Mesoporous Colloidal Photonic Crystal Particles for Intelligent Drug

Subscriber access provided by Kaohsiung Medical University

Biological and Medical Applications of Materials and Interfaces

Mesoporous Colloidal Photonic Crystal Particles for Intelligent Drug Delivery Xiaoxiao Gu, Yuxiao Liu, Guopu Chen, Huan Wang, Changmin Shao, Zhuoyue Chen, Peihua Lu, and Yuanjin Zhao ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.8b11175 • Publication Date (Web): 14 Sep 2018 Downloaded from http://pubs.acs.org on September 14, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 32 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

ACS Applied Materials & Interfaces

Mesoporous Colloidal Photonic Crystal Particles for Intelligent Drug Delivery †,‡

†

§

†

†

Xiaoxiao Gu, Yuxiao Liu, Guopu Chen, Huan Wang, Changmin Shao, Zhuoyue Chen,

†

Peihua Lu,*,‡ Yuanjin Zhao*,† †

State Key Laboratory of Bioelectronics, School of Biological Science and Medical Engineering,

Southeast University, Nanjing 210096, China ‡

Department of Medical Oncology, Wuxi People’s Hospital, Nanjing Medical University, Wuxi,

214023, China §

Department of General Surgery, Jinling Hospital, Medical School of Nanjing University,

Nanjing 210002, China Keywords: mesoporous; colloidal crystals; drug delivery; particle; microfluidics

Abstract

Particle-based delivery systems demonstrate a pregnant value in the fields of drug research and development. Efforts to advance this technology are focusing on the fabrication of functional particles with enhanced efficiency and performance for drug delivery. Here, we present a new type of mesoporous colloidal photonic crystal particle (MCPCP)-based drug delivery system

ACS Paragon Plus Environment

1

ACS Applied Materials & Interfaces 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 2 of 32

with distinct features. As the MCPCPs were constructed by self-assembling of monodisperse mesoporous nanoparticles in microfluidic droplet templates, they were with hierarchical macroand mesoporous structures, and could provide plenty of nanopores and interconnected nanochannels for synergistic loading of both micro- and macro-molecule drugs with large quantity and sustained releasing. In addition, by integrating stimuli-responsive poly(Nisopropylacrylamide) (pNIPAM) hydrogel into the MCPCPs and employing it as a “gating” to control the opening of the macro- and mesopores, the MCPCPs delivery systems were imparted with the function of controllable releasing. More attractively, as the average refractive index of the MCPCPs was decreased during the releasing of the loaded actives, the photonic band gaps (PBGs) of the MCPCPs blue shifted correspondingly; this provided a novel stratagem for real time self-reporting the therapeutic agents releasing process of the MCPCPs. Thus the MCPCPs are ideal for intelligent drug delivery due to these dramatical features.

1. Introduction Particle-based delivery systems have received increasing attention in the area of drug research and development1-5. Compared with conventional administration approaches by way of long-term frequent oral administration or injections to maintain a constant drug concentration, which usually lead to the inconvenience of administration, potential overdose and patient pains, particle-based systems can deliver drugs at specific site to reduce systemic side effects and enhance the drug delivery efficiency6-11. These could effectively improve the bioavailability, therapeutic efficacy12-14, and safety of drugs15, and ultimately relieve the pains of patients. Among different particle-based systems of gold, iron, polymers, liposomes, metal organic


2

Page 3 of 32 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


frameworks (MOFs), mesoporous silica nanoparticles (MSNs), etc16, MSNs have been frequently used as drug carriers due to their distinct features, such as large surface areas, strong loading capacity, steady pore volume, convenient surface functionalization, excellent biocompatibility, and so on17-25. In addition, by attaching organic molecules “gating” at the opening pore of the MSNs26-28, decorating the nanoparticles with polymer shells, or encapsulating them into polymer materials29, stimuli-responsive drug delivery nanosystems can be achieved for many valuable applications30-34. However, due to the tiny size of mesoporous channel, most of the MSNs could only load small molecular actives, and need additional complex surface modifications to adsorb macro-molecule activities35. These limited the diversity of drug loading in the MSN-based delivery systems. Furthermore, stratagem for real-time selfmonitoring of the molecule release process from the MSNs, which is essential to assess the efficency of the delivery system, is lacking. Therefore, the development of functional mesoporous materials is still expected to realize intelligent drug delivery systems. In this paper, we report a novel mesoporous colloidal photonic crystal particle (MCPCP)based delivery system with the features of synergistic loading of both micro- and macromolecule drugs, as well as real-time self-monitoring the releasing process. Colloidal photonic crystals (CPCs) are a kind of 3D highly ordered macro porous material which can be quickly assembled from monodisperse nanoparticles36-39. The periodic variety in the refractive index of the assembled materials brings about amusing optical properties, such as photonic band gaps (PBGs) and vivid structural colors, which have great prospects in the fields of biosensor, multiplex analysis and cellular morphology40-43. Particularly, when the CPCs were assembled by the MSNs44-46 (termed as MCPCs), they are imparted with hierarchical macro- and mesoporous structures and possess much higher specific surface area for improving their adsorption


3


Page 4 of 32

capability, and thus have acted a considerable role in visual adsorption, gas sensing, dynamic security, etc47-48. However, the potential value of the MCPCs in drug delivery remains unexplored, and their current forms of bulk films have also restricted their potential role as the delivery systems. Thus, we herein constructed the spherical MCPCs (MCPCPs) via self-assembly of monodisperse MSNs in microfluidic droplet templates, as schemed in Figure 1a. The resultant MCPCPs were with tailorable sizes and hierarchical macro- and meso-porous structures, which provided large surface areas, numerous nanopores and intricate nanochannels for synergistic loading of both micro- and macro-molecule drugs with large quantity and sustained releasing. In addition, by integrating thermo-sensitive poly (N-isopropylacrylamide) (pNIPAM) hydrogel into the MCPCPs, both the macrovoids of the MCPCPs and the surfaces of MSNs were capped with a “gating” to control the opening of their macro- and mesopores, which was superior to those previous nanoparticle systems. Therefore the delivery systems were imparted with the function of controllable releasing. More importantly, with the releasing of the loaded actives, the average refractive index of the MCPCPs was decreased, and the PBGs of the MCPCPs blue shifted correspondingly. Thus, the process of the therapeutic agents releasing from the MCPCPs could be self-monitored simultaneously. These crucial features enable the MCPCPs ideal for drug delivery systems.


4

Page 5 of 32 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


Figure 1 (a) Schematic of the fabrication process of the MCPCPs by a droplet microfluidic device. (b) The schematic diagrams of the DOX and protein synergistic delivery system and its drug release process. 2. Experimental Section Materials. Mesoporous silica nanoparticles (MSNSs) with size of 224, 235, 252, 277, 298 nm and with 30, 40, 50 nm mesoporous shells were purchased from NanJing Nanorainbow Biological Technology Co., Ltd. N-hexadecane was purchased from Sinopharm Chemical Reagent Co., Ltd. Doxorubicin (DOX) hydrochloride, N-Isopropylacrylamide (NIPAM, 97%), Poly (ethylene glycol) diacrylate (PEGDA, average molecular weight of 700) and 2-hydroxy-2methylpropiophenone photoinitiator were purchased from Sigma-Aldrich (St. Louis, MO, USA). N-Methylolacrylamide was purchased from Aladdin Industrial Corporation (Shanghai, China). Albumin bound paclitaxel (ABP) was purchased from Celgene Corporation. Albumin bovine


5


Page 6 of 32

serum-FITC (FITC-BSA) was purchased from ZhongKeChenYu Biological Technology Co., Ltd. Phosphate buffered saline (PBS, PH=7.4) were prepared in our laboratory and deionized water was gained from a Millipore Milli-Q system. In addition, all other chemical reagents were the best available and used as received. The deionized water was utilized for all experiments. Fabrication of mesoporous colloidal photonic crystal particles. One capillary microfluidic chip was composed of two coaxial cylindrical capillary tubes (outer and inner) nested in a square capillary. All glass capillaries were acquired from World Precision Instruments, Inc. The inner capillary was coned by a laboratory portable Bunsen burner and polished to reach an orifice diameter of about 100 µm. The inner phase was comprised of 20% MSN (w/v) dispersed in deionized water and the outer phase was n-hexadecane with 1% surfactant. Each fluid was injected to the microfluidic device by a glass syringe through a polyethylene tube. (The glass syringe and the polyethylene tube were purchased from SGE Analytical Science and Scientific Commodities Inc. respectively.) These fluids were pumped by a syringe pump (Harvard PHD 2000 Series). The flow rates of the outer and inner phase were 5 mL/h and 0.5 mL/h, respectively. (The speed of outer phase could be adjusted from 3mL/h to 7mL/h and the speed of inner phase could be adjusted from 0.1 mL/h to 0.5 mL/h.) The MSN solution was cut into emulsion droplets by the outer phase at the junction of the microfluidic device. The MSN droplets were collected in Teflon treated metal box with a layer of n-hexadecane on the bottom, and this container was heated at the temperature of 60℃. The MSNs gradually self-assembled into ordered arrangement during the water evaporation in the droplets at the temperature of about 60℃ in the container. After solidification overnight, the mesoporous colloidal crystal particles were transferred from the n-hexadecane solution to the crucible and subsequently calcined at 550℃ for 3 to 4 hours to


6

Page 7 of 32 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


enhance their mechanical strength. Finally, the Mesoporous Colloidal Photonic Crystal Particles (MCPCPs) were obtained. Characterization. The microstructures of the MSNs were observed by a transmission electron microscope (TEM, JEOL, JEM-2100). The microstructures of the MCPCPs were observed by a scanning electron microscope (SEM, Hitachi, S-300N). The reflection photos of the MCPCPs were obtained from a metalloscope (OLYMPUS BX51) with a color CCD camera (Media Cybernetics Evolution MP 5.0). Characteristic reflection peaks of the MCPCPs were detected by the metalloscope (OLYMPUS BX51) with a fiber optic spectrometer (Ocean Optics, QE65000). Micro-/macro-molecule drug loading and releasing in vitro. 0.5, 1 and 1.5 mg/mL DOX and 5, 10 and 15 mg/mL FITC-BSA were previously prepared. The MCPCPs composed of MSN@30nm, MSN@40nm and MSN@50nm were immersed into the DOX/FITC-BSA solution for a whole day. Then the particles were taken out and washed in the PBS quickly to get rid of the drugs remaining on the surface of particles and subsequently dried in the air to obtain the DOX-MCPCPs/FITC-BSA-MCPCPs. The fluorescent cross-sectional photos were obtained by a confocal microscope (OLYMPUS FV500-IX81). The loading amounts of DOX/FITC-BSA were obtained by subtracting the free unload amounts of DOX/FITC-BSA in the solution from the total drugs used initially. And the loading amounts of the free drugs could be detected through the ultraviolet spectroscopy method at 480 nm/493 nm with a microplate reader (SYNERGY|HTX). To detect the drug release kinetics, ten drug-loaded MCPCPs were put in a centrifuge tube filled with 1mL PBS and oscillating incubated at the room temperature. In addition, the drug release amounts were calculated through the changes of the fluorescence of the MCPCPs. At every fixed time, the fluorescence images of DOX-MCPCPs were taken by the


7


Page 8 of 32

microscope (OLYMPUS BX53) equipped with a high resolution CCD (OLYMPUS DP73), and to maintain the same experimental condition, 0.5 mL supernatants were removed and the equal amount of new PBS was replenished into the centrifuge tube. The fluorescence images were processed by the ImageJ software to calculate the optical density (OD) value of the MCPCPs. Synergistic drug loading, controlled releasing in vitro and monitoring experiment. DOXMCPCPs (MSN@50nm) were prepared by immersing into the DOX (1 mg/mL) solution for more than 24 hours and then dried in the air. FITC-BSA (10 mg/mL) was diffused in the NIPAM pre-gel solution which was comprised of N-isopropylacrylamide and N-methylolacrylamide (9:1, 20% v/v), 2-hydroxy-2-methylpropiophenone (1% v/v), poly (ethylene glycol) diacrylate (5% v/v) and deionized water. The dried DOX-MCPCPs were immersed into the FITC-BSA-NIPAM pre-gel solution for more than 2 hours that enabled the pre-gel solution to fill the macro-porous entirely. Afterwards, the pre-gel solution was polymerized in and out of the particles upon UV irradiation (365nm, 100W). The UV light intensity was relatively weak, and the irradiation time was no more than 30 seconds. The prepared hydrogel containing MCPCPs was immerged into the buffer solution. Due to the space constraints of the solid particles, the hydrogel locked in the interior of the particles has a smaller volume expansion than the external hydrogel, which leads to the the formation of gaps between the particles and hydrogel. Thus, the MCPCPs could be peeled off from the hydrogel by a stirrer, and then the drug-loaded MCPCPs were filtered from the buffer solution. The size and morphology of the final drugs loaded MSNs assembly were the same as the MCPCPs from about 5 to 100 microns and with a great shape of sphere. Meanwhile, the final drug loaded particles had the well uniformity. For the temperature-responsive release, ten prepared DOX- (FITC-BSA)-MCPCPs were put in the PBS (1 mL, PH 7.4) in a centrifuge tube. The centrifuge tube was placed at 40°C for about


8

Page 9 of 32 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


15 minutes to reach a shrinking state and then kept at room temperature for more than 15 minutes to recover back to swelling state. To maintain the constant condition after each temperature change, 0.5 mL supernatants were removed and the equal amount of fresh PBS was added into the centrifuge tube. Fluorescent images of DOX-(FITC-BSA)-MCPCPs under green and blue light excitation were taken and processed by the ImageJ software, respectively. During the release process, the reflection spectra of the drug-loaded MCPCPs with MSN@30nm,40nm and 50nm were recorded after every release procedure. The effects of the synergistic drug delivery system on tumor cells. The effects of this synergistic drug delivery system on tumor cells were assessed by the way of cell viability analysis treated with the different kinds of generated microparticles. The human hepatoma (HepG2) cells were chosen in this experiment, and the cells were classified into four groups, that were treated by unloaded-MCPCPs (1 mg/mL), DOX-MCPCPs (1 mg/mL), ABP-MCPCPs (1 mg/mL) and DOX-ABP-MCPCPs (1 mg/mL), respectively. The four groups of cells were seeded in a 12-well plate (each group occupied 3 wells) with 3 mL Dulbecco’s modified eagle medium (DMEM) in each well for about 24 hours. The 12-well plate together with particles and tumor cells were incubated at 37℃ for 24 hours. Thereafter, the HepG2 cells were observed by the optical and fluorescent microscopes, respectively. Besides, the cell viability was assessed by MTT assay. To obtain the fluorescent images of cell configurations, the cultured HepG2 cells were cultured with calcein-AM (2 µg/mL, 15min, 37℃) in the darkness. Then the cells were washed by PBS and observed by fluorescent microscope to obtain the images. To prepare the MTT assay, MTT powders were dispersed in PBS (5 mg/mL). Each well was added in 10% MTT and


9


Page 10 of 32

incubated at 37℃ for about 4 hours in darkness. Thereafter, the previous liquid was removed and 1mL dimethyl sulfoxide (DMSO) was added to per well, dissolving the formazan crystals. Each 100 µL solution was taken out and transferred into a 96-well plate. The plate was detected through the ultraviolet spectroscopy method at 490nm with a microplate reader. The relative cell viability (%) was calculated by the equation: Cell viability (%) = [Absorbance]experimental/[Absorbance]control ×100%. Antitumor efficacy in vivo. Nude mice were applied to the research of antitumor efficacy in vivo. Approximately 1×108 BCG-823 cells were resuspended in 500 µL of serum-free medium and then injected into the armpit of mice subcutaneously. When tumors grew for 7 days, all mice were randomly divided into two groups (nine for each). On the 8th day, physiological saline and drug-loaded MCPCPs (1g/kg) were subcutaneously injected into the tumor-bearing mice by the syringe with 23G needle. And the injected MCPCPs were dispersed in viscosity hydrogels such as sodium alginate to control their precipitation. On day 1, 3, 7 after injection, three mice of each group were killed and the tumors were exposed. Photos were taken by the digital camera to observe the size of tumors. Then the tumors were excised and weighed. 3. Results and Discussion In a typical experiment, a capillary microfluidic device for the fabrication of water-in-oil (w/o) droplet templates was composed of two coaxial cylindrical capillaries (outer and inner) nested in a square capillary. The generation process of the MCPCPs by the microfluidic chip was shown in Figure S1a. The inner phase was consisted of deionized water with different concentration of MSNs and the outer phase was n-hexadecane with 1% surfactant. When these


10

Page 11 of 32 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


two phases flowed through the microfluidic channels, the dispersed phase was cut into monodispersed droplet templates by the continuous oil phase. The diameters of the droplets could be well controlled from several to hundreds of micrometers by adjusting the flow rates of the dispersed and continuous phase (Figure S1b). The MSNs were closely packed in the droplet templates and induced into a highly ordered arrangement in the MCPCPs during the water evaporation in the droplet templates. The diameters of the MCPCPs were determined by the diameters of the droplet templates and the concentrations of the MSNs in the droplets (Figure S1c-e). It was worth to mention that during the water evaporation and MSNs assembly, the continue oil phase would penetrate into the mesoporous shells and void spaces of the MSNs, which was difficult to be removed by using organic solvents. Thus long-chain alkanes were used as the out phase for the self-assembly of the MCPCPs as they could be pyrolyzed thoroughly by calcining. The high temperature of the calcination could strengthen the van der Waals forces between each nanoparticle. Moreover, MSNs in the particles shrank and melted slightly, which made particle adhesion occurred between the adjacent MSNs and improved the stability of the MCPCPs. However, the particular structure of MSNs would be collapsed if the calcination temperature exceeded a range (Figure S2). Therefore, an optimized temperature at approximately 500℃ was employed for treating the MCPCPs. These MCPCPs were stable for shaking and mixing in physiological solution. The micro-structures of the MCPCPs were characterized by using a field emission scanning electron microscope, as shown in Figure 2a-c. It was obviously that the MCPCPs had a great shape of sphere (Figure 2a). The high magnification images of a MCPCP surface showed that the MSNs mainly induced a highly ordered hexagonal close packing arrangement (Figure 2b), and the ordered structure also extended to the inner of the MCPCP (Figure 2c). Thus, the void


11


Page 12 of 32

spaces among the adjacent MSNs were with a similar ordered three-dimensional macro-porous channel structure. It was also observed by a transmission electron microscope that the MSNs of the MCPCPs were monodisperse spheres comprised of uniform solid cores and mesoporous shells with serried pore structure (Figure 2d). These indicated that the MCPCPs possessed hierarchical macro- and mesoporous structures and could provide higher specific surface area and loading spaces for delivering of different sizes of actives.

Figure 2 (a-c) SEM images of (a) the MCPCPs, (b) the surface and (c) inner structure of a MCPCP. (d) TEM image of the MSNs. The scale bars are 50 µm in (a), 1 µm in (b-c) and 100 nm in (d). To demonstrate the loading and delivering capabilities of the mesoporous structures, the porosity and adsorption rate of the MCPCPs were investigated according to the nitrogen adsorption/desorption curve (Figure S3), both of which showed big values and indicated a large number of active adsorption capability of the MSNs. As the MSNs average pore size was about 3 nm, only the actives with small sizes could be loaded in the mesoporous structures of the


12

Page 13 of 32 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


MCPCPs. Thus, a hydrophilic doxorubicin (DOX) was selected as a typical model drug for the loading and release experiments. Compared with some complex methods, the drug loading in this work was realized by simply immersing the dehydrated MCPCPs into the DOX aqueous solution for a whole day, and the water soluble drugs would diffuse from the MCPCPs when placed in the aqueous solution. The drug distribution in the MCPCPs was observed by laser scanning confocal microscope (Figure 3a). The cross-sectional fluorescent images indicated that the DOX was encapsulated uniformly and completely in the whole particle as expected. It was worth to mention that this method for drug loading was more convenient and versatile compared with other traditional delivery systems as it was suitable for various drugs with different concentrations.

Figure 3 (a) The layer by layer scanning images of the DOX drug-loaded MCPCPs. The scale bar is 50 µm. (b) The loading amount of DOX in MCPCPs composed of MSN@30nm,


13


Page 14 of 32

MSN@40nm, MSN@50nm. (c) The release curves of DOX from the MCPCPs with MSN@30nm, MSN@40nm and MSN@50nm in vitro for 100 hours. (d) The release curves of FITC-BSA from the MCPCPs with MSN@30nm, MSN@40nm and MSN@50nm in vitro for 80 hours. The error bars represent standard deviations. To investigate the loading amount and releasing kinetics of the MCPCPs with different amounts of mesoporous structures, three kinds of the MCPCPs were prepared by using MSNs with mesoporous shell thicknesses of 30 nm, 40 nm and 50 nm, respectively. These particles were immersed in the same concentrations of DOX solution. The loading amounts and release kinetics were recorded in Figure 3b-c and Figure S4a, c. According to the results, it was obvious that the MCPCPs with the thickest mesoporous shells could load maximum DOX (Figure 3b) and the release curve of MCPCPs with the thickest mesoporous shells was most sustained. About 60% DOX released tardily within 80 hours (Figure 3c and Figure S4c). These should be ascribed to the larger mesoporous loading spaces and nanochannels of the MSNs with the thickest shells. In addition, the release properties of DOX in different sizes MCPCPs were similar as shown in Figure S4e. Besides the delivery of small molecular activities, the MCPCPs could also be loaded with macro-molecule activities as their have highly ordered macro porous channels. To demonstrate this feature, albumin bound paclitaxel (ABP) was applied as a model drug and the fluorescein isothiocyanate (FITC) labeled albumin bovine serum (FITC-BSA) was employed for the fluorescence observation during the loading and releasing process of macro-molecule drugs in vitro. The dehydrated MCPCPs were immersed into the FITC-BSA aqueous solution for the drug loading. It was found by confocal microscope that the MCPCPs were imparted with obviously fluorescence of the FITC-BSA in their inner space, as shown in Figure S5. Thus, we could


14

Page 15 of 32 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


conclude that the ABP could also disperse into the void structures of the MCPCPs. The loading amounts of the FITC-BSA were related with the concentrations of the FITC-BSA solution for the immersing, which was about 6.5µg/mg immersed in the 10% FITC-BSA solution (Figure S4b). As the loading positions of the FITC-BSA in the macro porous channels were much simple than the DOX in mesoporous structures, the release of the ABP was also much faster, which even showed a burst release at the beginning within 12 hours, as shown in Figure 3d and Figure S4d. Meanwhile, the MCPCPs with different sizes possess similar release properties of FITC-BSA in Figure S4f. It was worth to mention that the synergistic delivery of both micro- and macro-molecular drugs could be realized by immersing the dehydrated MCPCPs into the mixture solution of these targets. This characteristic could endow MCPCPs with higher therapeutic effect compared with other MSN-based delivery systems. To demonstrate this feature, small molecular DOX and macro-molecular ABP or FITC-BSA were mixed and loaded into the MCPCPs. The loading ratio of macro- and micro molecule drugs could be controlled by choosing MSNs with different mesoporous shell thicknesses. In addition, to promote the synergistic delivery system, a thermosensitive poly (N-isopropylacrylamide) (pNIPAM) hydrogel was also perfused into the void space of the MCPCPs and used as the “gating” for tuning the release of the drugs. The grafting ratio of pNIPAM on MSNs was shown in Figure S6. It is well know that temperatures of most inflammatory pathways and some tumor tissue were slightly higher than normal tissues temperature. Meanwhile, local temperatures in tumor tissues could have a significant increase by magneto-heat or light-heat conversion effect. Therefore, the thermo-sensitive delivery system could release drugs in particular locations when above lower critical solution temperature (LCST). In our system, the pNIPAM hydrogel can transform its framework from a swelling state


15


Page 16 of 32

to a shrunken state in response to the change of temperature. When the temperature was higher than LCST, the polymer chains would be dehydrated and collapse in the void space of the MCPCPs, leading to the opening of the macro-/mesoporous and subsequent diffusion of the water soluble drugs in the aqueous solution. The LCST of the pNIPAM is determined by mixing diverse concentrations of the N-methylolacrylamide monomer (NMAM) into the pre-gel solution. With the increase of NMAM, the LCST of hydrogel could rise continuously from 32℃ to 48℃, and about 10% weight ratio of NMAM/NIPAM monomers was chose for achieving a critical temperature closer to the body temperature (about 40℃). In order to confirm the “gating” function of the pNIPAM hydrogel in the MCPCPs, DOX and FITC-BSA synergistic loaded MCPCPs were prepared, as schemed in Figure 1b. The DOX was mainly loaded in the mesoporous channels, and the FITC-BSA as well as the NIPAM hydrogel was filled in the macro porous channel of the MCPCPs. These particles were divided into two groups, one group was put at the room temperature continuously as a control group, and the other group was exposed to several temperature cycles of about 40℃ (for 15 min) and the room temperature (for about 15 min). During these temperature cycles, the hydrogel shrank and extrude the loaded FITC-BSA, and the mesoporous were exposed so that the loaded DOX could be released from the MCPCPs. As shown in Figure 4a-b, it was obvious that the drugs in the MCPCPs at room temperature had been reserved mostly, while they released normally in the MCPCPs after several temperature cycles. Thus, the proposed drug delivery system could effectively avoid the drugs loss during the transport process, and regulate the level of the released drug delivery with an optimized selection of hydrogel “gating”. The PNIPAM was demonstrated as a proof-of-concept of the thermo-responsive drug delivery system. Meanwhile,


16

Page 17 of 32 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


through some chemical modifications49-50, the pNIPAM hydrogel would be imparted with biodegradable abilities, which could be more versatile for biomedical applications in further research.

Figure 4 (a-b) Release curves of DOX and FITC-BSA synergistic loaded MCPCPs in the room temperature (control group) and in 10 cycles of room temperature to 40℃ (experimental group). Error bars represent standard deviations.


17


Page 18 of 32

Figure 5 (a-h) Optical and fluorescent microscope photos of the HepG2 cells dealt with unloaded MCPCPs (a, d), DOX-loaded MCPCPs (b, e), ABP-loaded MCPCPs (c, f) and DOXABP-loaded MCPCPs (g, h). The scale bar is 50 µm. (i) MTT assays of the HepG2 cells dealt with unloaded MCPCPs, DOX-loaded MCPCPs, ABP-loaded MCPCPs and DOX-ABP-loaded MCPCPs for 24 hours. Error bars represent standard deviations. The efficiency of the MCPCPs for oncotherapy was investigated on HepG2 cells, demonstrating the superiority of the DOX and ABP synergistic delivery system. DOX can insert and bind to DNA and motivate a series of biochemical events such as apoptosis in tumor cells14, and ABP can curb cell mitosis thereby inhibiting the cell division and proliferation51, which has been applied in clinical therapy with great performance. In this experiment, the HepG2 cells


18

Page 19 of 32 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


were co-cultured with unloaded, DOX loaded, ABP loaded, and both DOX and ABP loaded MCPCPs for 24 hours, respectively. In addition, the HepG2 cells respectively treated with free DOX, ABP, and DOX/ABP solutions were set as control groups. The results of the typical optical and fluorescence microscopy cell culture could be observed in Figure 5a-h. The HepG2 cells grew well in the culture plate treated with the unloaded MCPCPs and the cells were killed mostly with the presence of DOX-ABP-MCPCPs. These effects were consistent with the cell MTT assay result (Figure 5i), which is the most common method to evaluate cell viability. When cultured with either DOX-loaded or ABP-loaded MCPCPs, more than 60% and 40% HepG2 cells were killed, respectively. More attractively, less than 30% HepG2 cells survived that treated with the synergistic drug delivery MCPCPs (Figure 5i). Therefore, the synergistic DOX-ABP-loaded MCPCPs delivery system can effectively weaken the cell viability, and greatly improve the therapeutic efficacy in treating tumor cells. It is fascinating that the MCPCPs could real-time self-report their actives release process. Due to the periodic arrangement of the MSNs, the MCPCPs were endowed with a PBG property, which could prohibit the propagating of certain wavelengths of light that located in the PBG and reflected them from the MCPCPs. Thus, these MCPCPs were imparted with gorgeous structural colors and characteristic reflection peaks, which can be calculated by Bragg’s equation under a normal incident beam: λ = 1.633dnaverage

(1)

where d is the center-to-center distance between two adjacent MSNs and naverage is the average refractive index of the MCPCPs. Therefore, the MCPCPs with different structural colors and characteristic reflection peaks could be obtained by using different sizes of MSNs (Figure


19


Page 20 of 32

S7) or changing the average refractive index of the MCPCPs. Moreover, the structure colors of MCPCPs with different sizes from about 5 to 100 microns were all observed clearly (Figure S8).

Figure 6 (a) The reflection peak blue shift process of the MCPCPs (with MSN@50nm) during the drug release. Insert is the scheme of the self-monitoring property of the MCPCPs. (b) The relationship between the reflection peak positions and the release percentages. (c) The reflection spectras of three kinds of non-covered, tissue covered and mice skin covered MCPCPs. (d-f) The reflection images of uncovered MCPCPs (d) and MCPCPs covered by tissus (e-f). The scale bars are 50 µm. To confirm the self-monitoring property of the MCPCPs during the actives release, drugs loaded particles with fixed MSN size were employed, and the monitoring process was in terms of the changes to the average refractive index. Besides, the average refractive index of the drug loaded MCPCPs was depending on the mean value of all the components refractive indices in the particles, which can be estimate by the following formula: naverage2=∑ni2Vi

(2)


20

Page 21 of 32 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


where ni and Vi are the refractive index and the volume fraction of each components in the MCPCPs, respectively. Apparently, the average refractive index could be changed by changing the components or adjusting the refractive index of the comprised materials, which could lead to the shift of the structure colors and the reflection peak of the MCPCPs. In this study, because of the difference between the refractive indices of the drug solution and the buffer solution, the average refractive index of the drug loaded MCPCPs decreased during the releasing of the loaded drugs, which were reported as a corresponding blue shift of their reflection peaks, as shown in Figure 6a-b. The shift values of the peak position could be exploited to estimate the quantity of the released and remaining actives. As the monitoring was conducted as a label-free manner, it could be more versatile for the MCPCPs-delivery systems to monitor the releasing process. To further demonstrate the practical values of the proposed MCPCPs as drug delivery and monitor systems, the MCPCPs required to be detected in a highly scattering environment such as living tissue. To investigated this feature, an in vitro experiment was performed, in which the MCPCPs were injected under the slices of tissue (chicken breast), as shown in Figure 6c-f. It was found from the result that the structural colors and the characteristic reflection peaks of the MCPCPs beneath the slices of biological tissue were still observable and detectable, which had a relative decline but showed the same reflection peak position as the uncovered MCPCPs. These results exhibited the potential values of the MCPCP materials for in vivo applications. To confirm the antitumor potentiality of the drug-loaded MCPCPs in vivo, physiological saline (set as control group) and the drug-loaded MCPCPs with size of 20 µm (set as experimental group) were injected respectively into the prepared tumor-bearing nude mice and the drug-loaded particles well accumulated in the surface of tumor (Figure 7a). The reflection


21


Page 22 of 32

peaks of MCPCPs under mice skin were also detected, which showed a lager decline and the same reflection peak positions compared with the uncovered MCPCPs, as shown in Figure 6c. Furthermore, the deeper MCPCPs could also be probed through introducing a finespun optical fibers into bodies. From the results, it could be found that the tumor volume of mice in the control group was increased obviously while in the experimental group the tumor volume was effectively inhibited (Figure 7c). After 7 days, the tumor weight of mice injected with drugloaded MCPCPs was about 45% of the saline-treated mice (Figure 7b). Thus, these results proved that the particles injected in the tumor inhibited the growth of tumor effectively, which indicated the MCPCPs are desirable for drug delivery and oncotherapy.


22

Page 23 of 32 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


Figure 7. (a) Injecting the drug-loaded MCPCPs into the armpit of nude mice. (b) Quantification of the tumor weight in control and experimental groups during 7 days. (c) The comparison of the tumor proliferation between two groups during 7 days. 4. Conclusion In summary, we have demonstrated the properties of this designed new type of MCPCPs-based drug delivery system by self-assembling of monodisperse MSNs in microfluidic droplet templates. The hierarchical macro- and meso-porous structures of the MCPCPs provided large


23


Page 24 of 32

surface areas, plenty of nanopores, and intricate nanochannels for synergistic loading of both micro- and macro-molecule drugs with large quantity and sustained releasing. With the integration of temperature responsive pNIPAM hydrogel into the void spaces of the MCPCPs, the delivery system was imparted with a “gating” to open and close the macro- and mesopores for controllable drugs release. It was demonstrated that synergistic delivery of DOX and ABP in these MCPCPs could effectively weaken the cell viability and greatly improve the therapeutic efficacy in treating tumor cells. Besides, due to the blue-shift of the MCPCPs characteristic reflection peak with release of the drugs, the system created a novel stratagem for real time selfreporting the therapeutic agents releasing process of the MCPCPs. These unique features make the MCPCPs a potential system in overcoming many restrictions of some conventional particlebased delivery systems, and are promising to open new prospects in the fields of drug research and development. Supporting Information Available Materials and experimental details, the real-time microscopic image of the generation process of emulsion templates in the microfluidic device, the influence factors of the droplet templates/MCPCPs diameters; the TEM images of MSNs calcined at different temperatures; the adsorption/desorption curve, surface area, pore volume and pore width of MSN@50nm; the supplementary release dates of drugs from the MCPCPs and the loading amount of the drugs; the layer by layer images of the FITC-BSA loaded MCPCPs; the reflection images and characteristic reflection peak positions of five kinds of particles with different structural colors; the reflection pictures of the MCPCPs with different sizes. The following files are available free of charge. This material is available free of charge via the Internet at http://pubs.acs.org.


24

Page 25 of 32 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


Corresponding Author * E-mail: [email protected] (Y. J. Z.), [email protected] (P. H. L.) Author Contributions X.X.G., Y.X.L. and G.P.C. contributed equally to this work; Y.J.Z. conceived the idea and designed the experiment; X.X.G. and Y.X.L. carried out the experiments; X.X.G. and Y.J.Z. analysed data and wrote the paper; G.P.C., H.W., C.M.S., Z.Y.C. and P.H.L. contributed to scientific discussion of the article. Notes The authors declare no competing financial interests. Acknowledgment This work was supported by the National Science Foundation of China (Grant Nos. 21473029 and 51522302), the NSAF Foundation of China (Grant No.U1530260), the Scientific Research Foundation of Southeast University, the Scientific Research Foundation of Graduate School of Southeast University. References 1.

Mitragotri, S.; Burke, P. A.; Langer, R. Overcoming the Challenges in Administering Biopharmaceuticals: Formulation and Delivery Strategies. Nat. Rev. Drug Discov. 2014, 13, 655-672.

2.

Qiu, Y.; Park, K. Environment-sensitive Hydrogels for Drug Delivery. Adv. Drug Deliver. Rev. 2012, 64, 49-60.


25


3.

Page 26 of 32

Bysell, H.; Mansson, R.; Hansson, P.; Malmsten, M. Microgels and Microcapsules in Peptide and Protein Drug Delivery. Adv. Drug Deliver. Rev. 2011, 63, 1172-1185.

4.

Prow, T. W.; Grice, J. E.; Lin, L. L.; Faye, R.; Butler, M.; Becker, W.; Wurm, E. M.T.; Yoong, C.; Robertson, T. A.; Soyer, H. P.; Roberts, M. S. Nanoparticles and Microparticles for Skin Drug Delivery. Adv. Drug Deliver. Rev. 2011, 63, 470-491.

5.

Yan, L.; Yang, Y.; Zhang, W. J.; Chen, X. F. Advanced Materials and Nanotechnology for Drug Delivery. Adv. Mater. 2014, 26, 5533-5540.

6.

Zhang, L.; Qiang, F.; Wang, J. L.; Sun, J. S.; Shi, X. H.; Jiang, X. Y. Microfluidic Synthesis of Rigid Nanovesicles for Hydrophilic Reagents Delivery. Angew. Chem. Int. Ed. 2015, 54, 3952-3956.

7.

Shang, L. R.; Cheng, Y.; Zhao, Y. J. Emerging Droplet Microfluidics. Chem. Rev. 2017, 117, 7964-8040.

8.

Liu, D. F.; Cito, S.; Zhang, Y. Z.; Wang, C. F.; Sikanen, T. M.; Santos, H. A. A Versatile and Robust Microfluidic Platform toward High Throughput Synthesis of Homogeneous Nanoparticles with Tunable Properties. Adv. Mater. 2015, 27, 2298-2304.

9.

Yu, Y. R.; Fu, F. F.; Shang, L.R.; Cheng, Y.; Gu, Z.Z.; Zhao, Y.J. Bio-inspired Helical Microfibers from Microfluidics. Adv. Mater. 2017, 29, 16057-16065.

10. Meng, J. X.; Liu, H. L.; Liu, X. L.; Yang, G.; Zhang, P. C.; Wang, S. T.; Jiang, L. Hierarchical Biointerfaces Assembled by Leukocyte-inspired Particles for Specifically Recognizing Cancer Cells. Small 2015, 10, 3735-3741. 11. Sun, T. M.; Zhang, Y. S.; Pang, B.; Hyun, D. C.; Yang, M. X.; Xia, Y. N. Cheminform Abstract: Engineered Nanoparticles for Drug Delivery in Cancer Therapy. Angew. Chem. Int. Ed. 2014, 53, 12320-12364.


26

Page 27 of 32 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


12. Mekaru, H.; Lu, J.; Tamanoi, F. Development of Mesoporous Silica-based

Nanoparticles

with Controlled Release Capability for Cancer Therapy. Adv. Drug Deliver. Rev. 2015, 95, 40-49. 13. Vasconcelos, T. C.; Sarmento, B.; Costa, P. J. C.; Solid Dispersion as Strategy to Improve Oral Bioavailability of Poof Water Soluble Drugs. Drug Discov. Today 2008, 12, 1068-1075. 14. Li, Y. N.; Yan, D.; Fu, F. F.; Liu, Y. X.; Zhang, B.; Wang, J.; Shang, L. R.; Gu, Z. Z.; Zhao, Y. J. Composite Microparticles from Microfluidics for Synergistic Drug Delivery. Sci. China Mater. 2017, 60, 543-553. 15. Guo, X.; Wei, X.; Jing, Y. T.; Zhou, S. B. Size Changeable Nanocarriers with Nuclear Targeting for Effectively Overcoming Multidrug Resistance in Cancer Therapy. Adv. Mater. 2015, 27, 6450-6456. 16. Petros, R. A.; Desimone, J. M. Strategies in the Design of Nanoparticles for Therapeutic Applications. Nat. Rev. Drug Discov. 2010, 9, 615-627. 17. Tarn, D.; Ashley, C. E.; Xue, M.; Carnes, E. C.; Zink, J. I.; Brinker, J. Mesoporous Silica Nanoparticle Nanocarriers: Biofunctionality and Biocompatibility. Accounts Chem. Res. 2013, 3, 792-801. 18. Lu, J.; Liong, M.; Li, Z. X.; Zink, J. I.; Tamanoi, F. Biocompatibility, Biodistribution, and Drug-Delivery Efficiency of Mesoporous Silica Nanoparticles for Cancer Therapy in Animals. Small 2010, 6, 1794-1805. 19. Lu, J.; Liong, M.; Zink, J. I.; Tamanoi, F. Mesoporous Silica Nanoparticles as a Delivery System for Hydrophobic Anticancer Drugs. Small 2007, 3, 1341-1346. 20. He, Q. J.; Shi, J. L. MSN Anti-cancer Nanomedicines: Chemotherapy Enhancement, Overcoming of Drug Resistance, and Metastasis Inhibition. Adv. Mater. 2014, 26, 391-411.


27


Page 28 of 32

21. Baek, S.; Singh, R. K.; Khanal, D.; Patel, K. D.; Lee, E. J.; Leong, K. W.; Chrzanowski, W.; Kim, H. W. Smart Multifunctional Drug Delivery towards Anticancer Therapy Harmonized in Mesoporous Nanoparticles. Nanoscale 2015, 7, 14191-14216. 22. Xie, Z. Y.; Cao, K. D.; Zhao, Y. J.; Bai, L.; Gu, H. C.; Xu, H.; Gu, Z. Z. An Optical Nose Chip Based on Mesoporous Colloidal Photonic Crystal Beads. Adv. Mater. 2014, 26, 24132418. 23. Wang, J. D.; Chen, W. W.; Sun, J. S.; Liu, C.; Yin, Q. F.; Zhang, L.; Xianyu, X. L.; Shi, X. H.; Hu, G. Q.; Jiang, X. Y. A Microfluidic Tubing Method and its Application for Controlled Synthesis of Polymeric Nanoparticles. Lab Chip 2014, 14, 1673-1677. 24. Kong, T. T.; Wang, L.Q.; Wyss, H. M.; Shum, H. C. Capillary Micromechanics for CoreShell Particles. Soft Matter 2014, 10, 3271-3276. 25. Sun, J. S.; Xianyu, Y. L.; Li, M. M.; Liu, W. W.; Zhang, L.; Liu, B. B.; Liu, C.; Hu, G. Q.; Jiang, X. Y. A Microfluidic Origami Chip for Synthesis of Functionalized Polymeric Nanoparticles. Nanoscale 2013, 5, 5262-5265. 26. Hegazy, M.; Zhou, P.; Wu, G. Y.; Wang, L.; Rahoui, N.; Taloub, N.; Huang, X.; Huang, Y. D. Construction of Polymer Coated Core-shell Magnetic Mesoporous Silica Nanoparticles with Triple Responsive Drug Delivery. Polym. Chem. 2017, 8, 5852-5864. 27. Zhang, X.; Yang, P. P.; Dai, Y. L.; Ma, P. A.; Li, X. J.; Cheng, Z. Y.; Hou, Z. Y.; Kang, X. J.; Li, C. X.; Lin, J. Multifunctional Up-Converting Nanocomposites with Smart Polymer Brushes Gated Mesopores for Cell Imaging and Thermo/pH Dual-Responsive Drug Controlled Release. Adv. Funct. Mater. 2013, 23, 4067-4078. 28. Wu, X.; Wang, Z. Y.; Zhu, D.; Zhong, S. F.; Yang, L. P.; Zhong, Y.; Cui, Y. P. PH and Thermo Dual-Stimuli-Responsive Drug Carrier Based on Mesoporous Silica Nanoparticles


28

Page 29 of 32 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


Encapsulated in a Copolymer-Lipid Bilayer. ACS Appl. Mater. Interfaces 2013, 5, 1089510903. 29. Roy, D.; Brooks, W. L. A.; Sumerlin, B. S. New Directions in Thermoresponsive Polymers. Chem. Soc. Rev. 2013, 42, 7214-7243. 30. Zhu, J. H.; Niu, Y. M.; Li, Y.; Gong, Y. X.; Shi, H. H.; Huo, Q.; Liu, Y.; Xu, Q. W. Stimuliresponsive Delivery Vehicles Based on Mesoporous Silica Nanoparticles: Recent Advances and Challenges. J. Mater. Chem. B 2016, 5, 1339-1352. 31. Chang, D. F.; Gao, Y. F.; Wang, L. J.; Liu, G.; Chen, Y. H.; Wang, T.; Tao, W.; Mei, L.; Huang, L. Q.; Zeng, X. W.; Polydopamine-based Surface Modification of Mesoporous Silica Nanoparticles as pH-sensitive Drug Delivery Vehicles for Cancer Therapy. J. Colloid Interface Sci. 2016, 463, 279-287. 32. Zhang, B.; Cheng, Y.; Wang, H.; Ye, B. F.; Shang, L. R.; Zhao, Y. J.; Gu, Z. Z. Multifunctional Inverse Opal Particles for Drug Delivery and Monitoring. Nanoscale 2015, 7, 10590-10594. 33. Kim, S. H.; Kim, J. W.; Kim, D. H.; Han, S. H.; Weitz, D. A. Polymersomes Containing a Hydrogel Network for High Stability and Controlled Release. Small 2013, 9, 124-131. 34. Wang, Y.; Shim, M. S.; Levinson, N. S.; Sung, H. W.; Xia, Y. N. Stimuli-responsive Materials for Controlled Release of Theranostic Agents. Adv. Funct. Mater. 2014, 24, 42064220. 35. Argyo, C.; Weiss, V.; Bräuchle, C.; Bein, T. Multifunctional Mesoporous Silica Nanoparticles as a Universal Platform for Drug Delivery. Chem. Mater. 2014, 26, 435−451. 36. Shang, L. R.; Fu, F. F.; Cheng, Y.; Wang, H.; Liu, Y. X.; Zhao, Y. J.; Gu, Z. Z. Photonic Crystal Microbubbles as Suspension Barcodes. J. Am. Chem. Soc. 2015, 137, 15533-15539.


29


Page 30 of 32

37. Shaha, R. K.; Shum, H. C.; Rowata, A. C.; Leea, D.; Agrestia, J. J.; Utadaa, A. S.; Chua, L. Y.; Kima, J. W.; Fernandez-Nievesa, A.; Martineza, G. J.; Weitz, D. A. Designer Emulsions Using Microfluidics. Mater. Today 2008, 11, 18-27. 38. Fu, F. F.; Shang, L. R.; Zhen, F. Y.; Chen, Z. Y.; Wang, H.; Gu, Z. Z.; Zhao, Y. J. Cell Cultured on Core-shell Photonic Crystal Barcodes for Drug Screening. ACS Appl. Mater. Interfaces 2016, 8, 13840-13848. 39. Shang, L. R.; Gu, Z. Z.; Zhao, Y. J. Structural Color Materials in Evolution. Mater. Today 2016, 19, 420-421. 40. Zhao, Y. J.; Cheng, Y.; Shang, L. R.; Wang, J.; Xie, Z. Y.; Gu, Z. Z. Microfluidic Synthesis of Barcode Particles for Multiplex Assays. Small 2015, 11, 151-174. 41. Wang, H.; Gu, H. C.; Chen, Z. Y.; Shang, L. R.; Zhao, Z.; Gu, Z. Z.; Zhao, Y. J. Enzymatic Inverse Opal Hydrogel Particles for Biocatalyst. ACS Appl. Mater. Interfaces 2017, 9, 12914-12918. 42. Fu, F. F.; Chen, Z. Y.; Zhao. Z.; Wang, H.; Shang, L. R.; Gu, Z. Z.; Zhao, Y. J. Bio-inspired Self-healing Structural Color Hydrogel. P. Nat. Acad. Sci. USA. 2017, 114, 5900-5905. 43. Liu, C. H.; Ding, H. B.; Wu, Z. Q.; Gao, B. B.; Fu, F. F.; Shang, L. R.; Gu, Z. Z.; Zhao, Y. J. Tunable Structural Color Surfaces with Visually Self-reporting Wettability. Adv. Funct. Mater. 2016, 26, 7937-7942. 44. Hao, N. J.; Nie, Y.; Zhang, J. X. J. Microfluidic Flow Synthesis of Functional Mesoporous Silica Nanofibers with Tunable Aspect Ratios. ACS Sustain. Chem. Eng. 2018, 6, 1522-1526. 45. Bchellaoui, N.; Hayat, Z.; Mami, M.; Dorbez-Sridi, R.; Abed, A. I. E. Microfluidic-assisted Formation of Highly Monodisperse and Mesoporous Silica Soft Microcapsules. Sci. Rep. 2017, 7, 16326.


30

Page 31 of 32 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


46. Hao, N. J.; Nie, Y.; Tadimety, A.; Closson, A. B.; Zhang, J. X. J. Microfluidics-mediated Self-template Synthesis of Anisotropic Hollow Ellipsoidal Mesoporous Silica Nanomaterials. Mater. Res. Lett. 2017, 5, 584-590. 47. Liu, D. F.; Mäkilä, E.; Zhang, H. B.; Herranz, B.; Kaasalainen, M.; Kinnari, P.; Salonen, J.; Hirvonen, J.; Santos, H. A. Nanostructured Porous Silicon-solid Lipid Nanocomposite: towards Enhanced Cytocompatibility and Stability, Reduced Cellular Association and Prolonged Drug Release. Adv. Funct. Mater. 2013, 23, 1893-1902. 48. Zhang, H. B.; Liu, D. F.; Shahbazi, M. A.; Mäkilä, E.; Herranz-Blanco, B.; Salonen, J.; Hirvonen, J.; Santos, H. A. Fabrication of a Multifunctional Nano-in-micro Drug Delivery Platform by Microfluidic Templated Encapsulation of Porous Silicon in Polymer Matrix. Adv. Mater. 2014, 26, 4497-4503. 49. Zhang, B. Y.; He, W. D.; Li, L. Y.; Sun, X. L.; Li, W. T.; Zhang, K. R. Reducibly Degradable Hydrogels of PNIPAM and PDMAEMA: Synthesis, Stimulus-response and Drug Release. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 3604-3612. 50. Cui, R. G.; Zhang, Z. J.; Nie, J. J.; Du, B. Y. Tuning the Morphology, Network Structure, and Degradation of Thermo-sensitive Microgels by Controlled Addition of Degradable Cross-linker. Colloid Polym. Sci. 2017, 295, 665-678. 51. Gradishar, W. J. Albumin-bound Paclitaxel: a Next-generation Taxane. Expert Opin. Pharmaco. 2006, 7, 1041-1043.


31


Page 32 of 32

TOC graphic


32

Mesoporous Colloidal Photonic Crystal Particles for Intelligent Drug

Recommend Documents