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SCIENCE CHINA Materials, Volume 60, Issue 6: 543-553(2017) https://doi.org/10.1007/s40843-016-5151-6

Composite core-shell microparticles from microfluidics for synergistic drug delivery

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  • ReceivedOct 27, 2016
  • AcceptedDec 13, 2016
  • PublishedJan 22, 2017

Abstract

Microparticles have a demonstrated value for drug delivery systems. The attempts to develop this technology focus on the generation of featured microparticles for improving the function of the systems. Here, we present a new type of microparticles with gelatin methacrylate (GelMa) cores and poly(L-lactide-co-glycolide) (PLGA) shells for synergistic and sustained drug delivery applications. The microparticles were fabricated by using GelMa aqueous solution and PLGA oil solution as the raw materials of the microfluidic double emulsion templates, in which hydrophilic and hydrophobic actives, such as doxorubicin hydrochloride (DOX, hydrophilic) and camptothecine (CPT, hydrophobic), could be loaded respectively. As the inner cores were polymerized in the microfluidics when the double emulsions were formed, the hydrophilic actives could be trapped in the cores with high efficiency, and the rupture or fusion of the cores could be avoided during the solidification of the microparticle shells with other actives. The size and component of the microparticles can be easily and precisely adjusted by manipulating the flow solutions during the microfluidic emulsification. Because of the solid structure of the resultant microparticles, the encapsulated actives were released from the delivery systems only with the degradation of the biopolymer layers, and thus the burst release of the actives was avoided. These features of the microparticles make them ideal for drug delivery applications.


Funded by

National Natural Science Foundation of China(21473029,51522302)

NSAF Foundation of China(U1530260)

National Science Foundation of Jiangsu(BK20140028)

the Program for New Century Excellent Talents in University

Scientific Research Foundation of Southeast University. D Yan also thanks the Foundation of Jiangsu Cancer Hospital(ZN201609,Beijing Medical Award Foundation (YJHYXKYJJ-433)


Acknowledgment

This work was supported by the National Natural Science Foundation of China (21473029 and 51522302), the NSAF Foundation of China (U1530260), the National Science Foundation of Jiangsu (BK20140028), the Program for New Century Excellent Talents in University, and the Scientific Research Foundation of Southeast University. D Yan also thanks the Foundation of Jiangsu Cancer Hospital (ZN201609) and Beijing Medical Award Foundation (YJHYXKYJJ-433).


Interest statement

The authors declare that they have no conflict of interest.


Contributions statement

Zhao Y conceived the idea and designed the experiments; Li Y, Yan D and Fu F carried out the experiments; Zhao Y and Li Y analyzed the data and wrote the manuscript; Liu Y, Zhang B, Wang J, Shang L and Gu Z contributed to scientific discussion of the article.


Author information

Yanna Li is currently a graduate student at the School of Biomedical Engineering, Southeast University. She joined Prof. Yuanjin Zhao’s research group in 2013. Her current research focuses on the fabrication of microparticles by using droplet microfluidics.


Dan Yan is currently an associate chief physician at the Department of Pharmacy, Jiangsu Cancer Hospital. She received her PhD degree in 2011 from China Pharmaceutical University. Her current research focuses on the clinical drug delivery.


Yuanjin Zhao received his PhD degree in 2011 from Southeast University. In 2009–2010, he worked as a research scholar in Prof. David A. Weitz’s group at the School of Engineering & Applied Sciences, Harvard University. Since 2015, he has been a full professor of Southeast University. His current scientific interests include microfluidic-based materials fabrication, biosensors, and bio-inspired photonic nanomaterials.


Supplement

Supplementary information

Supporting data are available in the online version of the paper.


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  • Figure 1

    (a) Schematic diagram of a capillary microfluidic system for generating the W/O/W double emulsion templates with polymerized cores; (b) schematic diagram of the fabrication process of the drug loaded GelMa-PLGA core-shell microparticles.

  • Figure 2

    (a–c) Real-time microscopic images of the microfluidic generation process of the W/O/W double emulsion templates encapsulated with tunable number of cores. The scale bar is 100 μm; (d–f) optical microscope image of the monodisperse core-shell double emulsions with one, two and three cores, respectively. The scale bar is 200 μm; (g–i) the size distributions of the inner radiuses and outer radiuses of the double emulsions with one, two and three cores, respectively.

  • Figure 3

    Optical microscopy images (a, e and i) and CLSM images (others) of the DOX and CPT drugs loaded core-shell microparticles. (a–d) Microparticle with single core; (e–h) microparticle with two cores; (i–l) microparticle with three cores. The red and blue fluorescence indicates DOX and CPT, respectively. The scale bar is 100 μm.

  • Figure 4

    SEM images of the core-shell structure microparticles. (a) External view of a whole microparticle; (b) external view of a shell opened microparticle encapsulated with one core; (c) cross section image of the GelMa-PLGA core-shell microparticle; (d and e) magnified images of shell surfaces of the microparticles in (a, b); (f) magnified image of a partial structure of GelMa core. The scale bars are 100 μm in (a–c) and 10 μm in (d–f).

  • Figure 5

    (a) Schematic diagram of the microparticle degradation and its drug release; (b–d) SEM images of the GelMa-PLGA core-shell microparticles during the degradation and release periods of 72, 168, 360 h, respectively. The scale bar is 50 μm.

  • Figure 6

    In vitro accumulative CPT and DOX release from GelMa-PLGA core-shell microparticles. (a, c) Drugs release from thin shell (22 μm) microparticles; (b, d) drugs release from thick shell (60 μm) microparticles. (c, d) The first 12 h processes of (a, b), respectively. Error bars represent standard deviations.

  • Figure 7

    Optical and fluorescence microscopy images of HCT116 cells treated with unloaded microparticles (a, d), only CPT-loaded microparticles (b, e), and DOX-CPT-co-loaded microparticles (c, f) for 24 h, respectively. The scale bar is 50 μm.

  • Figure 8

    Result of the MTT assay of the HCT116 cells treated with unloaded microparticles (MPs), only DOX-loaded microparticles (DOX-MPs), only CPT-loaded microparticles (CPT-MPs), and DOX-CPT-co-loaded microparticles (DOX-CPT-MPs) for 24 h. Error bars represent standard deviations.

  • Table 1   Effects of the shell thickness on loading content of drugs and encapsulation efficiency

    Shell thickness (μm)

    Encapsulation efficiency of CPT (%)

    Encapsulation efficiency of DOX (%)

    Loading content (%)

    22

    45.80±2.02

    85.13±0.99

    4.06±0.02

    40

    57.27±0.89

    89.22±1.12

    6.17±0.15

    60

    60.50±1.24

    92.73±2.57

    6.88±0.24

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