Self-propelled manganese oxide-based catalytic micromotors for drug delivery

Abstract

A manganese oxide-based catalytic tubular micromotor (PEDOT/MnO₂) is described that displays effective autonomous motion in hydrogen peroxide with high speed (318.80 µm s⁻¹) and can operate in very low levels of fuel, down to 0.4%. The polymer bilayer micromotor also exhibits efficient locomotion in different biological media including bovine serum albumin and bovine serum. Moreover, the micromotor is applied to deliver a chemotherapeutic anticancer drug, camptothecin, using electrostatic interactions, offering considerable potential for diverse clinical and biomedical applications such as drug delivery for theranostic microsystems.

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Introduction

Micromotors, micro- or nanoscale devices that can move autonomously by converting energy into motion, have attracted considerable scientific interest owing to their potential applications in detoxification,¹ motion-based sensing,^2–7 bacterial isolation,⁸ drug delivery,^9–12 water cleaning,^13–17 microsurgery,^18–20 and environmental monitoring.^21,22 Among these, drug delivery technology is a vital domain of health care which aims to manage the deficiencies of conventional means for drug conveyance.²³ Particularly, nanotechnology has enabled drug delivery systems to attract considerable interest due to their significant impact on the treatment of diseases.^24,25 Most notably, acting as new delivery vehicles, micromotors are able to integrate self-driving and navigation capabilities, thereby they may achieve not only smart encapsulation and release but also precise guidance and control.^11,26 Recently, particular attention has been given to self-propelled, chemically powered micromotors with bubble propulsion mechanisms for their efficient movement in corresponding fuels,²⁷ such as extremely acidic environments²⁸ – HCl, H₂SO₄, H₃PO₄, gastric acid,²⁹ water,¹⁵ hydrazine,³⁰ 4-nitrophenol,¹⁶ Br₂ and I₂,³¹ and hydrogen peroxide.^32,33 However, the micromotors that are powered by hydrogen peroxide commonly require Pt,^34,35 an efficient catalyst for hydrogen peroxide with high activity but a noble metal, thus leading to unavailability for extensive use. Catalase-based micromotors also have potential applications such as in water-quality testing based on changes in the propulsion behavior of microswimmers due to the inhibition of the enzyme catalase induced by aquatic pollutants,²¹ but catalase-based micromotors have the shortcomings of mild operating conditions and easy inactivation. Above all, to extend the application of micromotors, it is imperative to probe an efficient catalyst for hydrogen peroxide.

Manganese dioxide (MnO₂) is an efficient catalyst for hydrogen peroxide,³⁶ which has the advantages of low-cost, abundance, and good stability that holds the potential to replace expensive Pt. To date, only a few reports of MnO₂ used as a micromotor have been recorded. For instance, Li et al. designed piezoelectric tubes for cylindrical ultrasonic micromotors through the electrophoretic deposition method using MnO₂ as a raw material. However, it’s not actually an autonomous motor.³⁷ Our group synthesized MnO₂/graphene micromotors with “sandwich”-like structures,³⁸ via a one-step hydrothermal method, which can move rapidly in biological media. MnO₂ particle-based bubble-powered micromotors were synthesized by M. Pumera with a speed of 50 µm s⁻¹ in 12% H₂O₂,³⁹ but a high fuel level limits their application. Recently, Safdar et al. synthesized MnO₂-based micromotors with different shapes including tube, rod, and sphere.⁴⁰ However, a high H₂O₂ fuel level was needed to propel the motion of their micromotors. In addition, the application of MnO₂-based micromotors has been exploited, for instance, MnO₂ microparticles exhibiting a dual effect, that is, catalytic degradation and adsorptive bubble separation, were employed for the decontamination of organic pollutants from wastewater.⁴¹ Magneto-catalytic paper microjets were prepared by MnO₂ deposition and manual rolling for fluorescent rhodamine 6G loading.⁴² Overall, MnO₂-based micromotors have great application prospects.

The emergence of nanotechnology has expanded the horizons of drug delivery systems.²⁵ Furthermore, the development of micromotors that act as new-generation drug delivery vehicles is of great interest.¹² For instance, Wang’s group demonstrated drug delivery through magnetic interactions between a rocket and an iron-oxide encapsulated PLGA, and a liposome drug.⁴³ Gao et al. described the cargo delivery of PEDOT/Zn micromotors with AuNPs using the encapsulation method.²⁹ Sen’s research group proposed the loading of PS microparticles on metallic nanowires with electrostatic interactions and biotin–streptavidin interactions before fuel addition.⁴⁴ He et al. described polymer multilayer capsules and assembled nanotubes for encapsulation of the chemotherapeutic anticancer drug doxorubicin, for navigation to target a cell layer.^10,11 However, there are still some inherent limitations of the technology, such as complex preparation technology, difficulty of surface modification, and poor biocompatibility or biodegradability. Moreover, the capability of synthetic rockets that can load and transport substances by themselves in an easy and controllable way, particularly in the biomedical field, is also most significant. Therefore, it still remains a challenge to develop a new system of drug delivery with the properties of simplicity and accuracy.

Here, we demonstrate a bilayer tubular micromotor in which the outer layer is poly(3,4-ethylenedioxythiophene) (PEDOT) that acts as a conductive material and the inner layer is MnO₂, which can decompose H₂O₂ efficiently to generate O_2, due to the high specific surface of MnO₂ with alveolate structure, leading to effective motion. The manganese oxide-based micromotors show powerful motion with high speed (318.80 µm s⁻¹) and can operate in very low levels of hydrogen peroxide fuel, down to 0.4%. In addition, movement in bovine serum albumin (BSA) and pure bovine serum of PEDOT/MnO₂ micromotors offers great potential application in complex environments. Moreover, this is the first example of the execution of drug capture and delivery by electrostatic interactions between micromotors and drugs in aqueous solution. The micromotor was positively charged after modification with poly(sodium 4-styrenesulfonate) (PSS) and poly(diallyldimethylammonium chloride) (PDDA), while the camptothecin (CPT) was capped with a negative charge owing to its inherent properties. Thus, the micromotors can capture and transport CPT effectively, which holds considerable promise for biomedical applications such as clinical therapy treatments. The overall drug delivery mechanism is depicted in Fig. 1.

Fig. 1 Schematic illustration showing the fabrication and modification processes of the PEDOT/MnO₂ micromotors and the drug delivery mechanism.

Experimental section

Materials and reagents

Manganese(II) acetate tetrahydrate (Mn(Ac)₂·4H₂O), potassium nitrate (KNO₃), sodium dodecyl sulfate (SDS) and hydrogen peroxide (30%) were purchased from Shanghai Chemical Reagent Co., Ltd. Poly(diallyldimethylammonium chloride) (PDDA, MW = 200 000–350 000, 20 wt% in water) and 3,4-ethylenedioxythiophene (EDOT) were purchased from Aladdin Chemistry Co., Ltd. Poly(sodium 4-styrenesulfonate) (PSS, MW = 70 000), bovine serum albumin (BSA), pure bovine serum and camptothecin (CPT) were all purchased from Sigma-Aldrich Chemical Co. Triton X-100 was obtained from Alfa Aesar Chemical Reagent Co. Ltd. All reagents were of analytical grade and used as received without further treatment. Ultrapure water (Milli-Q) was used in all experiments.

Characterization

The morphologies of the micromotors were characterized using scanning electron microscopy (SEM, S-4800). X-ray diffraction patterns were taken on a Philip-X’Pert X-ray diffractometer with a CuKα X-ray source. The composition of the products was examined using Fourier transform infrared spectroscopy (FT-IR, Bruker model VECTOR-22 Fourier transform spectrometer). The synthesis of the PEDOT/MnO₂ micromotor was conducted with a CHI660C workstation (Shanghai Chen hua). Videos showing the micromotor motion were captured by an inverted optical microscope (Nikon Instrument Inc. Ti–S/L100). The speed of the micromotors was calculated using NIS-Elements software and zeta potential tests were carried out with a Zeta-PALS.

Synthesis of micromotors

The PEDOT/MnO₂ micromotors were synthesized by electrodepositing sequential layers into a cyclopore polycarbonate membrane (Catalog no. 7060-2511; Whatman), which contained 2 µm diameter micropores.⁴⁵ Firstly, a 75 nm gold film was sputtered on one side of the polycarbonate membrane to serve as a working electrode. A Pt wire and Ag/AgCl with 3 M KCl were used as counter and reference electrodes, respectively. The membrane was then assembled in a plating cell with aluminum foil serving as contact. Poly(3,4-ethylenedioxythiophene) (PEDOT) microtubes were electropolymerized for 0.06C at +0.80 V from a plating solution containing 15 mM EDOT, 7.5 mM KNO₃ and 100 mM sodium dodecyl sulfate (SDS); subsequently, the inner MnO₂ tube was deposited at +1.0 V for 60 s from a plating solution containing 100 mM Mn(Ac)₂·4H₂O and 100 mM Na₂SO₄ with a mechanism according to the following equation: Mn²⁺ + 2H₂O → MnO₂ + 4H⁺ + 2e⁻.⁴⁶ In control experiments, deposition of the MnO₂ tubes was carried out for times of 40 s and 80 s. Then, the sputtered gold film was completely removed by polishing with 1 µm alumina slurry. Finally, the template was dissolved in methylene chloride for 10 min to release the PEDOT/MnO₂ micromotors that were then collected by centrifugation and washed repeatedly with methylene chloride (three times), ethanol and ultrapure water (twice each). Finally, the micromotors were stored in ultrapure water at room temperature.

Fabrication of positively charged micromotors and negatively charged drug particles

The PEDOT/MnO₂ micromotors were incubated with 0.1 mg mL⁻¹ PSS and PDDA for 30 min in turn,⁷ leading to a positively charged surface of the micromotor. A self-assembly method was used to prepare the drug cargos. Briefly, 2 mM CPT was added into 1 mL of ethyl acetate and then mixed homogeneously using sonication. Subsequently, the solution above was injected into 5 mL aqueous solution containing 8 mM SDS, which plays the role of a surfactant to prevent the particles reuniting, under vigorous stirring for 5 min. Finally, the homogeneous mixture was placed at room temperature for 24 h to form uniform drug microparticles. The spherical drug particles with regular shape and a uniform size of about 2 µm, were viewed using a microscope. Moreover, the results of the zeta potential test shows that they are negatively charged.

Drug delivery experiments

Experiments on the drug delivery by electrostatic interactions between the micromotors and CPT particles were carried out by mixing 5 µL of the micromotor solution sequentially with 5 µL 0.33% Triton X-100, 5 µL drug solution and 5 µL 4% H₂O₂ on a clean glass slide.

Results and discussion

Scanning electron microscopy (SEM) images, at different magnifications, of the PEDOT/MnO₂ micromotors are shown in Fig. 2. The PEDOT/MnO₂ bilayer conical microtubes are about 8 µm long and have a defined geometry with outer diameters between 2 and 1.4 µm, along with inner openings between 1.7 and 1.1 µm (Fig. 2B). They elucidate the alveolate structure of the MnO₂ layer which has a high specific surface area to facilitate the decomposition of H₂O₂ (Fig. 2C). After coating the PEDOT/MnO₂ micromotors with PSS and PDDA, there is no significant change in the structure except increased surface roughness (Fig. S2†). Furthermore, to optimize the thickness of the MnO₂ layer, we executed control experiments with different deposition times of MnO₂ (Fig. S1A–C†). As expected, with increasing deposition time, much thicker MnO₂ was electropolymerized on the inner wall of PEDOT. When the deposition time was 40 s (Fig. S1A†), the thickness of the formed MnO₂ layer was too thin to support the tube leading to lower navigation speed and shorter life of the micromotors. Meanwhile, almost complete blockage of the openings was caused by increasing the deposition time to 80 s resulting in a smaller inner opening (Fig. S1C†). Thus, 60 s was used for electrodeposition of the MnO₂ layer, which leads to efficient motion of the micromotors.

Fig. 2 SEM images with different magnification (A–C), XRD pattern (D) and FTIR spectrum (E) of the PEDOT/MnO₂ micromotors.

The structure and bilayer content of the prepared PEDOT/MnO₂ micromotors have been investigated by X-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FTIR). The XRD pattern of PEDOT/MnO₂ in Fig. 2D reveals that the diffraction peaks are analogous to those of the tetragonal phase of α-MnO₂ (JCPDS no. 44-0141).⁴⁷ The spectrum of the micromotors in Fig. 2E shows that PEDOT and MnO₂ are successfully synthesized. The peak at 1521 cm⁻¹ is attributed to asymmetric C_α=C_β stretching, and the peak at 1636 cm⁻¹ is ascribed to the C=C stretching vibration of the thiophene ring. The bending vibration of C–O–C appears at about 1066 cm⁻¹.⁴⁸ The peak at 1113 cm⁻¹ is attributed to the C–O–C symmetric stretching vibration.⁴⁹ The sharp peaks appearing at 543 and 423 cm⁻¹ are characteristic vibrations of Mn–O bonds, and the weak band at 1395 cm⁻¹ is a characteristic vibration of the O–Mn–O bonding in α-MnO₂.⁵⁰ Meanwhile, the peak observed around 3436 cm⁻¹ corresponds to the stretching mode of the H–O–H vibration of an absorbed water molecule.^50–52

The tubular micromotors can move efficiently by decomposing H₂O₂ both in pure water, BSA and bovine serum. Fig. 3 displays time-lapse images depicting the powerful propulsion of the PEDOT/MnO₂ micromotors in different media with different fuel concentrations, pure water with 0.4% H₂O₂ (A), 25 µM BSA with 2% H₂O₂ (B) and pure bovine serum with 2% H₂O₂ (C). Fig. 3A, the time-lapse images taken from Video S1† over an 8 s period at 2 s intervals in pure water with 0.4% H₂O₂, illustrates efficient motion with a tail of oxygen microbubbles generated on the inner MnO₂ alveolate surface and released from the rear large-opening side of the micromotor. This indicates a lower fuel level compared with the MnO₂ microtube synthesized by Safdar et al. suggesting that the PEDOT/MnO₂ micromotor has a higher activity.⁴⁰ The micromotor is self-propelled at a speed of about 31.57 µm s⁻¹ and such speed is stable during its 7 minute lifetime. In addition, exceptional motion performance in different biological media such as BSA and pure bovine serum indicates the practical utility of the new micromotor. For example, Fig. 3B displays time-lapse images for the movement of a PEDOT/MnO₂ micromotor over a 1280 ms period at 320 ms intervals in 25 µM BSA powered by 2% H₂O_2, illustrating excellent propulsion at a speed of 65.47 µm s⁻¹ in the protein-rich system. Similar to the motion in BSA, the micromotors displayed circular motion in pure bovine serum with a speed of 38.19 µm s⁻¹. The time-lapse images taken from Video S2† over a 2.32 s period at 0.58 s intervals are shown in Fig. 3C, which offers great potential application in complex matrices.

Fig. 3 Time-lapse images depicting efficient propulsion of the PEDOT/MnO₂ micromotors in different media with different fuel concentrations containing 0.33% Triton X-100: pure water with 0.4% H₂O₂ (A), 25 µM BSA with 2% H₂O₂ (B) and pure bovine serum with 2% H₂O₂ (C). Scale bar, 10 µm.

The influence of the hydrogen peroxide concentration and the viscosity effect of the biological protein-rich system on the velocity of the micromotors was examined. Firstly, the results displayed that the concentration of hydrogen peroxide fuel significantly influences the speed of the PEDOT/MnO₂ catalytic micromotors. As shown in Fig. 4A, the speed of the micromotors in pure water is increased from 31.57 µm s⁻¹ to 318.80 µm s⁻¹ with H₂O₂ concentration increasing from 0.4% to 10%. As expected, the speed of the PEDOT/MnO₂ micromotor greatly increases over the entire range of H₂O₂ fuel (0.4–10%) resulting from higher pressure experienced by the bubbles. Video S1† displays the autonomous locomotion of the PEDOT/MnO₂ micromotors in pure water with different concentrations of H₂O₂ correspondingly. As reported by Pumera et al., pure MnO₂ micromotors can be moved at high H₂O₂ concentration and can achieve a speed of about 100 µm s⁻¹ with 18% H₂O₂ fuel concentration³⁸ which shows lower speed than that of the PEDOT/MnO₂ micromotors with about 318.80 µm s⁻¹ with 10% H₂O₂ fuel. Secondly, the viscosity effect of the protein-rich media system also affects the velocity of the micromotors (Video S2†). As shown in Fig. 4B, in the absence of biological media, the micromotor speed was about 69.50 µm s⁻¹ in pure water powered by 2% H₂O_2, and then the speed decayed from 65.47 µm s⁻¹ to 60.07 µm s⁻¹ with an increasing BSA concentration from 25 µM to 100 µM. In addition, a lower speed of 38.19 µm s⁻¹ was obtained in the presence of pure bovine serum, indicating that an increase in biological media viscosity is responsible for the decreasing speed of the micromotors. The good motion performance of the PEDOT/MnO₂ micromotors both in pure water and protein-rich systems showed practical potential applications of the catalytic micromotors in complex bio-media.

Fig. 4 Dependence of the PEDOT/MnO₂ micromotor speed on the hydrogen peroxide concentration over the 0.4–10% range in pure water (A), and in different media (B) in the presence of 0.33% Triton X-100. Error bars show standard deviations of the measured speeds from 15 micromotors.

Application of the PEDOT/MnO₂ micromotors as drug carriers to approach, capture, and transport the drug was finally explored. With the excellent curative effect of gastrointestinal and head-neck cancer, the anticancer drug CPT was chosen as a model drug. Considering the insoluble properties of CPT in water, we prepared drug nanoparticles by dealing blocky CPT into uniform particles of about 2 µm using the self-assembly method and they were negatively charged with a potential of −48.08 mV (Fig. S3B†), as determined by zeta potential measurements. On the contrary, the final micromotor has a positively charged surface with a potential of 66.61 mV after modification with PSS and PDDA repeatedly (Fig. S3B†). The zeta potential of the micromotors when coated with a monolayer of the polymer PDDA is 57.37 mV and when coated with a bilayer of polymers PDDA/PSS, the potential is −58.50 mV (Fig. S3A†) indicating that the micromotor surface charge can be changed successfully with oppositely charged polyelectrolytes. The optical images in Fig. 5 and the corresponding Video S3† illustrate an entire “on the fly” drug “approach, capture, and transport” operation by the PEDOT/MnO₂ micromotors in 4% H₂O₂ fuel. The micromotor approached the 2 µm diameter drug particle and once the micromotor had captured CPT, it would navigate together with the drug due to the interaction of attaching a negatively charged CPT drug to a positively charged micromotor with surface modifications. Here, the processes of adsorption and delivery of the target drug were accomplished in aqueous solution, which were different with other cargo loading methods, such as, vacuum infiltration,²⁹ encapsulation,^10,11 and electrostatic attachment,⁴⁴ in which, the cargo was included in the preparation process before navigation. Furthermore, the modification of the micromotor is simplified and drug loading does not need other coatings, for example, poly(D,L-lactic-co-glycolic acid) (PLGA),⁴³ an indirect drug vector. Hence, a convenient, direct, and label-free optic visual process of drug delivery is achieved successfully, which offers considerable potential for diverse clinical and biomedical applications.

Fig. 5 Drug delivery: time-lapse images of a PEDOT/MnO₂ micromotor approaching (a), capturing (b), and transporting (c) the drug CPT in 4% H₂O₂ and 0.33% Triton X-100. Scale bar, 10 µm.

Conclusions

In conclusion, we have demonstrated efficient, low-cost, stable and environmentally friendly PEDOT/MnO₂ micromotors that were propelled efficiently by the thrust of oxygen bubbles. The micromotors were produced by a greatly simplified membrane template electrodeposition method. The resulting micromotors display efficient propulsion (as high as 318.80 µm s⁻¹) and demonstrate good movement in biological media which is a crucial advantage for various relevant biomedical applications. Moreover, these modified micromotors offer very attractive capabilities for autonomous capture and transport of the CPT drug. Such ability to perform as a self-propelling therapeutics device may help in designing miniaturized therapeutic microsystems in the vicinity of cells and tissues in an organism. Therefore, such self-propelled noble metal-free multilayer micromotors hold great promise for the development of new-generation drug delivery vehicles.

Acknowledgements

This work is jointly supported by the Ministry of Education of China (No. IRT1148), NSFC (20905038, 61504066), the Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Synergistic Innovation Center for Organic Electronics and Information Displays, Jiangsu Province ‘‘Six Talent Peak’’ (2015-JY-015), Jiangsu Provincial NSF (BK20141424, BK20150838), the Program of NUPT (NY214088), and the Open Research Fund of the State Key Laboratory of Bioelectronics (I2015010), Southeast University.

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Footnote

† Electronic supplementary information (ESI) available: SEM images of PEDOT/MnO₂ micromotors with different electrodeposition time, 40 s, 60 s and 80 s respectively; zeta potential tests of the modified micromotors and the drug CPT; Video S1: autonomous motion of PEDOT/MnO₂ micromotors in pure water with different H₂O₂ concentrations ranging from 0.4% to 10%; Video S2: autonomous propulsion of PEDOT/MnO₂ micromotors in 25 µM BSA, 100 µM BSA and pure bovine serum with 2% H₂O₂; Video S3: drug picking-up and transport in pure water with 4% H₂O₂. See DOI: 10.1039/c6ra13739c

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