Applied Materials Today
Volume 21, December 2020, 100839
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Water powered and anti-CD3 loaded mg micromotor for t cell activation

https://doi.org/10.1016/j.apmt.2020.100839Get rights and content

Highlights

  • PLGA/ALG/CHI mg micromotor systems, with biodegradable constituents and water powered propulsion, ensuring superior biocompatibility.

  • High loading capacity of t cell stimulating antigen (anti-CD3).

  • Efficient activation of the jurkat t cell calcium ion channel, extending the application scope of micro/nanomotors from cargo delivery to immune response modulation and immunotherapy.

Abstract

Here we present an anti-CD3 loaded PLGA/ALG/CHI Mg micromotor systems, with degradable constituents and Mg-water reaction propulsion, thus ensuring a superior biocompatibility. Porous hydrogel formed by ALG/CHI offers high capacity of antigen loading, along with biocompatibility. By efficient loading of anti-human CD3 as an antigen and activating the calcium ion channel of Jurkat T cell, vital for immunotherapy, the motor system extends the application scope of micro/nanomotor systems from cargo (drug) delivery to interaction with the biointerface and immune activity modulation.

Introduction

In the past decade, self-propelled micro-nanomotors have attracted much attention due to their inherent capabilities of fast moving and efficient cargo towing. These miniaturized devices have demonstrated power to revolutionize the biomedical fields, such as on-demand drug delivery [1], [2], [3], cell transportation [4], [5], [6] and on-the-fly biosensing [7], [8], [9] etc. While bimetals motors (such as pallium and gold, titanium and gold, etc.) were the first to be used, their rigidness as well as unbiodegradability impedes their applications in biofield [10, 11]. After that, exploring biocompatible materials as frameworks for micro-nanomotors has become a central issue. Materials including soft polymer materials [12, 13] and active inorganic nanoparticles [14, 15] have been proposed to fabricate motors for biomedical applications, for instance an Au-polymer nanoswimmer has been reported to photomechanically drill the target tumor cell [16]. Among them, magnesium(Mg) [17], [18], [19] based motors can be powered in pure water via the hydrogen gas generated from moderate Mg-water reaction [20], [21], [22] (compared with violent active metals-water reaction) and are degradable after propulsion, thus ensuring superior biocompatibility. Unlike hydrogen bubbles violently generated by active metals-water reaction, which is unstable and uncontrollable when applied into micromotors, Mg can continually and stably generate hydrogen bubbles due to a compact passivation layer on the surface. This passivation layer can be depleted at a proper speed during Mg-based micromotor motion. Besides, water as a fuel to propel micromotors is regarded as attractive power source due to its harmlessness and abundance. Compared with micromotors propelled by H2O2, acidic and alkaline solutions, water-driven micromotors are considered to be more biocompatible in biofluid. Such micromotors triggered by H2O2, acidic and alkaline solutions as the fuel resources are almost incompatible in vivo because they can result in corrosion and strong oxidation, which impedes the clinical translation of self-propelled micromotors in complex biological context. In addition, Mg could be absorbable in biofluid while applied for biomedical application. In the human body, Mg2+ ion is the fourth richest and naturally found as a cofactor for over 300 enzymes, which is critical for many tissues and organs to function properly. Therefore, Mg is a promising candidate as the framework of water-driven micromotors for biomedical application. In recent years, the Mg micromotors [23] have been reported to be utilized as drug carriers [21, 24]. For example, drug loaded and polymer (parylene) coated Mg-Au micromotors have demonstrated targeted delivery in intestines [25]. Yet this versatility of this platform should be far beyond simple cargo delivering. We proposed to use Mg motors as artificial antigen presenting agent for triggering calcium ion channel response and activating T cells. This platform allows for regulation of immune response and interaction of nanointerface-biosystem. The activation of T cells plays a central role in immunotherapy. Upon activation, T cells could proliferate, differentiate, and trigger the immune downstream signaling [26], [27], [28], [29] to remove pathogens and malignant cells. This research offers a groundbreaking trial for self-propelled Mg-based micromotors as artificial antigen presenting agents. Here the concept of anti-human CD3 (anti-CD3) loaded Mg micromotors for activating the calcium ion channel (indicator for T-cell activation) of Jurkat T cells is illustrated in Fig. 1.

Section snippets

Materials

~20 μm (average-diameter)  Mg microspheres were purchased from Tangshan WeiHao Magnesium Powder Co. Poly (lactic-co-glycolic acid) (PLGA 50/50) was obtained from Jinan Daigang Biotechnology Co. Sodium alginate (ALG) (viscosity was 200 ± 20 mpa.s) was obtained from Aladdin and chitosan (CHI) was obtained from Sigma-Aldrich. Anti-human CD3(anti-CD3) was obtained from Dakewei Biotech Co., Ltd. Hoechst c1022 and Fluo 4 AM (Calcium fluorescent probe) were purchased from Biyuntian Co. RhodamineB

Fabrication and characterization of Mg micromotors

The Mg motors were fabricated with method as follows [31, 32]. Firstly, the Mg microspheres (about 20 µm) were spread on the glass substrate. Then, PLGA, ALG, CHI and anti-CD3 were sequentially dropped cast onto the upper surface of Mg microsphere at room temperature. With PLGA layer, Mg-based micromotor could avoid sinking to the bottom and sticking to the glass despite the low viscosity of the aqueous medium for insufficient suspending Mg-based Janus micromotor. Importantly, PLGA, as a FDA

Conclusion

In summary, the PLGA/ALG/CHI/anti-CD3 Mg motor based system we proposed possess a superior biocompatibility, with all constituents degradable, which could avoid undesirable toxicity bioenvironment. High loading capacity of antigens offered by ALG/CHI-formed porous hydrogel was demonstrated. In addition, the Mg@anti-CD3 micromotors exhibit efficient propulsion in aqueous solution by pure water splitting, from which almost reaction products were harmless for biological context. Finally, these

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

The authors declare no conflicts of interest.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant No. 21805318, 51973241 and 31800835) and Guangdong Provincial Science Foundation for Distinguished Young Scholars (Grant No. 2018B030306007). The authors thank the support from the Chinese 1000-Talent Young Program and Pearl Youth Scholar Funded Scheme. "Group-type" Special Support Project for Education Talents in Universities (G61908043) are acknowledged.

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