Research Article: Trojan‐Horse‐Like Stimuli‐Responsive Microcapsules

Date Published: March 13, 2018

Publisher: John Wiley and Sons Inc.

Author(s): Chuan‐Lin Mou, Wei Wang, Zhi‐Lu Li, Xiao‐Jie Ju, Rui Xie, Nan‐Nan Deng, Jie Wei, Zhuang Liu, Liang‐Yin Chu.


Multicompartment microcapsules, with each compartment protected by a distinct stimuli‐responsive shell for versatile controlled release, are highly desired for developing new‐generation microcarriers. Although many multicompartmental microcapsules have been created, most cannot combine different release styles to achieve flexible programmed sequential release. Here, one‐step template synthesis of controllable Trojan‐horse‐like stimuli‐responsive microcapsules is reported with capsule‐in‐capsule structures from microfluidic quadruple emulsions for diverse programmed sequential release. The nested inner and outer capsule compartments can separately encapsulate different contents, while their two stimuli‐responsive hydrogel shells can individually control the content release from each capsule compartment for versatile sequential release. This is demonstrated by using three types of Trojan‐horse‐like stimuli‐responsive microcapsules, with different combinations of release styles for flexible programmed sequential release. The proposed microcapsules provide novel advanced candidates for developing new‐generation microcarriers for diverse, efficient applications.

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Stimuli‐responsive microcapsules that enable on‐demand content release show great power for myriad applications such as drug delivery, self‐healing, and confined microreaction.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 For developing new‐generation microcarriers,12 multicompartmental microcapsules, with each compartment protected by a distinct and stable stimuli‐responsive shell for versatile coencapsulation and controlled release, are highly desired. Their multicompartments allow separate coencapsulation of multiple contents without crosscontamination, which is crucial to achieve enhanced performances for biomedical applications such as combination cancer therapy,2, 13, 14 tissue regeneration,14 theranostics,15 and confined enzymatic reactions.16 For example, in combination cancer therapy, codelivery of two or more drugs that work synergistically, such as drugs and genes,13 can achieve greater synergistic efficacy than the sum of each drug delivered alone. In tissue regeneration, codelivery of two different growth factors allows formation of mature vessels while delivery of one alone is insufficient for the promotion of a stable, dense vasculature.14 In confined enzymatic microreactions, coencapsulation of multiple enzymes in the separate compartments of a microcarrier can provide improved enzymatic activity and stability as compared with free enzymes and enzymes homogeneously coimmobilized in a microcarrier.16 Based on the coencapsulation, flexible control of the release sequence of different contents can further achieve therapeutic synergy for enhanced chemotherapy and reduced toxicity.17, 18, 19, 20 For example, sequential release of multiple therapeutic agents allows first genetically sensitizing the cancer cells to the sequentially administered drug for enhanced chemotherapy.17 Improved therapeutic index with reduced toxicity can also be realized via sequential release of an antiangiogenesis agent for vascular collapse, and then a cytotoxic agent for chemotherapy inside a tumor.19 Moreover, besides the coencapsulation and sequential release, control of the compartment structure, capsule size, and uniformity allows accurate adjustment of the stoichiometric ratio and release kinetics of the contents for optimized efficacy.21, 22, 23 However, although many multicompartmental microcapsules have been developed,1, 3, 4, 5, 12, 16, 21, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 most cannot combine different release styles to achieve flexible programmed sequential release.

In summary, controllable Trojan‐horse‐like stimuli‐responsive microcapsules with capsule‐in‐capsule structures for versatile programmed sequential release are developed by one‐step template synthesis from microfluidic quadruple emulsions. The emulsion templates can be converted into the microcapsules with hierarchical capsule‐in‐capsule structures, by incorporating different functional shell materials into their inner and outer aqueous layers. This also enables flexible engineering of different triggering mechanisms into the two shells to achieve versatile programmed sequential release. The microcapsules can controllably load different contents in their separate capsule compartments and release each of the contents in a predefined order and different manner. Further, control of the compartment size and shell thickness by tuning flow rates enables fine adjustment of the content amount in each compartment as well as their release profiles. Meanwhile, the outer and inner shells of microcapsules can be engineered with diverse stimuli‐responsive materials,43 such as ion‐responsive,44 glucose‐responsive,45 and multistimuli‐responsive ones,46 for more flexible codelivery. With controllable number and composition of inner drops,38, 39 the diverse multiple emulsions from microfluidics create opportunities to further fabricate Trojan‐horse‐like microcapsules containing inner capsules with controlled numbers and with different stimuli‐responsive shells for more versatile sequential release. Moreover, based on the microfluidic techniques for producing multiple emulsions,47, 48, 49 the microcapsule size can be further adjusted in the range from several tens of micrometers to a few millimeters. With such a size range, the microcapsules can be used for in vivo drug release via routes such as oral, subcutaneous, and intramuscular administrations.50, 51, 52 The proposed Trojan‐horse‐like stimuli‐responsive microcapsules provide novel advanced candidates for developing new‐generation microcarriers for programed sequential release, and on‐demand microreactions.

Microfluidic Generation of Quadruple Emulsions: A glass‐capillary microfluidic device, constructed according to the previous work,39 was used for generating quadruple emulsions as templates for synthesis of the Trojan‐horse‐like microcapsules. For generating the O1/W2/O3/W4/O5 quadruple emulsions, typically, an oil mixture of SO(Kerry Oils & Grains Co., Ltd.) and BB(Sinopharm Chemical Reagent Co., Ltd.) with VSO:VBB = 46:54, containing 2% (w/v) surfactant PGPR(Danisco), was used as the O1 phase. Deionized water (Milli‐Q) containing 0.5% (w/v) surfactant Pluronic F‐127 (Sigma‐Aldrich) and 10% (w/v) glycerin was used as the W2 and W4 phases. O3 phase was the SO–BB mixture containing PGPR (4%, w/v), while O5 phase and the collection solution were SO containing PGPR (5%, w/v) (Table S1). These solutions were injected into the microfluidic device by syringe pumps (LSP01‐1A, Baoding Longer Precision Pump) for emulsion generation. The flow rates of O1, W2, O3, W4, and O5 were 230, 440, 850, 1400, and 6000 µL h−1, respectively. Dyes Sudan Black (0.1%, w/v) and Lumogen@ F Red 300 (LR 300) (0.1%, w/v) were, respectively, added in O1 and O3 phases for better observation. For fabricating the Trojan‐horse‐like microcapsules, the W2 and W4 phases of the quadruple emulsions were added with functional shell materials.

The authors declare no conflict of interest.




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