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Ordered DNA-Surfactant Hybrid Nanospheres Triggered by Magnetic Cationic Surfactants for Photon- and Magneto-Manipulated Drug Delivery and Release Lu Xu, Yitong Wang, Guangcheng Wei, Lei Feng, Shuli Dong, and Jingcheng Hao* Key Laboratory of Colloid and Interface Chemistry & Key Laboratory of Special Aggregated Materials, Shandong University, Ministry of Education, Jinan 250100, China S Supporting Information *

ABSTRACT: Here we construct for the first time ordered surfactant− DNA hybrid nanospheres of double-strand (ds) DNA and cationic surfactants with magnetic counterion, [FeCl3Br]−. The specificity of the magnetic cationic surfactants that can compact DNA at high concentrations makes it possible for building ordered nanospheres through aggregation, fusion, and coagulation. Cationic surfactants with conventional Br− cannot produce spheres under the same condition because they lose the DNA compaction ability. When a light-responsive magnetic cationic surfactant is used to produce nanospheres, a dualcontrollable drug-delivery platform can be built simply by the applications of external magnetic force and alternative UV and visible light. These nanospheres obtain high drug absorption efficiency, slow release property, and good biocompatibility. There is potential for effective magnetic-field-based targeted drug delivery, followed by photocontrollable drug release. We deduce that our results might be of great interest for making new functional nucleic-acid-based nanomachines and be envisioned to find applications in nanotechnology and biochemistry.

1. INTRODUCTION Because of their remarkable molecular self-recognition ability and unique structural motif, nucleic acids including various DNA and RNA have been developed as important building blocks for nanotechnology. Nucleic-acid-based nanomachines have been used for applications in logic gate operation, molecular sensing, and biomedicine.1−3 Interactions between nucleic acids and cationic surfactants have been investigated for several decades4−8 and have been applied to control the delivery,9 transformation,10 activation,11 and separation12 of nucleic acids. To date, there have been few reports on “nanoarchitectures” made of nucleic acids and cationic surfactants as well as using nucleic acid-surfactant self-assembly materials for drug-delivery applications. It has been evidenced from fluorescence microscopy (FM) observations by Yoshikawa et al.10,13 and Lindman et al.14−16 that cationic surfactants can compact DNA from original stretched “coil” state to small-sized “global” one as they form micelles at the DNA surface. The atomic force microscopy (AFM) observations performed by Wang et al.17 and LopezCornejo et al.18 have shown that DNA−surfactant complexes at the condensed state are not true “spheres”. It is a false appearance by the low-magnification ability of FM. Moreover, both Lopez-Cornejo et al.18 and our previous work19 have revealed that at high concentrations cationic micelles with conventional Br− or Cl− counterions lose the DNA compaction ability and DNA convert to original stretched coil state. The © XXXX American Chemical Society

disappearance of compaction ability of cationic surfactants is caused by the strong association between counterions and cationic micelles at high surfactant concentrations screening the electrostatic interaction between DNA and cationic aggregates.19 Here we report a strategy for creating highly ordered functional nucleic-acid-surfactant hybrid nanospheres by dropwise adding double-strand (ds) DNA with proper concentration (∼60 mmol L−1) into a solution containing high concentration (>8 mmol L−1) cationic surfactants with magnetic counterion, [FeCl3Br]−. The investigation on cationic surfactants with magnetic counterions was pioneered by Eastoe et al. in recent years;20−22 this kind of surfactants can be produced simply by coordinating conventional cationic surfactants having halide ions with FeCl3 in methanol. These magnetic surfactants provide possibilities for controlling liquid surface property,20 delivery of biomolecules,21 or producing magnetic emulsions22 without the addition of any magnetic nanoparticles. Meanwhile, the advantages of using magnetic surfactants instead of nanoparticles include their easy preparation, good dispersibility, and stability in solution and no disruption on the native conformation of biomolecules. In this work, we found that these magnetic cationic surfactants have specificity that can compact DNA at high concentrations, Received: October 12, 2015 Revised: November 16, 2015

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DOI: 10.1021/acs.biomac.5b01372 Biomacromolecules XXXX, XXX, XXX−XXX

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of the two compounds are standard paramagnetic substances at room temperature.31,33 Doxorubicin HCl (Dox, > 98%) was purchased from Dalian Meilun Biotech, China. Salmon testes double-strand DNA (dsDNA) sodium salt was purchased from ACROS (Fairlawn, NJ). Its molar weight was about 100 to 300 bp, as determined by agarose gel electrophoresis (AGE), and its concentration was examined by considering DNA bases molar extinction coefficient to be 6600 mol−1 cm−1 at 260 nm. The absorbance ratio of DNA stock solution was 1.8 to 1.9 at 260 and 280 nm, suggesting no existence of protein. Thrice-distilled water was used to prepare each sample solution. Sample Preparation. dsDNA stock solutions were prepared in 10 mmol L−1 NaBr buffer. The D−S hybrid nanospheres were prepared by adding a drop of 4 μL, 60 mmol L−1 DNA solution to a 4 mL azoTAFe or CTAFe micellar solution at above the concentration 8.0 mmol L−1. The added DNA droplets immediately formed flocculates once the droplets contact with the cationic micellar solutions. After 2 to 4 h, nanospheres can be obtained. The samples were filtrated and washed with thrice-distilled water several times to remove extra salts. Below 8 mmol L−1, the addition of one drop of DNA solution resulted in discrete precipitates, in which structures without defined sizes and shapes were discovered. The Dox-loaded D−S hybrid nanospheres were prepared by adding one drop of 4 μL DNA-Dox solution (60 mmol L−1 DNA and 2 mmol L−1 Dox) to a CTAFe or azoTAFe solution. After 2 to 4 h, the Doxloaded nanospheres were filtrated and washed with thrice-distilled water several times. SQUID Magnetometry. Dried samples of the D−S nanospheres were placed in sealed polypropylene tubes and mounted inside a plastic straw for measuring in a magnetometer with a superconducting quantum interference device (MPMSXL, Quantum Design, USA) and a reciprocating sample option (RSO). The data were collected at 300 K. Scanning Electronic Microscopy. A JSM-6700 instrument (JEOL, Japan) was used to evaluate surface morphology of the nanospheres. The samples were lyophilized for 12 h (−65 °C, 0.05 mbar) before measured. After sputter coating with gold, the samples were transferred onto the microscope stage and examined at ∼10 kV. Transmission Electronic Microscopy. A sample needs to be dispersed uniformly in water before observation. A drop of dispersion liquid (∼4 μL) was dropped on TEM grid (copper grid, 3.02 mm, 200 mesh, and coated with Formvar film). After drying under an infrared lamp for 30 min, transmission electronic microscopy (TEM) observations were performed with a JEOL’s JEM 100 cx TEM (Japan) at an accelerating voltage of 100 kV. Energy-Dispersive Spectrometer. An Oxford INCA X Sight instrument (England) was used to help estimate the basic elements of the nanospheres. Circular Dichroism. A JASCO J-810 spectropolarimeter was used to perform circular dichroism (CD) spectra. Samples were located in 10 mm path length cells, and the scanning speed was controlled to be 100 nm min−1 with the measuring range from 220 to 320 nm. Each sample was measured three times for the average value. The number of repeats of each sample was set to be 3, and the resulting average curves were calculated automatically. Zeta Potential Measurements. Nanospheres were dispersed in water uniformly before measurements. The zeta potential of the dispersions was measured with a Zeta PALS potential analyzer instrument (Brookhaven, USA) with parallel-plate platinum black electrodes spaced 5 mm apart and a 10 mm path length rectangular organic glass cell. All samples were measured using a sinusoidal voltage of 80 V with a frequency of 3 Hz. Degradation Experiments. About 10 mg of nanospheres were placed in 10 mL of thrice-distilled water. After specific time interval, dissolution media were removed and the amount of DNA or drugs in media was examined by a UV spectrometer. The above procedures were repeated several times until all floccules dissolved completely. Irradiation Experiments. A CHF-XM35-500W ultra-high-pressure short arc mercury lamp equipped with two light sources was utilized for light irradiation experiments to isomerize azobenzene

and this property induces the formation of highly ordered nanospheres through aggregation, fusion, and coagulation of the DNA−surfactant (D−S) complexes. Cationic surfactants with conventional Br− cannot lead to the formation of nanospheres under the same condition. When a specific light-responsive magnetic cationic surfactant was used as a component to produce hybrid nanospheres, these nanostructures are endowed drug vehicle applications. Nowadays, finding strategies for controlling pharmaceutical delivery and release is one of the major challenges in biomedicine and tissue engineering. Nanovehicles, taking advantages of their versatile properties, have achieved some success.23,24 Smart nanovehicles, which are sensitive to physicochemical changes in responsive to temperature,25 pH,26,27 and molecular recognition,28 have aroused particular attention. Multiple stimuli can trigger degradation or permeability variations of nanovehicles, thereby making them responsive to environmental changes, in turn, enabling the drug release; however, although such smart drug carriers have been used with success, they still exist challenges in creating novel vehicles with high sensitivity when stimulus is subtle, especially for biochemical signals present at very low concentrations as well as an external actuated property and remote controllability. Thus, smart nanovehicles that can be controlled exogenously by irradiation with light or exposure to magnetic or electrical fields have been increasingly investigated.29,30 A most important challenge is creating multiple responsive nanovehicles that can effectively combine and abundantly utilize these novel triggers to control the drug delivery more intelligently and powerfully. In this work, DNA was used as an electrostatic scaffold to help load an anticancer drug doxorubicin (Dox), with the Doxbinding DNA backbones assembling with the light-responsive magnetic surfactants into nanospheres; drugs can be encapsuled into each nanosphere with high efficiency. The dual-responsive property was used to control the drug transport and release. Although some responsive D−S complexes without the ordered spherical shape may also be applied to load and control the delivery of drugs, the fracture of these structures upon exposure to external stimuli is normally too fast (within few minutes),6,31,32 which cannot offer slow release of drugs that are very important in realizing controllable drug release in clinical situations. The advantages of employing the light- and magneto-responsive D−S nanospheres as drug vehicles on not only their rapid response and external automatic controllability but also their slow release property and potentials in targeted drug delivery, point-to-point drug release and more complicated on-demand cargo delivery. In vitro experiments proved that the D−S nanospheres have good biocompatibility and can increase the drug-absorbing efficiency. Switching the light from visible to UV can accelerate the release of drugs from spheres and lead to an obviously increased cytotoxicity on cancer cells.

2. EXPERIMENTAL SECTION Chemicals and Materials. Magnetic cationic surfactants cetyltrimethylammonium trichloromonobromoferrate (C16H33(CH3)3N+[FeCl3Br]−, CTAFe) and 4-ethoxy-4′- (trimethylaminoethoxy) azobenzene trichloromonobromoferrate (C2H5O-azobenzene-OC2H4(CH3)3N+[FeCl3Br]−, azoTAFe) were synthesized according to reported procedure.31,33 The critical micelle concentrations (cmc) as well as the dissociation constants (β) were determined, respectively, to be about 0.60 mmol L−1 and 0.66 for azoTAFe31 and 0.42 mmol L−1 and 0.68 for CTAFe33 by means of the electrical conductivity method. SQUID magnetometry shows that both B

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Biomacromolecules moieties from trans to cis state in UV light (350 nm) and cis to trans state in visible light (455 nm). Internalization Study. Samples containing A549 or MCF-7 cells were incubated with the desired concentrations of Dox-loaded DNAazoTAFe nanospheres at 37 °C in a volume of 0.1 mL of binding buffer for 3 h with 5% CO2 atmosphere. The cells were then subjected to fluorescent microscopy analysis. A 450 or 488 nm argon laser was used to excite Dox. Cytotoxicity Assay. The cytotoxicty study was conducted using MTT assay for A549 and HePG2 cell lines. Cells were incubated for 48 h at 37 °C under 5% CO2. The DNA-azoTAFe nanospheres with different amounts were added to the wells. 6-fold diluted MTT (0.15 mL/well) in PBS solution was added to each well and incubated at 37 °C for 4 h. The cell viability was colorimetrically detected by using a microplate reader (VERSA), which was used to measure the OD490 nm (absorbance value).

Figure 2. Photograph of precipitates from DNA-CTAFe mixtures by one drop of 60 mmol L−1 dsDNA solution added into a CTAFe solution below 8 mmol L−1 (a). The precipitates are too small that can hardly be observed clearly in the picture. The bar is 5 mm. T = 298 K. SEM images of the DNA-CTAFe complexes in the precipitates resulting from 60 mmol L−1 DNA added into 2 (b) and 6 mmol L−1 (c) CTAFe solution at 298 K.

S2a,b in the Supporting Information (SI)); otherwise, floccules that contain no spheres were obtained (Figure S2c,d). It can be concluded from the above results that the highly ordered D−S hybrid nanospheres cannot be produced by simply mixing DNA with magnetic cationic surfactant CTAFe in an aqueous solution; they can only be gained by dropwise addition of ∼60 mmol L−1 DNA solutions into a CTAFe solution above 8 mmol L−1. To prove the generality of this method of using magnetic cationic surfactants for producing highly ordered hybrid nanospheres, we replace CTAFe with a light- and magnetoresponsive cationic surfactant, azoTAFe (C2H5O-azobenzeneOC2H4(CH3)3N+[FeCl3Br]−). DNA-azoTAFe hybrid nanospheres with average size = 104.33 ± 20.40 nm can also be obtained as 60 mmol L−1 DNA solution droplets were added to an azoTAFe micellar solution (Figure 3a,b, Figure S2e,f). The typical element P derived from DNA backbones as well as Fe from the azoTAFe in energy-dispersive spectrometer (EDS, Figure S3) proved that the formation of nanospheres is absolutely a result of the azoTAFe and DNA hybrids. When cationic surfactants with Br−, that is, CTABr and azoTABr, were used, the flocculation of added DNA droplets gave rise to the formation of cross-linked network structures (Figure 3c,d); no spheres can be received under the same condition as those of DNA-CTAFe and DNA-azoTAFe systems. This behavior demonstrates the importance of counterion, [FeCl3Br]−, in constructing the D−S hybrid nanospheres. Apart from losing the magnetism which may be important in realizing the targeted transport,30,31 considering the fact that the size of nanovehicles should normally be controlled below 200 nm for achieving high drug absorption efficiency by cells through endocytosis,34 the D−S hybrid network structures are less suitable for acting as drug carriers because of the too large size (at least several micrometers).34 In comparison, both DNA-CTAFe and DNA-azoTAFe nanospheres whose sizes are 8 mmol L−1), Dox can equably be incorporated into the DNA-azoTAFe nanospheres. The red Dox-loaded DNA-azoTAFe nanospheres are shown in Figure S6a. An SEM image (Figure S6b) reveals that the Dox-loaded DNA-azoTAFe spheres can still be produced with the same size and shape as those without drugs. A significant increase in the ξ from +37.34 to +49.06 mV confirmed that the azoTAFe-DNA nanospheres were filled with positively charged Dox. The photon-triggered drug release can be fully detected from Figure 7b. A UV−vis spectrometer was chosen to quantitatively analyze the released Dox in media. Under visible light, no noticeable release of drugs from the Dox-loaded DNAazoTAFe nanospheres (1 mg mL−1) was found, indicating good loading efficiency; however, when exposing to UV irradiation, drugs present quick escape into media as determined by a UV spectrometer, and a complete release can be reached after 960 min. For obtaining the key role of UV irradiation in promoting the drug release, comparison measurements of Dox release from DNA-azoTAFe and DNA-CTAFe nanospheres were performed with the same irradiation time of ∼60 min under UV light. As shown in Figure 7c, no obvious release from DNA-CTAFe nanospheres can be detected, while ∼21.6% drugs can be released from DNA-azoTAFe nanospheres. These data clearly show that the rapid release is essentially caused by the trans-to-cis transition of azoTAFe under UV illumination. It could raise the cac of azoTAFe in cis state under UV irradiation to promote the fracture of azoTAFe micelles and DNA-azoTAFe nanospheres. Because of a consequence of diffusion-controlled kinetics for the fracture of nanospheres under UV irradiation, the Dox release process is quite slow. This slow release property could result in the optimum therapeutic effect without overdose in clinical situations. In contrast, the rapid responsiveness to UV light

can rapidly enhance the release rate, allowing exact point-topoint drug release in clinical trials. A characteristic advantage of our system is the switchable property, which enables more complicated on-demand cargo delivery. As a proof in Figure 7d, the release of Dox molecules was regulated with open-close cycles via alternating light sources. A distinct release of Dox could be found in the open state when exposed to UV light in the first 60 min. On the contrary, the closed state with visible irradiation bounded the delivery in the next 60 min. The release of entrapped drugs was again triggered by converting to UV light from 120 to 180 min. After 180 min, further delivery was constrained with visible irradiation. Subsequent UV illumination initiated the release from 240 min again. On the basis of the photosensitivity, an automatic drug delivery platform can be built through adjusting light. This rapid switchable property between UV and visible light could be smartly applied to on-demand dose in clinical trials, thereby avoiding side effects caused by overdose. On the basis of experimental results of Dox transport and release regulated by DNA-azoTAFe nanospheres, we concluded a schematic diagram of drug delivery using azoTAFe-DNA hybrid nanospheres via both magneto and photon means (Scheme 2). Internalization studies using FM confirmed the Dox uptake of cancer cells from the drug-loaded DNA-azoTAFe nanospheres. As shown in Figure 8a,c, the fluorescence signals of human lung adenocarcinoma A549 cells as well as human breast adenocarcinoma MCF-7 cells were traced because of the high Dox intake from the drug-loaded nanospheres. In the absence of nanospheres, both cells show low efficiency in absorbing Dox with obscure fluorescence, as shown in Figure 8b,d. The difference of fluorescence suggests that the DNAazoTAFe nanospheres can enhance the delivery efficiency of Dox. The cytotoxicity of the DNA-azoTAFe nanospheres was studied to examine their feasibility in biorelated applications. The effect of DNA-azoTAFe nanospheres on cell proliferation F

DOI: 10.1021/acs.biomac.5b01372 Biomacromolecules XXXX, XXX, XXX−XXX

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for the both cells (Figure 9b), even though the amount of Doxloaded DNA-azoTAFe nanospheres is as high as 12.5 μg mL−1. Because Dox molecules were effectively imprisoned in the nanospheres, after being treated with UV illumination, Doxloaded DNA-azoTAFe nanospheres exhibit dose-dependent cytotoxicity. An obviously high killing efficiency on the two cells (Figure 9c) can be obtained, demonstrating the Dox release from nanospheres. The killing efficiency on A549 cells is much higher than that on HePG2 cells; the IC50 of Dox-loaded DNA-azoTAFe spheres is 1.75 μg mL−1 for A549 cells.

Scheme 2. Schematic Diagram Showing the Photon- and Magneto-Manipulated Drug Delivery and Release Using the DNA-azoTAFe Nanospheres

4. CONCLUSIONS In this work, we created highly ordered DNA-surfactant hybrid nanospheres by dropwise adding ∼60 mmol L−1 DNA solutions into a magnetic cationic surfactant solution (>8 mmol L−1) based on the specificity of cationic surfactants with magnetic [FeCl3Br]− ions that can compact DNA at high concentrations. Cationic surfactants with Br− losing the DNA compaction ability at high concentrations give rise to the formation of cross-linked network structures under the same condition. The too large size of these network structures makes them be less suitable to act as vehicles for cargo delivery because they can hardly cross cell membranes through endocytosis. Because of their facile fabrication, rapid responsiveness, and external automatic controllability, these DNA-surfactant hybrid nanospheres might be of great interest for making new functional nucleic-acid-based nanomachines. It was proved that the photon- and magneto-responsive DNA-azoTAFe spheres can be used as promising drug vehicles. DNA can serve as an electrostatic scaffold to help load a positively charged anticancer drug Dox; with the Dox-binding DNA assembling with azoTAFe into nanospheres, Dox can be encapsuled into each sphere with high efficiency. The slow fracture behavior of nanospheres in aqueous solutions ensures a slow release property of Dox. The MTT assays proved the good biocompatibility of the DNA-azoTAFe nanospheres. The endocytosis of the Doxloaded nanospheres was demonstrated by FM observations. Efficiently magnetic control over migration property was demonstrated for targeted drug delivery, and effective photocontrolled drug release was proved for cancer therapy. The switchable property shows potentials in further helping achieve more complicated on-demand drug delivery. These DNAsurfactant hybrid nanospheres are anticipated to find applications in cancer therapy and nanomedicine.

Figure 8. FM images of A549 cells after incubation with Dox-loaded DNA-azoTAFe nanospheres (a) and Dox (b) and MCF-7 cells after incubation with Dox-loaded nanospheres (c) and Dox (d) for 3 h at 310 K. A 488 nm argon laser was used for panels a and c and a 543 nm argon laser was used for panels b and d for the excitation of Dox.

was evaluated with A549 cells and human liver adenocarcinoma HePG2 cells by means of a methyl thiazolyl tetrazolium (MTT) assay (Figure 9a). After both cells were incubated with DNAazoTAFe nanospheres for 24 h, the cytotoxicity was tested. Although the dose of DNA-azoTAFe nanospheres reaches to be 12.5 μg mL−1, the cell viability still remained to be 87.11% for A549 cells and 88.76% for HePG2 cells, respectively. The result suggests that the DNA-azoTAFe nanospheres have low in vitro cytotoxicity, confirming the good biocompatibility of this kind of vehicles. The light-responsive in vitro cytotoxicity for both A549 and HePG2 cells of the Dox-loaded DNA-azoTAFe nanospheres was also determined. Both cells were incubated with different amounts of Dox-loaded DNA-azoTAFe nanospheres for 3 h and then treated with UV and visible light for 30 min, respectively. After being treated with UV and visible light, both cells were incubated for 24 h at 37 °C. It makes sure that Dox can be abundantly released from the dissociated DNA backbones and interact with cancer cells. Figure S7 demonstrates that UV illumination did not result in cytotoxicity. Under visible-light illumination, the Dox-loaded DNA-azoTAFe nanospheres showed low in vitro cytotoxicity

Figure 9. In vitro cytotoxicity of A549 cells or HePG2 cells after being incubated with different amounts of DNA-azoTAFe nanospheres for 24 h at 37 °C (a). Cytotoxicity assays of both A549 and HePG2 cells treated with different amounts of Dox-loaded DNA-azoTAFe nanospheres with visible (b) and UV (c) irradiation for 30 min and then incubated for 24 h were measured at 310 K. G

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.biomac.5b01372. Figure S1. Phase diagram of 60 mmol L−1 DNA with varying the concentration of CTAFe at 298 K. Figure S2. SEM images. Figure S3. EDS results of hybrid DNA/ azoTAFe nanospheres. Figure S5. SQUID magnetometry of DNA/azoTAFe nanospheres at 300 K. Figure S6. Photograph of the red Dox-loaded DNA/azoTAFe nanospheres in an azoTAFe micellar solution. Figure S7. In vitro cytotoxicity assay of A549 and HePG2 cells after being treated with visible and UV light for 30 min at 37 °C. (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +86-531-88363768. Fax: +86531-88564750. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the NSFC (21420102006 & 21273136). REFERENCES

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DOI: 10.1021/acs.biomac.5b01372 Biomacromolecules XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.biomac.5b01372 Biomacromolecules XXXX, XXX, XXX−XXX