45 Generally, a larger insertion force may result in a greater insertion depth, thus leading to a higher drug permeation. To assess the skin insertion capability, prepared microneedles were inserted into porcine cadaver skin at an application force of approximately 10 N/patch by using a homemade applicator. After insertion, the test skin was stained with a blue tissue marking dye that selectively marked sites of the pierced skin to calculate the insertion ratio. As shown in Fig. 3D, the skin surface exhibited a complete array of blue spots corresponding to the microneedle insertion sites, indicating that all of the microneedles were inserted into the skin. A histological examination revealed that

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the composite microneedles created approximately 200-µm-deep cavities in the skin (Fig. 3E). The arrows in Figs. 3E point to the skin insertion sites. Near-infrared-light-responsive Property of Composite Microneedles To test whether the composite microneedles were stimuli-responsive materials that can undergo conformation changes when exposed to an external trigger, microneedles were irradiated with NIR light continuously or intermittently. Figure 4A shows the temperature and morphology changes of microneedles following continuous NIR-light irradiation at an output power of 7 W/cm2 for 5 min. Exposure to NIR light resulted in a rapid elevation of the temperature of the microneedles. After 1 min of exposure, the surface temperature of the microneedles was elevated to 60 °C and reached a steady state. The increase in temperature resulting from the surface plasmon resonance of the encapsulated LaB6@SiO2 nanostructures caused a phase transition in the polymers (i.e., the melting of the microneedles; insets of Fig. 4A). Infrared thermal images showed the time course of the NIR-light-induced melting of the microneedles (Fig. 4B), and the microneedles completely melted within 5 min. Blank PCL microneedles (without LaB6@SiO2) did not cause notable temperature and morphology changes when irradiated with NIR light (data not shown). To evaluate the repeatability of light triggering, the microneedles were exposed to the NIR laser at a power density of 5 W/cm2 for 4 laser on/off cycles. In each cycle, the sample was irradiated until the temperature reached 50 °C for 3 min, and the laser was then turned off for 2 min (Fig. 5A). The maximal temperature was maintained at 50 °C to prevent possible thermal injury to the skin. Infrared thermal video was recorded in real time to observe the morphological changes of the microneedles throughout the period (Video 1). Figure 5B shows selected thermal images of the microneedles at 35 and 80 s of light exposure, and at the end of each laser on state. After the needles were exposed to NIR light for 80 s, the temperature of the microneedles rose to 50 °C and the microneedles began to melt and gradually become blunt. When the laser was turned off, the samples rapidly cooled to the initial temperature within 2 min and returned to the solidified state (Video 1). This light-triggered melting behavior was repeatable over several cycles. A stepwise melting of

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the microneedles during intermittent irradiation was observed (Fig. 5B). Light-to-heat transduction mediated by NIR irradiation of the loaded LaB6@SiO2 caused a rapid rise in the temperature of the microneedles.11 The heat generated by LaB6@SiO2 also triggered structural alteration of the microneedles. These results indicated that the LaB6@SiO2-loaded microneedles are stimuli-responsive systems that can be remotely and repetitively activated by NIR light.

Figure

4.

Temperature

changes

of R6G-loaded microneedles after continuous

exposure to 808-nm NIR laser at an output power of 7 W cm−2 (A). Infrared thermal 14


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images of microneedles after continuous irradiation for 10, 30, 90, 120, 240, and 300 s (B). The insets in (A) show the light-triggered melting behavior of microneedles. Tmax: the maximum temperature in the image.

Figure 5. Temperature changes of R6G-loaded microneedles after intermittent exposure to 808-nm NIR laser at an output power of 5 W cm−2 for 4 laser on/off cycles (A). In each cycle, the samples were irradiated until the temperature reaches to 50 °C for 3 min (laser on) and then the laser was turned off for 2 min (laser off). Infrared thermal images of microneedles at 15


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35 and 80 s of light exposure, and at the end of each laser on state (B). Tmax: the maximum temperature in the image.

Repeated Near-infrared-light-triggered Release of Rhodamine 6G to Porcine Cadaver Skin An ideal on-demand drug delivery device should release little or none of the drug in the off state and should be repeatedly switchable to the on state.38,46 To confirm that the composite microneedles enabled switchable on-off drug release, the release of R6G from microneedles in 4 laser on/off cycles was evaluated. Microneedles were inserted into the porcine cadaver skin and subsequently exposed to NIR light until the maximal sample temperature of 50 °C was reached and maintained for 3 min (laser on). The laser was then turned off for 30 min (laser off). The microneedles in the control group were inserted into the skin for 132 min (i.e. 4 on/off cycles) without laser treatment (no NIR). Figure 6A shows images of the R6G-loaded microneedles before insertion and the samples being removed from the punctured skin after each laser on/off cycle. A light-triggered melting behavior was evident, even in the microneedles inserted into the skin, implying that NIR light can penetrate the skin and be absorbed by LaB6@SiO2 to generate heat, thus causing the microneedles to melt. No notable shape changes were observed in the control group (no NIR); slight bending of the tip occurred, possibly during the removal of the patch from the skin. Figure 6B shows corresponding images of the skin into which the microneedles were inserted. After NIR irradiation, the skin surface exhibited an array of red spots corresponding to the sites of microneedle insertion, indicating the light-triggered release of R6G from the microneedle. These spots could not be washed or wiped from the skin surface, indicating that the red dye was located within the skin. These red marks on the skin become more apparent as the number of irradiation cycles increased. Only microneedle-created puncture marks were observed on the skin surface in the control group. These results implied that the light-induced phase transition in the polymer enabled a preloaded drug to leak from the

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melted microneedles, and drug release could be repeatedly triggered and enhanced using NIR irradiation.

Figure 6. Bright-field micrographs of R6G-loaded microneedles before insertion and of the samples being removed from the punctured skin after each laser on/off cycle (A) and their corresponding images of the punctured skins (B). No NIR: the microneedles were inserted into the skin only, and were not exposed to the laser for 132 min (i.e. 4 on/off cycles). 17


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Figure 7 shows profiles of the release of R6G from microneedles that were (square) and those that were not (circle) subjected to laser treatment. The red lines in Fig. 7 indicate the periods during which the microneedles were irradiated by the NIR laser. The NIR absorbers embedded in the microneedles heated upon NIR irradiation. The induced heat was transferred to adjacent PCL microneedles, causing the microneedles to melt and a rapid increase in drug release from the microneedles. When the NIR light was switched off, the microneedles cooled and returned to their solid state. Consequently, drug release returned to a near-zero value.

Figure 7. In vitro release profiles of R6G-loaded microneedles with (square) or without (circle) NIR exposure for 4 laser on/off cycles (n = 5 for each data point).

In addition, the amount of the drug released by the composite microneedles could be controlled by adjusting the number of laser on/off cycles. As shown in Fig. 7, cumulative release continually increased as the number of laser cycles increased; the drug-release percentage was 20.9 ± 3.6% (n = 5) in each triggering cycle. However, the drug release of the microneedles that were not exposed to NIR light was negligible. These results indicated 18


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that small molecules can be released repeatedly on demand from the LaB6@SiO2-loaded microneedles. In Vivo Triggered Release of Doxorubicin to Rat Skin To evaluate the in vivo applicability of the NIR-responsive microneedles to anticancer drug delivery, DOX-loaded microneedles were applied to rat skin and then irradiated in 4 laser on/off cycles. DOX was used because of its characteristic orange-red fluorescence, which is easily detectable in tissues. After laser treatment, punctured skin appeared red (Fig. 8A) and emitted a strong fluorescent signal (Fig. 8A− −1) because of the released DOX. No notable drug leakage from the microneedles was observed in the control group, indicating that DOX was released only when triggered by NIR light. These results were further confirmed by histological observations, which revealed that the red DOX released from the triggered microneedles was deposited at the puncture sites (Fig. 8B). The NIR-irradiated microneedles were almost completely melted after 4 complete on/off cycles (Fig. 8C), which was consistent with the results of in vitro triggered release (Fig. 6A).

Figure 8. In vivo triggered release of doxorubicin (DOX) to rat skin. Bright-field micrograph (A) and in vivo fluorescence image (A−1) of microneedle-applied skin with (NIR) or without (no NIR) exposure to laser light for 4 laser on/off cycles. The corresponding histological sections of the insertion sites (B) and bright-field micrographs of microneedles being removed from the inserted skin (C). The dot squares in (A) indicate the microneedle-applied sites. The arrows in (B) point to the microneedle insertion sites.

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To visualize DOX penetration in the vertical direction of the rat skin, the puncture sites were imaged and recorded at increasing depths from the skin surface by using CLSM (Fig. 9). The fluorescence of the DOX was apparent in the skin and spread from the locations of microneedle penetration to the surrounding tissue. A confocal 3-dimensional reconstruction image shows that the maximal penetration depth of DOX in the skin was at least 300 µm. These results revealed that NIR-light-responsive microneedles that can be triggered remotely to release drugs in vivo would enable patients to achieve on-demand and self-administrable dosing of medication.

Figure 9. In vivo transdermal delivery of DOX from NIR-responsive microneedles after being remotely triggered by NIR light for 4 laser on/off cycles. Confocal micrographs and 3-D reconstruction images of penetration of DOX (red) across the rat skin at varying depths.

In this study, the rat skin was exposed to a 50 °C-microneedle for 3 min when the release was triggered. Such temperature may cause thermal injury to the skin. It has been reported that the degree of tissue thermal damage is related to the temperature and duration of contact with the heat source.47 Figure S1A (Supporting Information) shows the micrograph of the microneedle-applied rat skin without (no NIR) and with (NIR) exposure to 20


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laser light. Microneedles without DOX loading were used here to evaluate the heat effect created by this system on the skin. After exposure to 50 °C for 3 min, only mild and localized erythema was found on the skin surface, which was due to the microneedle insertion (Fig. S1A). No adverse events, such as edema or blister, were observed. Furthermore, there was no significant difference in histological features between the no NIR (Fig. S1C) and the NIR groups (Fig. S1D), indicating that 3-min exposure did not induce notable tissue damage. However, it should be noted that long-term exposure to 50 °C would be harmful and should be avoided.

Acute

Toxicity

and

Biodistribution

of

Silica-coated

Lanthanum

Hexaboride

Nanostructures in Rat To determine whether administration of the NIR-triggerable microneedle system was associated with acute toxicity in vivo, rats were treated with microneedles (without drug loading) and then exposed to NIR light for 3 laser on/off cycles (MN with NIR group). Histological examination revealed that the general appearance of the MN-treated tissues was similar to that of the control ones. In the MN with NIR group, no abnormal changes in the liver, kidney or spleen were found and no evidence of inflammatory reactions were observed at 24 h after treatment (Fig. 10A). Body weight loss, particularly that in excess of 10–20%, is an indicative of toxicity.48 In this study, all rats experienced normal weight gain for four weeks (Fig. 10B). Percent body weight change of rats treated with LaB6@SiO2-loaded microneedles did not differ from that of untreated control rats (n = 4, p > 0.05). Further, no abnormal clinical signs and behaviors were detected in both the control and treated groups (data not shown). These results indicated that administration of the NIR-triggerable microneedle system did not induce any apparent toxicity in rats. After NIR exposure for 3 laser on/off cycles, the lanthanum content in various tissues was quantified by ICP-MS to evaluate the clearance of LaB6@SiO2 nanostructures from the skin. The lanthanum content in rat skin quickly decreased (Supporting Information, Table

21


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S1). At 24 h after administration, lanthanum content was undetectable in the skin, demonstrating the LaB6@SiO2 nanostructures released from the microneedles can be cleared from the skin within 1 day. Moreover, lanthanum content cannot be detected in the kidney and spleen, and it was very low in the liver when normalized to the total amount of applied dose. These findings imply that LaB6 are likely to be cleared by transport to the lymphatic system as a result of interstitial fluid drainage or engulfment by immune cells. This is consistent with a recent finding suggesting that nanoparticles are cleared from the skin through the lymphatic system.49 However, the fate of nanoparticles within the lymphatic system remains unclear.49

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Figure 10. Acute toxicity in rat after administration of NIR-responsive microneedles. Representative H&E-stained sections of liver, kidney, and spleen of rats at 24 h after treatment (A) and changes in body weight with time (B, n = 4 for each group). The MN with NIR group was treated with microneedles and then irradiated with NIR light for 3 laser on/off cycles; the control group was not given any treatment.

Conclusion The developed LaB6@SiO2-loaded microneedles exhibit unique features suitable for on-demand triggering and are potentially applicable as a controlled drug-release system. The microneedles undergo rapid thermal transitions from a solid to a liquid state when exposed to external NIR light, enabling the release of encapsulated molecules to be photothermally modulated. They allow on-demand control of the timing and dose of drug released. We suggested that the NIR-light-responsive microneedles are a promising transdermal drug delivery system that enables the patient or physician to adjust therapy precisely to a target effect, thus improving treatment and reducing toxicity.

Supporting Information Available Evaluation of the heat effect of exposure to 50 °C for 3 min on rat skin and the lanthanum content in the organs of rats at 0, 6, and 24 h after administration of NIR-responsive microneedles. This material is available at free of charge via the Internet at http://pubs.acs.org.

Acknowledgments This work was supported by grants from the National Science Council (NSC 100-2628-E-006-029-MY3),

Ministry

of

Science

103-2221-E-006-083-MY3),

and

Ministry

of

and

Technology

Economic

103-EC-17-A-08-S1-204), Taiwan, Republic of China.

23


Affairs

(MOST (TDPA

Biomacromolecules

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References (1)

Kim, M.; Jung, B.; Park, J. H. Hydrogel swelling as a trigger to release biodegradable polymer microneedles in skin. Biomaterials 2012, 33 (2), 668–678.

(2)

Sun, W.; Araci, Z.; Inayathullah, M.; Manickam, S.; Zhang, X.; Bruce, M. A.; Marinkovich, M. P.; Lane, A. T.; Milla, C.; Rajadas, J.; Butte, M. J. Polyvinylpyrrolidone microneedles enable delivery of intact proteins for diagnostic and therapeutic applications. Acta Biomater. 2013, 9 (8), 7767–7774.

(3)

Ke, C. J.; Lin, Y. J.; Hu, Y. C.; Chiang, W. L.; Chen, K. J.; Yang, W. C.; Liu, H. L.; Fu, C. C.; Sung, H. W. Multidrug release based on microneedle arrays filled with pH-responsive PLGA hollow microspheres. Biomaterials 2012, 33 (20), 5156–5165.

(4)

Ling, M. H.; Chen, M. C. Dissolving polymer microneedle patches for rapid and efficient transdermal delivery of insulin to diabetic rats. Acta Biomater. 2013, 9 (11), 8952–8961.

(5)

Lee, J. W.; Choi, S. O.; Felner, E. I.; Prausnitz, M. R. Dissolving microneedle patch for transdermal delivery of human growth hormone. Small 2011, 7 (4), 531–539.

(6)

Chen, M. C.; Huang, S. F.; Lai, K. Y.; Ling, M. H. Fully embeddable chitosan microneedles as a sustained release depot for intradermal vaccination. Biomaterials 2013, 34 (12), 3077–3086.

(7)

Chen, M. C.; Ling, M. H.; Lai, K. Y.; Pramudityo, E. Chitosan microneedle patches for sustained transdermal delivery of macromolecules. Biomacromolecules 2012, 13 (12), 4022–4031.

(8)

Park, J. H.; Allen, M. G.; Prausnitz, M. R. Biodegradable polymer microneedles: fabrication, mechanics and transdermal drug delivery. J. Control. Release 2005, 104 (1), 51–66.

(9)

Timko, B. P.; Dvir, T.; Kohane, D. S. Remotely triggerable drug delivery systems. Adv. Mater. 2010, 22 (44), 4925–4943.

(10) Tong, R.; Hemmati, H. D.; Langer, R.; Kohane, D. S. Photoswitchable nanoparticles 24


Page 24 of 30

Page 25 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

for triggered tissue penetration and drug delivery. J. Am. Chem. Soc. 2012, 134 (21), 8848–8855. (11) Mura, S.; Nicolas, J.; Couvreur, P. Stimuli-responsive nanocarriers for drug delivery. Nat. Mater. 2013, 12 (11), 991–1003. (12) Wu, J.; Paudel, K. S.; Strasinger, C.; Hammell, D.; Stinchcomb, A. L.; Hinds, B. J. Programmable transdermal drug delivery of nicotine using carbon nanotube membranes. Proc. Natl. Acad. Sci. U. S. A. 2010, 107 (26), 11698–11702. (13) Timko, B. P.; Arruebo, M.; Shankarappa, S. A.; McAlvin, J. B.; Okonkwo, O. S.; Mizrahi, B.; Stefanescu, C. F.; Gomez, L.; Zhu, J.; Zhu, A.; Santamaria, J.; Langer, R.; Kohane, D. S. Near-infrared-actuated devices for remotely controlled drug delivery. Proc. Natl. Acad. Sci. U. S. A. 2014, 111 (4), 1349–1354. (14) Davies, A. N.; Dickman, A.; Reid, C.; Stevens, A. M.; Zeppetella, G. The management of cancer-related breakthrough pain: recommendations of a task group of the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland. Eur. J. Pain 2009, 13 (4), 331–338. (15) Bornemann-Cimenti, H.; Wejbora, M.; Szilagyi, I. S.; Sandner-Kiesling, A. Fentanyl for the treatment of tumor-related breakthrough pain. Dtsch. Arztebl. Int. 2013, 110 (16), 271–277. (16) Donnelly, R. F.; Singh, T. R.; Garland, M. J.; Migalska, K.; Majithiya, R.; McCrudden, C. M.; Kole, P. L.; Mahmood, T. M.; McCarthy, H. O.; Woolfson, A. D. Hydrogel-forming microneedle arrays for enhanced transdermal drug delivery. Adv. Funct. Mater. 2012, 22 (23), 4879–4890. (17) Donnelly, R. F.; Garland, M. J.; Alkilani, A. Z. Microneedle-iontophoresis combinations for enhanced transdermal drug delivery. Methods Mol. Biol. 2014, 1141, 121–132. (18) Garland, M. J.; Caffarel-Salvador, E.; Migalska, K.; Woolfson, A. D.; Donnelly, R. F. Dissolving polymeric microneedle arrays for electrically assisted transdermal drug

25


Biomacromolecules

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 26 of 30

delivery. J. Control. Release 2012, 159 (1), 52–59. (19) Bai, Y.; Sachdeva, V.; Kim, H.; Friden, P. M.; Banga, A. K. Transdermal delivery of proteins using a combination of iontophoresis and microporation. Ther. Deliv. 2014, 5 (5), 525–536. (20) Sachdeva, V.; Zhou, Y.; Banga, A. K. In vivo transdermal delivery of leuprolide using microneedles and iontophoresis. Curr. Pharm. Biotechnol. 2013, 14 (2), 180–193. (21) Han, T.; Das, D. B. Potential of combined ultrasound and microneedles for enhanced transdermal drug permeation: A review. Eur. J. Pharm. Biopharm. 2015, 89, 312–328. (22) Nayak, A.; Babla, H.; Han, T.; Das, D. B. Lidocaine carboxymethylcellulose with gelatine co-polymer hydrogel delivery by combined microneedle and ultrasound. Drug Deliv. 2014, 1–12. (23) Woodruff,

M.

A.;

Hutmacher,

D.

W.

The

return

of

a

forgotten

polymer−Polycaprolactone in the 21st century. Prog. Polym. Sci. 2010, 35 (10), 1217–1256. (24) Chen, C. J.; Chen, D. H. Preparation of LaB6 nanoparticles as a novel and effective near-infrared photothermal conversion material. Chem. Eng. J. 2012, 180, 337–342. (25) Lai, B. H.; Chen, D. H. LaB6 nanoparticles with carbon-doped silica coating for fluorescence imaging and near-IR photothermal therapy of cancer cells. Acta Biomater. 2013, 9 (7), 7556–7563. (26) Jiang, F.; Leong, Y. K.; Saunders, M.; Martyniuk, M.; Faraone, L.; Keating, A.; Dell, J. M. Uniform dispersion of lanthanum hexaboride nanoparticles in a silica thin film: synthesis and optical properties. ACS Appl. Mater. Interfaces 2012, 4 (11), 5833–5838. (27) Lin, Y. H.; Feng, C. L.; Lai, C. H.; Lin, J. H.; Chen, H. Y. Preparation of epigallocatechin gallate-loaded nanoparticles and characterization of their inhibitory effects on Helicobacter pylori growth in vitro and in vivo. Sci. Technol. Adv. Mate. 2014, 15, 045006. (28) Lin, Y. H.; Lin, J. H.; Chou, S. C.; Chang, S. J.; Chung, C. C.; Chen, Y. S.; Chang, C. H. 26


Page 27 of 30

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

Berberine-loaded targeted nanoparticles as specific Helicobacter pylori eradication therapy: in vitro and in vivo study. Nanomedicine 2015, 10, 57-71. (29) Nair, M.; Guduru, R.; Liang, P.; Hong, J.; Sagar, V.; Khizroev, S. Externally controlled on-demand release of anti-HIV drug using magneto-electric nanoparticles as carriers. Nat. Commun. 2013, 4, 1707. (30) Fabiilli, M. L.; Wilson, C. G.; Padilla, F.; Martín-Saavedra, F. M.; Fowlkes, J. B.; Franceschi, R. T. Acoustic droplet-hydrogel composites for spatial and temporal control of growth factor delivery and scaffold stiffness. Acta Biomater. 2013, 9 (7), 7399–7409. (31) Epstein-Barash, H.; Orbey, G.; Polat, B. E.; Ewoldt, R. H.; Feshitan, J.; Langer, R.; Borden, M. A.; Kohane, D. S. A microcomposite hydrogel for repeated on-demand ultrasound-triggered drug delivery. Biomaterials 2010, 31 (19), 5208–5217. (32) Hribar, K. C.; Lee, M. H.; Lee, D.; Burdick, J. A. Enhanced release of small molecules from near-infrared light responsive polymer-nanorod composites. ACS Nano 2011, 5 (4), 2948–2956. (33) Yan, B.; Boyer, J. C.; Habault, D.; Branda, N. R.; Zhao, Y. Near infrared light triggered release of biomacromolecules from hydrogels loaded with upconversion nanoparticles. J. Am. Chem. Soc. 2012, 134 (40), 16558–16561. (34) Sun, L.; Ma, X.; Dong, C. M.; Zhu, B.; Zhu, X. NIR-responsive and lectin-binding doxorubicin-loaded nanomedicine from Janus-type dendritic PAMAM amphiphiles. Biomacromolecules 2012, 13 (11), 3581–3591. (35) Fomina, N.; McFearin, C. L.; Sermsakdi, M.; Morachis, J. M.; Almutairi, A. Low power, biologically benign NIR light triggers polymer disassembly. Macromolecules 2011, 44 (21), 8590–8597. (36) Weissleder, R. A clearer vision for in vivo imaging. Nat. Biotechnol. 2001, 19 (4), 316–317. (37) Charati, M. B.; Lee, I.; Hribar, K. C.; Burdick, J. A. Light-sensitive polypeptide

27


Biomacromolecules

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

hydrogel and nanorod composites. Small 2010, 6 (15), 1608–1611. (38) Hoare, T.; Santamaria, J.; Goya, G. F.; Irusta, S.; Lin, D.; Lau, S.; Padera, R.; Langer, R.; Kohane, D. S. A magnetically triggered composite membrane for on-demand drug delivery. Nano Lett. 2009, 9 (10), 3651–3657. (39) Chen, M. C.; Wang, K. W.; Chen, D. H.; Ling, M. H.; Liu, C. Y. Remotely triggered release of small molecules from LaB6@SiO2-loaded polycaprolactone microneedles. Acta Biomater. 2015, 13, 344–353. (40) Lin, Y. H.; Lin, J. H.; Wang, S. H.; Ko, T. H.; Tseng, G. C. Evaluation of silver-containing activated carbon fiber for wound healing study: In vitro and in vivo. J. Biomed. Mater. Res. B Appl. Biomater. 2012, 100, 2288–2296. (41) Chang, M. Y.; Shiau, A. L.; Chen, Y. H.; Chang, C. J.; Chen, H. H.; Wu, C. L. Increased apoptotic potential and dose-enhancing effect of gold nanoparticles in combination with single-dose clinical electron beams on tumor-bearing mice. Cancer Sci. 2008, 99 (7), 1479–1484. (42) Lai, B. H.; Chen, D. H. Vancomycin-modified LaB6@SiO2/Fe3O4 composite nanoparticles for near-infrared photothermal ablation of bacteria. Acta Biomater. 2013, 9 (7), 7573–7579. (43) Schelm, S.; Smith, G. B.; Garrett, P. D.; Fisher, W. K. Tuning the surface-plasmon resonance in nanoparticles for glazing applications. J. Appl. Phys. 2005, 97, 124314. (44) Cheung, K.; Han, T.; Das, D. B. Effect of force of microneedle insertion on the permeability of insulin in skin. J. Diabetes Sci. Technol. 2014, 8(3), 444–452. (45) Olatunji, O.; Das, D. B.; Garland, M. J.; Belaid, L.; Donnelly, R. F. Influence of array interspacing on the force required for successful microneedle skin penetration: theoretical and practical approaches. J. Pharm. Sci. 2013, 102(4), 1209–1221. (46) Zhu, Z.; Gao, N.; Wang, H.; Sukhishvili, S. A. Temperature-triggered on-demand drug release enabled by hydrogen-bonded multilayers of block copolymer micelles. J. Control. Release 2013, 171 (1), 73–80.

28


Page 28 of 30

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Biomacromolecules

(47) Ng, E. Y.; Tan, H. M.; Ooi, E. H. Prediction and parametric analysis of thermal profiles within heated human skin using the boundary element method. Philos. Trans. A Math. Phys. Eng. Sci. 2010, 368 (1912), 655–678. (48) Ullman-Culleré, M. H.; Foltz, C. J. Body condition scoring: a rapid and accurate method for assessing health status in mice. Lab. Anim. Sci. 1999, 49 (3), 319–323. (49) Sykes, E. A.; Dai, Q.; Tsoi, K. M.; Hwang, D. M.; Chan, W. C. Nanoparticle exposure in animals can be visualized in the skin and analysed via skin biopsy. Nat. Commun. 2014, 5, 3796.

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Near-Infrared Light-Responsive Composite Microneedles for On

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