Letter Cite This: Nano Lett. 2019, 19, 4118−4125
pubs.acs.org/NanoLett
Ultrasonication-Triggered Ubiquitous Assembly of Magnetic Janus Amphiphilic Nanoparticles in Cancer Theranostic Applications Xiaoli Liu,†,# Mingli Peng,†,# Galong Li,†,# Yuqing Miao,† Hao Luo,‡ Guangyin Jing,‡ Yuan He,† Ce Zhang,‡ Fan Zhang,§ and Haiming Fan*,†
Downloaded via NOTTINGHAM TRENT UNIV on July 18, 2019 at 08:15:17 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
†
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry and Materials Science & The College of Life Sciences, Northwest University, Xi’an, Shaanxi 710127, People’s Republic of China ‡ School of Physics, Northwest University, Xi’an, Shanxi 710069, People’s Republic of China § Department of Chemistry, State Key Laboratory of Molecular Engineering of Polymers, Collaborative Innovation Center of Chemistry for Energy Materials, Fudan University, Shanghai 200433, People’s Republic of China S Supporting Information *
ABSTRACT: The ultrasonication-triggered interfacial assembly approach was developed to synthesize magnetic Janus amphiphilic nanoparticles (MJANPs) for cancer theranostic applications, where the biocompatible octadecylamine is used as a molecular linker to mediate the interactions between hydrophobic and hydrophilic nanoparticles across the oil−water interface. The obtained Co cluster-embedded Fe3O4 nanoparticles−graphene oxide (CCIO−GO) MJANPs exhibited superior magnetic heating efficiency and transverse relaxivity, 64 and 4 times higher than that of commercial superparamagnetic iron oxides, respectively. The methodology has been applicable to nanoparticles of various dimensions (5−100 nm), morphologies (sphere, ring, disk, and rod), and composition (metal oxides, noble metal and semiconductor compounds, etc.), thereby greatly enriching the array of MJANPs. In vivo theranostic applications using the tumor-bearing mice model further demonstrated the effectiveness of these MJANPs in high-resolution multimodality imaging and high-efficiency cancer therapeutics. The ubiquitous assembly approach developed in the current study pave the way for ondemand design of high-performance Janus amphiphilic nanoparticles for various clinical diagnoses and therapeutic applications. KEYWORDS: Magnetic Janus amphiphilic nanoparticles, ultrasonication-triggered, interfacial assembly, cancer theranostic applications
I
consuming and have limited scalability. Additionally, the unmanageable thermodynamic process of heterogeneous nucleation and the lattice mismatch problem are greatly restricted to the resulting Janus nanoparticles in materials type, domain size, and morphology. In contrast, assembly of hydrophobic and hydrophilic nanoparticles at the oil−water interface in combination with Pickering emulsion is a promising alternative. Pickering emulsion, which is stabilized by solid particles trapped at the oil−water interface, is likely to be an ideal template to attain the assembly of MJANPs for biomedical applications.17 Nevertheless, the in situ interfacial assembly of the homogeneous ultrasmall nanoparticles with distinct wetting properties in both phases through reported emulsion method18−20 is difficult, given the fact that reduced particle size leads to significantly decreased interfacial detachment energy and interparticle interaction across the oil−water interface.21−23 This effect eventually causes the tendency of these homogeneous nanoparticles to remain dispersed in either phase. Interestingly, the self-assembled nanostructures of the
norganic heterostructured Janus amphiphilic nanoparticles, which integrate the characteristics of biphasic core components with nanoscale dimension/morphology and Janus distribution of surface coatings, have provided many exciting new features for advanced cancer diagnosis and therapy.1−3 Among currently available biofunctional nanoparticles, magnetic iron oxide nanoparticles (MIONs) are important biomaterials widely utilized as imaging and therapeutic agents in clinical settings.4−6 Combination of MIONs with other functional nanoparticles gives rise to magnetic Janus amphiphilic nanoparticles (MJANPs) with enhanced magnetic, optical, and superficial properties, which are of particular interest for theranostic application. Au−Fe3O4 MJANPs, for example, can form a new class of double-layered plasmonic-magnetic vesicles with enhanced imaging properties that are superior to their homocounterparts.7 However, the synthesis of MJANPs with controllable size, morphology, and compositions remains a challenging task, which further hinders their theranostic applications. The current synthetic strategies for MJANPs include surfaceselective modification of prefabricated heterostructured nanoparticles3,7−9 and the seed-mediated interfacial growth.10−16 However, these methods are overly complicated and time© 2019 American Chemical Society
Received: April 13, 2019 Revised: May 13, 2019 Published: May 29, 2019 4118
DOI: 10.1021/acs.nanolett.9b01524 Nano Lett. 2019, 19, 4118−4125
Letter
Nano Letters
Figure 1. (a) Schematics of the ultrasonatically triggered interfacial assembly process. (b) Phase diagram of MJANPs formation with variable ODA, CCIO, and GO. (c) Photographs of the experimental stage for preparing CCIO−GO MJANPs: (i) mixture of starting materials; (ii) Pickering mini-emulsion; (iii) CCIO−GO MJANPs. (d) TEM of CCIO−GO MJANPs. (e) SAR of CCIO−GO MJANPs and commercial SPIOs (Resovist).
efficiency cancer therapeutics. This study aims to provide a general interfacial assembly strategy for synthesizing MJANPs in a controllable manner, which undoubtedly offers the possibilities for designing other high-performance Janus amphiphilic nanoparticles for various clinical diagnoses and therapeutic applications. The initially designed MJANPs were to construct highmagnetization hydrophobic Co cluster-embedded Fe3O4 nanoparticles (CCIO NPs) (Figure S1) based nanoagent for magnetic resonance imaging (MRI) guided efficient magnetic hyperthermia treatment. Small-sized hydrophilic GO nanosheets (NSs) (∼100 nm) were chosen as the counterpart because they can provide large electrostatic repulsion against aggregation induced by strong magnetic dipole−dipole interactions between CCIO NPs. In a typical experiment, oleic acid-capped CCIO NPs (2 mg) were mixed with ODA (100 mg) in 0.2 mL of CHCl3, and 5 mL of GO NSs in water dispersion (1 mg/mL) was added into the CHCl3 (left, Figure 1c). The mixture was emulsified using an ultrasonic homogenizer. After 30 min of ultrasonication, the stable Pickering emulsion was formed and stabilized by solid inorganic nanoparticles (middle of bottom, Figure 1c). The CCIO−GO MJANPs were then obtained by the evaporation of chloroform at 55 °C in a shaker. When any of the reactants (ODA, MIONs, GO) was absent, an unstable emulsion was formed, which finally produced the nanoparticle aggregation after the demulsification (Figure S2). The obtained CCIO− GO MJANPs could be well dispersed in both chloroform and water, confirming their amphiphilic nature (Figure S3a). When the starting materials were scaled up, CCIO−GO MJANPs could be produced on a large scale by this approach (Figure S3b). A transmission electron microscopy (TEM) image of CCIO−GO MJANPs is shown in Figure 1d. In most cases, each GO NS was conjugated with one or two CCIO NPs. The SAR of CCIO−GO MJANPs was measured to evaluate its
incompatible constituents are ubiquitous in natural living systems, such as viruses and organelles originating in the selective control of the interactions.24 For example, a T cell can precisely recognize and assemble with foreign molecules during acquired immune response, where the major histocompatibility complex (MHC) molecules play an important role by mediating the interactions between the antigens derived from pathogens and T-cell receptor.25,26 Inspired by this idea, we herein present a ubiquitous ultrasonication-triggered assembly strategy for MJANPs using octadecylamine as a linker bridging the hydrophobic and the hydrophilic functional nanoparticles at the oil−water interface (Figure 1a). In detail, octadecylamine (ODA), a biocompatible molecule, was used as the linker to mediate the interaction of the hydrophobic oleic acid capped MIONs and the hydrophilic functional nanoparticles with surface carboxyl groups at the chloroform−water interface (Figure 1a). Our results revealed that the formation mechanism of MJANPs resemble the biological assembly process, where the interactions of heterogeneous nanoparticles at the interface are regulated both by the chemical interaction that is ultrasonically triggered formation of the amide bonding between ODA molecule and hydrophilic nanoparticle and by the physical hydrophobic interaction between ODA molecule and hydrophobic nanoparticle. The thus obtained Co clusterembedded Fe3O4 nanoparticles−graphene oxide (CCIO−GO) MJANPs exhibited the significantly enhanced magnetic heating efficiency of 13 kW/g Fe and transverse relaxivity of 744 mM−1 s−1, which are 64 and 4 times higher than those of commercial superparamagnetic iron oxides, respectively. As proof of the concept, a series of multifunctional MJANPs were prepared using a similar procedure including MION−graphene oxide (GO), MION−noble metal nanoparticle, and MION−semiconductor quantum dot (QD). Advantages of these MJANPs were further demonstrated by their biomedical applications in high-resolution in vivo multimodality imaging and high4119
DOI: 10.1021/acs.nanolett.9b01524 Nano Lett. 2019, 19, 4118−4125
Letter
Nano Letters
Figure 2. (a) SIM image of the Pickering emulsion. Fluoresceinamine was used to label GO NSs (green), and rhodamine B isothiocyanate (RITC) was used to label CCIO NPs (red). (b) Schematic of the chemical structure of a MJANP at the interface. (c) Representative SIM image of a single droplet. (d) The desorption energy of CCIO−GO MJANPs varies with the coverage angle σ, depending on the wettability of the particle at the interface. Insets show the geometry of MJANPs at the liquid−liquid interface. (e) Diameters and interfacial thicknesses of the droplets with varied concentrations of CCIO NPs. The scale bar in the inset SIM images is 1 μm. (f) FTIR spectrum of GO, ODA, and CCIO NPs and CCIO−GO MJANPs in KBr pellets.
[tension 51.1 and 10.7 γ/(mN m−1)]. No emulsion or MJANPs were obtained, indicating that the appropriate interfacial tension is necessary for the assembly process. In addition, the ultrasonic power and ultrasonic time showed a threshold at 80 W for at least 20 min for the successful production of MJANPs, which suggests that ultrasonication actively participates in the formation of the MJANPs. These results demonstrated that the MJANPs were produced by the ultrasonically triggered interfacial assembly of hydrophobic and hydrophilic nanoparticles dispersed in two immiscible phases, in which certain oil/water solvents and additive molecules are all indispensable. Super-resolution structured illumination microscope (SIM) images provided detailed information on the fine structure of the emulsion droplet to further illuminate the interfacial selfassembly process. CCIO NPs and GO NSs were labeled with rhodamine B isothiocyanate (red) and fluoresceinamine (green), respectively. Figure 2a shows the large-scale SIM images of the as-prepared chloroform-in-water emulsion, which clearly indicated that the vast majority of CCIO NPs and GO NSs were trapped at the oil−water interface of the emulsion droplet (Figure S5). Insets of Figure 2a are the diagrammatic drawing of the droplet stabilized by the absorbed nanoparticles. These trapped nanoparticles can effective reduce interfacial energy,23 thereby facilitating the formation of thermodynamically stable Pickering emulsion. The representative SIM image of a single droplet with a diameter of approximately 2 μm and a liquid−solid−liquid interfacial thickness of approximately 280 nm is presented in Figure 2c. As shown in Figure 2c, the oil−water interface was constructed by a large of discrete CCIO−GO MJANPs. In addition, the diameter and interfacial thickness of the droplet were found to be dependent on the nanoparticles concentration. As the concentration of CCIO NPs increased from 1 to 5 mg/mL, the
magnetic heating efficiency under alternating magnetic field (AMF) for potential magnetic hyperthermia therapy. Benefiting from their unique Janus structure, the obtained CCIO− GO MJANPs have shown a significantly enhanced magnetic heating efficiency with the specific absorption rate (SAR) of 13 kW/g Fe at 380 kHz, ∼64 times higher than that of commercialized superparamagnetic iron oxides (SPIOs) (Resovist, 200 W/g) (Figure 1e). Several experiments have been conducted to investigate the influence of reaction conditions on the formation of CCIO− GO MJANPs, including reactant concentration, oil/water (O/ W) volume ratio and ultrasonication power. The preliminary results indicated that the appearance of stable emulsion is likely to be the precondition for MJANPs formation. Under the same conditions, the amount of GO required for MJANPs formation ranged from 2.5 to 10 mg (Figure S4a). As the amount increased further to 25 mg, the resultant suspension was not clear or even mud-like (Figure S4a). The formation diagram of the variations in ODA relative to the number of MIONs per GO is shown in Figure 1b. MJANPs could be produced only at N (number of MIONs per GO) = 5, 1 mg ≤ mODA ≤ 2 mg; N = 10, 2 mg ≤ mODA ≤ 6 mg; 20 ≤ N ≤ 40, 4 mg ≤ mODA ≤ 10 mg; 40 ≤ N ≤ 60, 6 mg ≤ mODA ≤ 10 mg. In all of the above conditions, the formation of the MJANPs is strongly associated with the stable emulsion, revealing that the on-site selfassembly of CCIO−GO MJANPs at the oil/water interface gives rise to Pickering emulsification rather than the opposite process. That process is distinctly different from the previously reported interfacial assembly process, in which the molten wax droplet is cooled first, followed by asymmetrical functionalization.10,27−33 The optimal O/W volume ratio was determined to be in the range 0.18−0.33 (Figure S4b). We also replaced chloroform [interface tension 32.8 γ/(mN m−1)] with other common organic solvents, such as hexane and diethyl ether 4120
DOI: 10.1021/acs.nanolett.9b01524 Nano Lett. 2019, 19, 4118−4125
Letter
Nano Letters
interaction is energetically favorable, which can minimize the surface free energy of the droplet greatly. The overall process of the ultrasonically triggered assembly of MJANPs can thus be elucidated. First, ultrasonication initiated the mixing of two liquids with an increased oil−water interface by forming microsized droplets for nanoparticle assembly and simultaneously activated the interfacial amide reaction to form GO−ODA. The amide bonding of GO−ODA improved the hydrophobicity of GO, making it pinning at the interface firmly. Second, CCIO NPs were then spontaneously assembled with GO−ODA, forming the CCIO−GO MJANPs through hydrophobic interactions driven by the minimization of surface free energy of the droplet. Finally, the evaporation of chloroform broke the Pickering emulsion, producing waterdispersible CCIO−GO MJANPs. The results revealed that the presence of ODA indeed regulated the particle interaction across the interface, facilitating the formation of MJANPs. The principle of ultrasonically triggered interfacial self-assembly of MJANPs can be briefly summarized by three criteria: (i) the system should consist of two immiscible liquid phases with suitable interfacial tension, such as chloroform and water, as well as two solid nanoparticles (hydrophobic nanoparticles capped with oleic acid and hydrophilic nanoparticles with surface −COOH functional groups). (ii) Ultrasonication must be performed with sufficient power to activate the amide reaction, followed by demulsified evaporation. (iii) Additive molecules should be present as linkers that can regulate the interparticle interaction across the oil−water interface effectively. To demonstrate the generality of this strategy, a large variety of MJANPs with diverse functions were produced using the same procedure, including MION−GO, MION−noble metal nanoparticle, and MION−semiconductor nanoparticle MJANPs. We first replaced CCIO NPs with other MIONs possessing different morphologies. This approach yielded additional ferrimagnetic vortex-state iron oxide nanorings (FVIOs)−GO, iron oxide nanodisks (IONDs)−GO, and iron oxide nanorods (IONRs)−GO. Figure 3a,b shows the hysteresis loops and a digital photograph of MION−GO MJANPs. As shown in Figure 3a, the MION−GO MJANPs exhibit tunable magnetic properties with saturation magnetizations (Ms, emu/g) of 95 (CCIO−GO), 51 (FVIOs−GO), 55 (IONDs−GO), and 62 (IONRs−GO). The assembly of these magnetic nanomaterials with GO did not affect their magnetic characteristics. For example, the FVIOs−GO MJANPs still maintain their magnetic vortex domain structures (Figure 3a). Most notably, these magnetic nanomaterials with strong magnetic dipole−dipole interactions, relatively large size, and variable shape could be dispersed very well in aqueous solutions by forming MJANPs, which not only break their biomedical application bottleneck of failing to be stable in aqueous dispersion but also confer the new feature of anisotropic hydrophobicity for lipophilic drug carriers. Magnetic-plasmonic and magnetic-fluorescent MJANPs were also synthesized, where noble metal nanoparticles and semiconductor QDs with oleic acid capping were dispersed in the oil phase, and MIONs with carboxyl terminal groups were dispersed in the water phase. The absorbance spectra and photographs of Ag NPs−MIONs, Au NPs−MIONs, Au NRs− MIONs, and Au HNSs−MIONs MJANPs are presented in Figure 3c,d. The absorbance bands of the noble metal−MION MJANPs were observed at 411, 522, 667, and 785 nm, respectively (Figure 3c) and are associated with the size,
average diameter of the emulsion droplet decreased from 2.31 to 1.64 μm (Figure 2e and Figure S6). At the same time, the average interfacial thickness of the droplets tended to become much thicker, from 240 to 430 nm, which is in good agreement with the modified thermodynamic theory,34 in which the thicker interface is required for energetic stabilization of the surface of the small droplet. A plausible structure of CCIO−GO MJANPs at the interface is shown in Figure 2b. We hypothesized that GO tethered with abundant COOH groups reacted with ODA, forming amide bonds during the ultrasonic process,35,36 and GO with an ODA linker then conjugated with CCIO NPs through hydrophobic interactions. To verify this hypothesis, FTIR spectra were measured for GO NSs, CCIO NPs, ODA, and CCIO−GO MJANPs (Figure 2f and Figure S7). New peaks at 1700, 1551, 1254, 1089, 872, and 805 cm−1 were observed for the CCIO− GO MJANPs, which correspond to the CO (amide I band), CN and NH (amide II bands), CN and NH (amide III bands), NC stretching, and CN/CC stretching and N H bending (out-of-plane),37−43 respectively. This result confirmed the ultrasonically initiated amide reaction between the −COOH groups in GO and −NH2 groups of ODA. Moreover, when this reaction is halted by either replacing the ODA with oleic acid or reducing the ultrasonic power below the threshold (Figure S8), no CCIO−GO MJANPs will be produced, indicating that the amide bonding of ODA to GO plays a crucial role in triggering the formation of the MJANPs. Once GO−ODA was formed, CCIO tended to conjugate with GO−ODA through the hydrophobic interaction forming a liquid−solid−liquid three-phase interface, and they try to adopt their lowest energy configurations to maximally reduce the area of the energetically interface.44 Modeling analysis was conducted using the homogeneous and MJANPs (Part 2 Supporting Information; Figure S9 and Figure S10). The minimum energy ΔGmin for a nanoparticle to detach from the interface, termed the desorption energy, was calculated. For a homogeneous nanoparticle, the desorption energy is mainly determined by its hydrophobicity. The measured water−oil− solid contact angles of CCIO NPs and GO NSs are 164.6° and 24°, respectively (Figure S11). As shown in Figure S12 and Figure S13, the ΔGmin values of CCIO NPs and GO NSs are comparable to the magnitude of the thermal energy at room temperature; therefore, they can readily escape from the interface toward being “wetted”. Unlike the homogeneous nanoparticles, MJANPs have both apolar and polar surface regions (Figure 2d), the desorption energy of a MJANP can be deduced as44,45 1 i y ΔGmin = 2πR2γOW jjj−cos θA − cos σ cos θA + (sin σ )2 zzz 2 k {
(1)
where θA and θ are the contact angles, β is the immersion angle, and σ is the coverage angle, which is used to measure the proportions of polar and apolar surface regions. The desorption energy variations of a CCIO−GO MJANP with the coverage angle are presented in Figure 2d. The dashed line represents the desorption energy of CCIO NPs. The contact angle of the CCIO−GO MJANP is measured to be 97.1° (Figure S14), and the coverage angle is thus calculated to be 99.3° (Figure S15). The MJANPs have a significantly increased ΔGmin of ∼1 × 105 KbT, 5 orders of magnitude higher than that of homogeneous CCIO NPs (Table S1). As a result, the formation of MJANPs at the interface via hydrophobic 4121
DOI: 10.1021/acs.nanolett.9b01524 Nano Lett. 2019, 19, 4118−4125
Letter
Nano Letters
magnetic properties at room temperature (Figure S16). TEM images of these synthesized MJANPs are shown in Figure S17. The fine structure of the MJANPs varies with the size and morphology of the components, which can be tuned to attain optimal amphiphilic activity at the oil/water interface. DLS and ζ potential data showed that all samples obtained have a uniform hydrodynamic size (Figure S18), revealing their nature as a stable colloid system. The results demonstrated the prominent ability of this interfacial assembly strategy to integrate functional nanoparticles with varied sizes, morphologies, and compositions into Janus amphiphilic nanoparticles, which in great measure lead us to the unconstrained design of novel Janus amphiphilic nanoplatforms with desirable functions. In vivo theranostic applications using tumor-bearing mice models were further performed to demonstrate the unique advantages of these synthesized MJANPs in multimodality imaging and therapeutics. Encouraged by the unprecedentedly high SAR value and amphiphilic nature of CCIO−GO MJANPs, they were used as drug carriers of lipophilic paclitaxel (PTX) for the in vivo MRI guided chemo-thermal synergistic therapy of cancer. CCIO−GO MJANP were also expected to be an ultrasensitive T2 contrast agents, which can greatly reduce the spin−spin relaxation time of water protons due to its high magnetization. The r2 relaxivity of CCIO−GO MJANPs was measured at 7 T and is presented in Figure 4a. The r2 value of CCIO−GO MJANPs was 744 mM−1 s−1, which was 4 times greater than that of the commercial SPIOs (188 mM−1 s−1). The in vivo contrast-enhanced MRI of tumor using CCIO−GO MJANPs is shown Figure 4b. The obviously darkened T2 signal in the tumor site after injected CCIO−GO MJANPs verified their effectiveness in MRI enhancement. The in vitro accumulative PTX release profiles (Figure S19) showed that in the presence of AMF, CCIO−GO MJANPs released significant amounts of PTX up to 20%, whereas only 1% of PTX was released in the absence of AMF, indicating AMFresponsive drug release behavior. The chemo-thermal combined therapeutic effect of PTX-loaded CCIO−GO
Figure 3. (a) Hysteresis loops and (b) digital photographs of MIONs−GO MJANPs, (c) UV−vis spectra, and (d) digital photographs of noble metal nanomaterials−MIONs MJANPs. (e) Emission spectra and (f) digital photographs of fluorescent QDs− MIONs MJANPs.
morphology, and composition of noble metal nanomaterials. Similarly, magnetic-fluorescent MJANPs (Figure 3f) are capable of multicolor emissions from 475 to 1050 nm (Figure 3e). Since the emission stability of QDs is frequently affected by the complex tumor microenvironment,46 hydrophobic QDs incorporated into MJANPs can exhibit much more stability under physiological conditions. All these MJANPs possess
Figure 4. (a) T2 relaxation rate (1/T2) as a function of Fe concentration for CCIO−GO MJANPs. (b) In vivo T2-weighted MRI images of tumorbearing mice pre- and post-injection of CCIO−GO MJANPs. Arrowheads indicate the tumor. (c) Plot of tumor volume (V/Vinitial) versus days after different treatments. (d) Photographs of pre- and post-treatment at the end point. 4122
DOI: 10.1021/acs.nanolett.9b01524 Nano Lett. 2019, 19, 4118−4125
Letter
Nano Letters MJANPs by intratumoral injection is shown in Figure 4c,d. Tumors on nude mice treated by combined therapy using PTX-loaded CCIO−GO MJANPs were completely eliminated within 12 days, in contrast to the free PTX and CCIO−GO MJANPs at the equivalent doses, indicating the excellent antitumor efficacy of the chemo-thermal combined treatment. Notably, the amount of CCIO−GO MJANPs administered (0.2 mg cm−3 of tumor tissue) was 2 orders of magnitude less than previously reported (ca. 5−10 mg cm−3 of tumor tissue). During the entire treatment period, the treated mice did not display an obvious body weight decrease, and there no statistical significance among the groups (Figure S20). Hematoxylin-eosin (HE) staining studies indicated no significant abnormality in major organs (Figure S21). In vivo multimodality imaging was carried out using Au− MION and CuInS/ZnS−MION MJANPs, in which the MIONs are able to shorten the T2 relaxation time of water protons, resulting in enhanced MRI contrast and sensitivity,47,48 while Au NPs and CuInS/ZnS NPs have been considered as more powerful contrast agents for CT and fluorescence imaging, respectively, than conventional molecular contrast agents.49,50 The in vitro T2-weighted imaging of these MJANPs was examined at various Fe concentrations. Significant dose-dependent inverse MR image contrast was observed, and the calculated r2 relaxivity was 272 and 180 mM−1 s−1 for Au NPs−MIONs and CuInS/ZnS−MIONs MJANPs (Figure S22a and Figure S23a), respectively. The in vitro CT imaging of the tube array illustrated the positive contrast enhancement of Au−MIONs MJANPs in a dosedependent manner (Figure S22b), while the CuInS/ZnS− MIONs MJANPs showed strong fluorescence emission with a peak at 650 nm (Figure S23b). In vivo multimodality imaging was performed in BALB/c mice bearing subcutaneous 4T1 breast tumor (CT/MRI) and nude mice bearing subcutaneous MCF-7 breast tumors (fluorescence/MRI), respectively. These MJANPs were intravenously injected into mice through the tail vein. For Au−MIONs MJANPs, the MR images and CT images were acquired before (0 h) and at different times after injection, as illustrated in Figure 5a and Figure S24. The positions of the tumor indicated by the arrow were analyzed quantitatively (Figure S24b). The tumor signal was the strongest at 6 h post-injection, indicating the maximum accumulation of Au−MIONs MJANPs in the tumor. With respect to the MR images at time 0, a significant reduction in the T2 signal of the tumor lesion to 66% was observed at 6 h after injection (Figure S24). Similarly, for CuInS/ZnS− MIONs MJANPs, the strongest fluorescent and MR signals in the tumor both appeared at 6 h after intravenous injection, whereas no significant signals were discerned in the tumor for the control group. Ex vivo fluorescent imaging was also performed to further investigate the biodistribution of the CuInS/ZnS−MIONs MJANPs. As shown in Figure 5b, the fluorescence signal is clearly visible in the tumor of the mouse injected with CuInS/ZnS−MIONs MJANPs but is barely observed in the spleen, heart, and lung, although some depositions appear in the liver and kidney. All results from the in vivo study prove that the MJANPs obtained by the current interfacial assembly strategy are capable of various theranostic applications with improved performance in bioimaging and treatment of cancer. The current molecule-mediated interface assembly strategy has several distinct advantages over conventional methods for the preparation of Janus amphiphilic nanoparticles. (I) This
Figure 5. (a) In vivo T2-weighted MRI and CT images of tumorbearing mice pre- and post-injection of Au NPs−MIONs MJANPs. Arrowheads indicate the tumor. (b) In vivo T2-weighted MRI and fluorescence images of tumor-bearing nude mice pre- and postinjection of CuInS/ZnS−MIONs MJANPs. Arrowheads indicate the tumor.
method is simple and cost-effective. The intrinsic feature of the self-assembly strategy allows us to maximize utilization of currently available functional nanoparticles, avoiding the complex synthetic process of the on-site growth of heterostructured nanoparticles. (II) This method can achieve superior tunability of Janus amphiphilic nanoparticles with respect to the size, morphology, and structure of assembled nanoparticles as well as their properties and functionality, for which the materials are selected rather than designed for specific biomedical applications. (III) This method is universal and is driven by the minimization of the surface free energy. It includes but is not limited to the MJANPs, and a wide range of Janus amphiphilic nanoparticles with appropriate superficial properties have the potential to be synthesized using a similar procedure. Nevertheless, this method cannot readily implement the precision of self-assembled structures such as dimers, trimers, or twist assembly structures at the current stage, which require further investigation on the precise regulation of molecule-mediated interactions between the nanoparticles across the interface in the future. In conclusion, a general and straightforward ultrasonically triggered interfacial self-assembly strategy has been successfully developed to synthesize various MJANPs with tunable properties and distinct functionality. The assembly process is achieved through ODA-molecule-mediated interparticle interaction at the interface, in which ultrasonication activated the interfacial amide bonding and the pattern of the nanoparticles by hydrophobic interaction. This methodology has proven to be applicable to a wide variety of functional inorganic nanoparticles, such as versatile GO, plasmonic nanoparticle, fluorescent QDs, etc., thereby greatly enriching the array of MJANPs available for various applications. The results from in 4123
DOI: 10.1021/acs.nanolett.9b01524 Nano Lett. 2019, 19, 4118−4125
Letter
Nano Letters
F.; Corot, C.; Coussens, L. M. Clin. Cancer Res. 2011, 17 (17), 5695− 5704. (6) Neuwelt, E. A.; Várallyay, C. G.; Manninger, S.; Solymosi, D.; Haluska, M.; Hunt, M. A.; Nesbit, G.; Stevens, A.; Jerosch-Herold, M.; Jacobs, P. M. Neurosurgery 2007, 60 (4), 601. (7) Song, J. B.; Wu, B. H.; Zhou, Z. J.; Zhu, G. Z.; Liu, Y. J.; Yang, Z.; Lin, L. S.; Yu, G. C.; Zhang, F. W.; Zhang, G. F.; Duan, H. W.; Stucky, G. D.; Chen, X. Y. Angew. Chem., Int. Ed. 2017, 56 (28), 8110−8114. (8) Xu, X.; Rosi, N. L.; Wang, Y.; Huo, F.; Mirkin, C. A. J. Am. Chem. Soc. 2006, 128 (29), 9286−9287. (9) Yabu, H.; Ohshima, H.; Saito, Y. ACS Appl. Mater. Interfaces 2014, 6 (20), 18122−18128. (10) Gu, H. W.; Yang, Z. M.; Gao, J. H.; Chang, C. K.; Xu, B. J. Am. Chem. Soc. 2005, 127 (1), 34−35. (11) Mou, F.; Xu, L.; Ma, H.; Guan, J.; Chen, D. R.; Wang, S. Nanoscale 2012, 4 (15), 4650−4657. (12) Ning, Y.; Wang, C.; Ngai, T.; Yang, Y.; Tong, Z. RSC Adv. 2012, 2 (13), 5510. (13) Reguera, J.; Jimenez de Aberasturi, D.; Henriksen-Lacey, M.; Langer, J.; Espinosa, A.; Szczupak, B.; Wilhelm, C.; Liz-Marzan, L. M. Nanoscale 2017, 9 (27), 9467−9480. (14) Ren, B.; Ruditskiy, A.; Song, J. H.; Kretzschmar, I. Langmuir 2012, 28 (2), 1149−1156. (15) Teo, B. M.; Suh, S. K.; Hatton, T. A.; Ashokkumar, M.; Grieser, F. Langmuir 2011, 27 (1), 30−33. (16) Zhang, L.; Zhang, F.; Dong, W. F.; Song, J. F.; Huo, Q. S.; Sun, H. B. Chem. Commun. 2011, 47 (4), 1225−1227. (17) Yang, Y.; Fang, Z.; Chen, X.; Zhang, W.; Xie, Y.; Chen, Y.; Liu, Z.; Yuan, W. Front. Pharmacol. 2017, 8, 287. (18) Tu, F.; Lee, D. J. Am. Chem. Soc. 2014, 136 (28), 9999−10006. (19) Liang, S.; Li, C.; Dai, L.; Qi, T.; Cai, X.; Zhen, B.; Xie, X.; Wang, L. Appl. Clay Sci. 2018, 161, 282−289. (20) Ge, L.; Cheng, J.; Wei, D.; Sun, Y.; Guo, R. Langmuir 2018, 34, 7386−7395. (21) Binks, B. P. Phys. Chem. Chem. Phys. 2007, 9 (48), 6298−6299. (22) Saha, A.; John, V. T.; Bose, A. ACS Appl. Mater. Interfaces 2015, 7 (38), 21010−21014. (23) Sacanna, S.; Kegel, W. K.; Philipse, A. P. Phys. Rev. Lett. 2007, 98 (15), 158301. (24) Glotzer, S. C. Science 2004, 306 (5695), 419−420. (25) Groh, V.; Steinle, A.; Bauer, S.; Spies, T. Science 1998, 279 (5357), 1737−1740. (26) Kisielow, P.; Teh, H. S.; Blüthmann, H.; Boehmer, H. V. Nature 1988, 335 (6192), 730−733. (27) Suzuki, D.; Tsuji, S.; Kawaguchi, H. J. Am. Chem. Soc. 2007, 129 (26), 8088. (28) Hong, L.; Jiang, S.; Granick, S. Langmuir 2006, 22 (23), 9495− 9499. (29) Li, X. Q.; Stepanenko, V.; Chen, Z.; Prins, P.; Siebbeles, L. D.; Würthner, F. Chem. Commun. 2006, 42 (37), 3871−3873. (30) Pardhy, N. P.; Budhlall, B. M. Langmuir 2010, 26 (16), 13130− 13141. (31) Qiang, W.; Wang, Y.; He, P.; Xu, H.; Gu, H.; Shi, D. Langmuir 2008, 24 (3), 606−608. (32) Jiang, S.; Schultz, M. J.; Chen, Q.; Moore, J. S.; Granick, S. Langmuir 2008, 24 (18), 10073−10077. (33) Jiang, S.; et al. Adv. Mater. 2010, 22 (10), 1060−1071. (34) Chevalier, Y.; Bolzinger, M. A. Colloids Surf., A 2013, 439 (2), 23−34. (35) Lindley, J.; Mason, T. Chem. Soc. Rev. 1987, 16, 275−311. (36) Srivastava, R. M.; Neves Filho, R. A. W.; da Silva, C. A.; Bortoluzzi, A. J. Ultrason. Sonochem. 2009, 16 (6), 737−742. (37) Frey, B. L.; Corn, R. M. Anal. Chem. 1996, 68 (18), 3187− 3193. (38) Bandekar, J. Biochim. Biophys. Acta, Protein Struct. Mol. Enzymol. 1992, 1120 (2), 123−143. (39) Ludwig, R.; Reis, O.; Winter, R.; Weinhold, F.; Farrar, T. C. J. Phys. Chem. B 1998, 102 (46), 9312−9318.
vivo studies of tumor-bearing mice have demonstrated the superior ability of the obtained MJANPs with enhanced properties for multimodality imaging and cancer therapy. Further exploration of a similar assembly process may extend current work to provide more Janus amphiphilic nanoparticles with improved fine structure and unusual properties. Ultimately, a range of new Janus amphiphilic nanoparticlesbased diagnostic and therapeutic nanoprobes can be constructed on demand through interfacial self-assembly.
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.nanolett.9b01524. Preparation and characterization of magnetic Janus amphiphilic nanoparticles, including TEM images, photographs of samples, Super-resolution structured illumination microscope images, table of FTIR absorption bands, FTIR spectrum; modeling analysis, including diagrams of the equilibrium-state geometries, images of the measured contact angles of chloroform droplets, desorption energy vs contact angle and coverage angle, table of calculation data; generality of strategy, including hysteresis loops, TEM images, hydrodynamic size and ζpotential, cumulative drug release, body weight of mice after treatment, histological evaluations of organs, T2 relaxation rate vs [Fe], CT signal intensities vs [Au], fluorescence spectrum, and MRI images of tumorbearing mice (PDF)
■
AUTHOR INFORMATION
Corresponding Author
*Tel: +86 29 81535040. Fax: +86 29 81535040. E-mail address:
[email protected]. ORCID
Guangyin Jing: 0000-0001-7636-3957 Yuan He: 0000-0002-1712-0776 Fan Zhang: 0000-0001-7886-6144 Haiming Fan: 0000-0002-0091-772X Author Contributions #
These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was financially supported by the National Natural Science Foundation of China (Grant No. 81771981 and 81571809).
■
REFERENCES
(1) Hu, J.; Zhou, S.; Sun, Y.; Fang, X.; Wu, L. Chem. Soc. Rev. 2012, 41 (11), 4356−4378. (2) Choi, S. H.; Na, H. B.; Park, Y. I.; An, K.; Kwon, S. G.; Jang, Y.; Park, M.; Moon, J.; Son, J. S.; Song, I. C.; Moon, W. K.; Hyeon, T. J. Am. Chem. Soc. 2008, 130 (46), 15573−15580. (3) Lattuada, M.; Hatton, T. A. J. Am. Chem. Soc. 2007, 129 (42), 12878. (4) Corot, C.; Robert, P.; Idée, J.-M.; Port, M. Adv. Drug Delivery Rev. 2006, 58 (14), 1471−1504. (5) Daldrup-Link, H. E.; Golovko, D.; Ruffell, B.; DeNardo, D. G.; Castaneda, R.; Ansari, C.; Rao, J.; Tikhomirov, G. A.; Wendland, M. 4124
DOI: 10.1021/acs.nanolett.9b01524 Nano Lett. 2019, 19, 4118−4125
Letter
Nano Letters (40) Wu, N.; Fu, L.; Su, M.; Aslam, M.; Wong, K. C.; Dravid, V. P. Nano Lett. 2004, 4 (2), 383−386. (41) Kong, J.; Yu, S. Acta Biochim. Biophys. Sin. 2007, 39 (8), 549− 559. (42) Nara, M.; Yonezawa, N.; Shimada, T.; Takahashi, K.; Tanokura, M.; Yumoto, F.; Nakagawa, H.; Ohashi, K.; Hamano, S.; Nakano, M. Exp. Biol. Med. 2006, 231 (2), 166−171. (43) Rumyantsev, M.; Kazantsev, O. A.; Kamorina, S. I.; Kamorin, D. M.; Sivokhin, A. P. J. Mol. Struct. 2016, 1121, 86−92. (44) Binks, B. P.; Fletcher, P. D. I. Langmuir 2001, 17 (16), 4708− 4710. (45) Isa, L.; Lucas, F.; Wepf, R.; Reimhult, E. Nat. Commun. 2011, 2, 438. (46) Lemon, C. M.; Curtin, P. N.; Somers, R. C.; Greytak, A. B.; Lanning, R. M.; Jain, R. K.; Bawendi, M. G.; Nocera, D. G. Inorg. Chem. 2014, 53 (4), 1900−1915. (47) Fan, H. M.; Olivo, M.; Shuter, B.; Yi, J. B.; Bhuvaneswari, R.; Tan, H. R.; Xing, G. C.; Ng, C. T.; Liu, L.; Lucky, S. S. J. Am. Chem. Soc. 2010, 132 (42), 14803−14811. (48) Zanganeh, S.; Hutter, G.; Spitler, R.; Lenkov, O.; Mahmoudi, M.; Shaw, A.; Pajarinen, J. S.; Nejadnik, H.; Goodman, S.; Moseley, M. Nat. Nanotechnol. 2016, 11 (11), 986−994. (49) Kim, D.; Park, S.; Lee, J. H.; Yong, Y. J.; Jon, S. J. Am. Chem. Soc. 2007, 129 (24), 7661−7665. (50) Popovtzer, R.; Agrawal, A.; Kotov, N. A.; Popovtzer, A.; Balter, J.; Carey, T. E.; Kopelman, R. Nano Lett. 2008, 8 (12), 4593.
4125
DOI: 10.1021/acs.nanolett.9b01524 Nano Lett. 2019, 19, 4118−4125
