Microfabrication and microfluidic devices for drug delivery

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Microfabrication and microfluidic devices for drug delivery

5

Niko Kimura*, Masatoshi Maeki†, Manabu Tokeshi† Graduate School of Chemical Sciences and Engineering, Hokkaido University, Kita-ku, Sapporo, Japan* Division of Applied Chemistry, Faculty of Engineering, Hokkaido University, Sapporo, Japan†

CHAPTER OUTLINE 1 Introduction .......................................................................................................123 2 Microfabrication and Pharmaceutical Application of Microfluidic Devices .............125 3 Microfluidic Devices for DDS Applications ...........................................................127 4 Conclusion ........................................................................................................133 References ............................................................................................................133

1 INTRODUCTION Carrier-assist drug delivery systems (DDSs) have been developed and expected to be prospective breakthrough in present problems of cancer chemotherapies. DDS carriers enable to control delivering and releasing processes of encapsulated pharmaceutical products. In the last decades, several DDS carriers in 10 nm to 5 μm diameter size range have been developed [1]. Natural materials, phospholipids [2–5] and polysaccharides (chitosan, dextran, and hyaluronan) [6], which expected to show high biocompatibility, were first used as main components of carrier particles. Synthesized lipids and polymers verified that biocompatibility was also employed for the carrier materials [7–9]. Based on the materials, liposomes or lipid nanoparticles (LNPs) [10] and polymeric nano-/microsized carriers (micelles [11–14], vesicles [15, 16], dendrimers [17], and nano-/microgels [18]) were developed as biocompatible and effective DDS carriers. In these DDS carriers, LNPs are the most widely used as the DDS-carrier particles for the cancer chemotherapies [19]. Synthesis of newly functionalized lipids and development of a surface modification technique of carrier particles enhanced the utility of DDS carriers for therapeutic applications [20–22]. These DDS carriers can contribute to improve the performance Microfluidics for Pharmaceutical Applications. https://doi.org/10.1016/B978-0-12-812659-2.00005-3 # 2019 Elsevier Inc. All rights reserved.

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of active targeting to the specific tissues [23–26]. The size of LNPs is also significant factor for therapeutic applications using DDS carriers. The enhanced permeability and retention (EPR) effect is gold standard strategy to obtain better performance for cancer chemotherapy [27, 28]. For the EPR effect, the DDS-carrier size should be controlled smaller than 200 nm. The effect of DDS-carrier size on the biodistribution, bioavailability, and activity has been reported in several papers. In 2000, Saez et al. reported that 100 nm-sized and 160 nm-sized cyclosporine (CyA)-loaded nanoparticles, which were the immunosuppressive drug, showed different organ distributions such as the liver, kidney, and spleen. They found that 160 nm-sized CyA-loaded nanoparticles were accumulated in the liver. However, 100 nm-sized CyA-loaded nanoparticles were homogeneously distributed in each organ. These results indicate that the size difference of DDS carrier may affect bioavailability [29]. In 2005, Hu-Lieskovan et al. firstly reported that systemic application of small interfering RNA (siRNA)-loaded nanoparticles in 50–100 nm size range could achieve safe and sequence-specific inhibition of tumor glowing in a disseminated tumor model. Their work provided breakthrough in the conventional naked siRNA delivery [30]. In the last few years, the strategy of DDS-carrier size-based cancer therapy has been shifted to use sub-100 nm-sized carrier particles. In 2011, Cabral et al. revealed different accumulability and permeability in hypovascular tumors using polymer micelles loaded with 1,2-diaminocyclohexane-platinum(II) (DACHPt) with diameters of 30, 50, 70, and 100 nm. They demonstrated that the carrier particle size from 50 to 100 nm did not show any size dependency on extravasation and penetration in highly permeable tumors. However, only 30 nm-sized carrier particles showed permeability in hypovascular tumors [31]. Controlling the LNP size in the size range of 20–100 nm is essential technique for the DDS-carrier size-based cancer therapy. For the conventional LNP production methods [32–35], precise controlling the LNP size and producing the small-sized LNPs are difficult due to the nonuniform reaction, and mixing time arises from batch-scale reaction system. This feature of the conventional reaction system affects the LNP size distribution. Flow-based reaction system in microfluidic devices offers many advantages in the pharmaceutical production. Microfluidic device can flexibly operate the chemical reaction and continuously produce the target pharmaceuticals including DDS-carrier particles. For the production of the DDS-carrier particles, the shorter diffusion length of microchannel compared with the conventional methods makes the precise LNP size control and production of the small-sized LNPs possible. In addition, microfluidic device enables the on-demand LNP production. Therefore, both of the reduction of sample consumption for screening and the mass production of DDS-carrier particles for the practical applications can be compatible by using the microfluidic device. From these unique features, microfluidic devices have been paid attention as novel apparatus in the field of DDS-carrier particle production. This chapter provides LNP production methods using microfluidic devices and overview from the microfabrication to DDS-carrier production and its application for DDS.

2 Microfabrication and pharmaceutical application

2 MICROFABRICATION AND PHARMACEUTICAL APPLICATION OF MICROFLUIDIC DEVICES A variety of microfabrication techniques have been developed depending on the kinds of substrates of the microfluidic device. Silicon, glass, polydimethylsiloxane (PDMS [36]), polymethyl methacrylate (PMMA), polycarbonate (PC), and stainless are the common substrates for microfluidic devices. Micromachining process is one of the simplest fabrication methods, and it can use silicon, glass, plastics, and stainless as substrates for microfluidic devices. In the case of the micromachining process, a design of microchannel is created by a computer-aided design (CAD) software and patterned the microchannel onto the substrate directly. For fabrication of silicon and glass substrates, chemical etching process can make a precise and smooth microchannel structure without cutting traces. The microchannel design is patterned by photolithography technique (or electron-beam lithography for nanochannel structure) with or without the designed photomask prior to start the chemical etching process [37] (Fig. 5.1A). In wet etching process for silicon substrate, hydrofluoric acid is used as an etchant, which enables isotropic etching on silicon and glass substrates. The etching rates are 1–3 μm/min and slower than 2 μm/min for silicon and glass substrates, respectively [38, 39]. Anisotropic etching of silicon substrate is available by using potassium hydroxide as an etchant, and the etching rate is 0.1–1 μm/min at 80°C [40]. Dry etching process using active radicals or reactive gaseous plasmas like CF4, SF6, and C4F8 can fabricate finer micro- and nanostructures on a silicon and glass substrates compared with wet etching process. However, the etching rate is slower than that of the wet etching process. The etching rates are slower than 1 μm/min and 30 nm/min for silicon and glass substrates, although it is varied by the operating condition [41, 42]. Microstructures with high

FIG. 5.1 Microfabrication process: (A) photolithography and etching and (B) soft lithography.

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aspect ratio onto silicon wafers can be made by deep reactive ion etching (DRIE [43]) [44, 45]. These etching processes are generally used for the fabrication of microstructures with 10–100 μm depth. Soft lithography process is usually used for the rapid prototyping PDMS device fabrication [46]. As shown in Fig. 5.1B, PDMS prepolymer is poured onto a master mold fabricated by photolithography followed by baking to obtain a PDMS replica. Soft lithography is the most widely used microfabrication method for PDMS device, because the master mold can be used repeatedly. Soft lithography method is generally employed for fabricating microstructures with 10–200 μm. The deeper microstructure is able to fabricate using a master mold made by thicker photoresist layer. PDMS replica (or substrate) has also optical clear characteristic like glass substrate and unlike gas permeability. These properties are preferable for the analytic chemistry and biological applications; therefore, PDMS is the most major substrate in the microfluidic device. After optimizing the microchannel structure using PDMS device, injection molding and hot embossing methods are suitable for the mass production of disposable microfluidic device [47]. The type of substrates should be selected relying on the experimental conditions such as dimension of microchannel structure, solvent resistance of substrates, and flow pressure. For practical pharmaceutical application, flow-based chemical synthesis systems using the microfluidic device have been reported. Kikutani et al. developed a glass microfluidic device with 240 μm width and 60 μm depth microchannel for phase transfer amide formation reactions [48]. Glass substrate has great solvent resistance to organic solvents and strong acids. Therefore, glass microfluidic devices are useful for various chemical reactions. De Mas et al. reported a unit operation integrated silicon device with 435 μm width and 305 μm depth microchannel for direct fluorination of aromatics [49]. The silicon device enabled to control the reaction temperature safely by effective cooling rates, because the silicon substrate showed high thermal conductivity and the shorter diffusion length of microscale system improved the reaction efficiency at the gas-liquid interface. Park et al. developed a dual-channel PDMS microreactor chip with 300 μm width and 50 μm depth microchannel for photosensitized oxygenation [50]. The microreactor consisted of a polyvinylsilazane (PVSZ) shielded upper channel for liquid flow with an organic solvent and a lower channel for oxygen flow. PDMS membrane is used for separating these channels and continuously supplying oxygen from the lower channel to the upper channel. Microchannel improved a problem of a short lifetime of activated singlet oxygen in organic solvent and reduction of a reaction efficiency at diffusion process. However, one of the drawbacks of the PDMS device is limitation of available organic solvent due to the swelling of low-polarity organic solvents. Therefore, the upper microchannel was shielded with PVSZ after PDMS replica fabrication to prevent the swelling of the organic solvent. Microfluidic devices allow the precise reaction time control by the shorter diffusion length of microchannel and the rapid mixing compared with the batchwise reaction systems [51]. These characteristics of the microfluidic device are useful for the production of pharmaceuticals including DDS-carrier particles. Parallelization or numberingup of the microfluidic devices enables the mass production of pharmaceuticals.

3 Microfluidic devices for DDS applications

3 MICROFLUIDIC DEVICES FOR DDS APPLICATIONS For DDS-carrier application, precisely size-controlled LNPs are desired for the cancer chemotherapy. In the several conventional LNP preparation methods, organic solvent injection method makes a single step of LNP production possible. In brief, lipid solution dissolved in organic solvent, such as ethanol and t-butyl alcohol, is injected into aqueous solution. LNPs are formed by self-assembly of lipid molecules. In this LNP formation process, lipid molecules are spontaneously aggregated by decreasing its solubility and start to form an intermediate structure. The intermediate structure finally turns into LNPs [52, 53]. When the organic solvent is diluted rapidly by the aqueous solution, the small-sized LNPs are able to form with narrow particle size distribution. Therefore, the vortex mixing is usually used for the LNP production by the conventional organic solvent injection method. A microchannel can promote the dilution rate of organic solvent by shorter diffusion length. In addition, micromixer structures enable the rapid dilution of organic solvent than that of the typical microchannels. Although many micromixer structures have been developed [54, 55], the chaotic mixer reported by Strook et al. showed great liquid mixing performance [56]. For the LNP production, the chaotic mixer is the most widely used microfluidic device in the world. In 2012, Zhigaltsev et al. reported a production of 20 nm-sized LNP using the chaotic mixer [57]. They found that LNP size was able to be controlled by flow rate and flow rate ratio (aqueous solution/lipid solution) (Fig. 5.2). Doxorubicin used as an antineoplastic agent was loaded into the 20 nm-sized LNPs by remote loading method, and the encapsulation efficiency was 60%–100%. Chen et al. reported rapid screening of lipid formulations for siRNA-loaded LNPs using the chaotic mixers (Fig. 5.3) [58]. Discovery of potent new materials for LNP-based DDS application is essential, because the carrier materials directly affect the performance of LNPs. To confirm the best materials and formulations, a large amount of siRNA-loaded LNPs is prepared to test in vitro and in vivo experiments. Therefore, rapid LNP production using microfluidic device expects to provide more effective screening system than the conventional LNP production methods. They explored the potency of lipid-like materials from a total number of 70 compounds using the chaotic mixer device. Synthesized siRNA-loaded LNPs were evaluated by remaining gene expression in vitro and in vivo experiments. The reported method facilitated the screening process of lipid formulation for LNP-based DDS application and enabled the reduction of large amount of sample consumption. Understanding the LNP formation behavior in a microchannel is the most important for the precise LNP size control. Dilution of the organic solvent is the driving force of the LNP formation process, regardless of the microfluidic the conventional organic solvent injection method. Thus, effects of the fluid dynamics in a microchannel on the LNP formation behavior should be elucidated to apply the LNP-based DDS-carrier particles for practical use. The number of chaotic mixer structures, dimensions of the microchannel and mixer structures, and flow conditions affect the fluid dynamics. Maeki et al. have reported the LNP formation mechanism in microfluidic devices using various types of chaotic mixers [59, 60]. In particular,

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FIG. 5.2 Chaotic mixing can produce limit size LNPs (20 nm diameter). Cryo-TEM micrographs of limit size LNP composed of (A) 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocoline (POPC), (B) POPC/cholesterol (55:45; mol/mol) and (C) POPC/triolein (60:40; mol/mol) produced at an aqueous/ethanol flow rate ratio of 3. Reprinted from I.V. Zhigaltsev, N. Belliveau, I. Hefez, A.K.K. Leung, J. Huft, C. Hansen, P.R. Cullis, Bottom-up design and synthesis of limit size lipid nanoparticle systems with aqueous and triglyceride cores using millisecond microfluidic mixing. Langmuir 28 (2012) 3633–3640 with the permission from the American Chemical Society.

the relationship between the fluid dynamics in microchannels and LNP formation behavior was investigated. The LNP formation experiments using the microfluidic device equipped with 31 μm depth chaotic mixers were carried out by changing the flow conditions and the number of chaotic mixer structures (Fig. 5.4A) [61]. For a model lipid solution, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) was dissolved in ethanol at a concentration of 10 mg/mL. Saline was used as an aqueous solution. LNP size was decreased with increasing the total flow rate and the flow rate ratio (flow rate of the aqueous solution to the lipid solution). Fig. 5.4B and C shows the

3 Microfluidic devices for DDS applications

FIG. 5.3 Schematic illustration of siRNA-loaded LNP production system: (A) effective diameter of the siRNA-LNPs as a function of the mixing flow rate. (B) Cryo-TEM image of siRNA-LNPs prepared in the microfluidic device at 300 μL/min. (C) Microfluidic-formulated siRNA-LNPs had a narrower size distribution than pipet-mixed particles. Reprinted from D. Chen, K.T. Love, Y. Chen, A.A. Eltoukhy, C. Kastrup, G. Sahay, A. Jeon, Y. Dong, K.A. Whitehead, D.G. Anderson, Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation. J. Am. Chem. Soc. 134 (2012) 6948–6951 with the permission from the American Chemical Society.

relationship between the number of chaotic mixer structures and the LNP size. This result indicates that at least 10 cycles of mixer structures were needed to produce the LNPs smaller than 50 nm. However, the fluid dynamics visualization experiment using a confocal microscope and a fluorescent lipid revealed that the solutions were not completely mixed under the flow conditions in the microchannel. These results

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FIG. 5.4 (A) Schematic illustration of microfluidic device with 69 cycle numbers of staggered herringbone micromixers (SHM). The distance between the merging point of solutions and the first SHM was 1, 6, and 15 mm. Microfluidic devices were equipped with 0, 2, 6, 10, and 20 SHM cycle numbers. (B) Dependence of LNP size on flow rate ratio (FRR) and the SHM cycle number (n ¼ 3). (C) Size distributions of LNPs formed in the microfluidic devices with 2, 6, and 10 SHM cycle numbers at the FRR of 3. Reprinted from M. Maeki, T. Saito, Y. Sato, T. Yasui, N. Kaji, A. Ishida, H. Tani, Y. Baba, H. Harashima, M. Tokeshi, A strategy for synthesis of lipid nanoparticles using microfluidic devices with a mixer structure. RSC Adv. 5 (2015) 46181–46185 with the permission from Royal Society of Chemistry.

suggest that rapid dilution of ethanol was more significant than complete mixing for precise LNP size control. To understand the LNP formation behavior in detail, the effect of ethanol dilution rate on the LNP size was investigated using the microfluidic devices with different depth of chaotic mixer structures [62]. Microfluidic devices with 0 (without mixer structures), 11, and 31 μm depth of chaotic mixer structures determined the LNP formation behavior and the mixing performance. The mixing performance of the microfluidic device showed a dependency on the height of chaotic mixer structures. The microfluidic device equipped with 31 μm depth chaotic mixers enabled the dilution of ethanol more effectively among the three microfluidic devices. Fig. 5.5 shows the effect of mixing performance of the microfluidic devices on LNP size. Fifty-to-sixty-

3 Microfluidic devices for DDS applications

FIG. 5.5 Evaluation of mixing performance of the chaotic mixer devices. Comparison of mixing rate for 500 ms between the CM_11 and CM_31 devices at FRR of 3. Reprinted from M. Maeki, Y. Fujishima, Y. Sato, T. Yasui, N. Kaji, A. Ishida, H. Tani, Y. Baba, H. Harashima, M. Tokeshi, Understanding the formation mechanism of lipid nanoparticles in microfluidic devices with chaotic micromixers. PLoS One 12 (2017) e0187962 with the permission from Public Library of Science.

nanometer LNPs formed using the 31 μm depth chaotic mixer device, regardless of the total flow rate, and 11 μm depth chaotic mixer device at 500 μL/min. Although the times necessary to reach the 80% mixing rate were different among these conditions, similar-sized LNP formed at the preparation conditions. From the view point of ethanol dilution, the ethanol concentration of 60%–80% (20%–40% mixing rate) was a critical ethanol concentration that influenced the final LNP size. These results indicate that for production of 30, 40, and 50 nm-sized LNPs, the residence time at the estimated critical ethanol concentration should be 10, 15–25, and 50 ms, respectively. Sato et al. produced a practical siRNA delivery nanocarrier using the chaotic mixer device [63]. The lipid solution was prepared using a pH-sensitive cationic

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FIG. 5.6 (A) Representative TEM micrographs of 1% PEG-LNPs (50 nm) and 3% PEG-LNPs (30 nm). Scale bars represent 50 nm. (B) Intrahepatic distribution of siRNAs delivered by the produced LNPs. Blood vessels and siRNAs are visualized as green and red, respectively. Scale bars represent 50 μm. Reprinted from Y. Sato, Y. Note, M. Maeki, N. Kaji, Y. Baba, M. Tokeshi, H. Harashima, Elucidation of the physicochemical properties and potency of siRNA-loaded small-sized lipid nanoparticles for siRNA delivery. J. Control. Release 229 (2016) 48–57 with the permission from Elsevier.

lipid, YSK05 [64] that has superior function of siRNA encapsulation, and 25 mM acetate buffer solution (pH 4.0) containing 0.071 mg/mL siRNA. The siRNA-loaded LNPs precisely size tuned in 30 and 50 nm were produced by mixing of these solutions in the microfluidic device with chaotic mixers. Both the 30 and 50 nm-sized LNPs showed excellent siRNA encapsulation rate higher than 90% and good gene silencing activity at mice hepatocytes. A difference of the biodistribution between the 30 nm and 50 nm LNPs was observed by in vivo experiment. Thirty-nanometer LNPs were delivered more specifically to mice hepatocytes than 60 nm-sized LNPs did (Fig. 5.6). Microfluidic devices with chaotic mixers can achieve rapid ethanol dilution in millisecond timescale. Therefore, small-sized LNPs expected to provide good penetration efficiency can be produced with narrower size distribution using microfluidic devices with chaotic mixers compared with the conventional methods. The LNP productivity of a single microfluidic device is small scale, which is roughly calculated to be several hundred milliliters per 1 hr. One of the great advantages of microfluidic device is parallelization or numbering-up of the microfluidic device. These scale-up methods enable mass production of LNPs even though the LNP size controllability does not change unlike the batchwise scale-up method [64]. Enlargement of the microchannel aspect ratio (channel width and depth) also could achieve the scale-up LNP production, because the microchannel offers the shorter diffusion distance than that of the batch-scale reaction system [64].

References

4 CONCLUSION For the development of carrier-assist DDS, precise size control of carrier particles is significant, because the biological performance and biodistribution of carrier particles depend on the size. Discovery of appropriate materials for providing the great therapeutic effect requires many in vitro and in vivo testing. Microfluidic devices offer rapid production of precisely size-controlled DDS carriers with low sample consumption. Notably, the chaotic mixer device is the most widely used for the LNP production. Rapid dilution of organic solvent of lipid solution by chaotic mixers enables smaller-sized LNP synthesis with narrower size distribution than that of the conventional synthesis. In addition, the chaotic mixer device also allows to produce practical siRNA delivery nanocarriers. Further understanding of LNP formation process is indispensable to improve the size controllability and productivity of LNP synthesis using microfluidic devices. The microfluidic devices are prospective apparatus for DDS-carrier production. The precise size-controlled LNPs produced by microfluidic devices are expected to accelerate the development of next-generation nanomedicine for DDS application.

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