Synthesis of Janus Nanocomposites for Drug Delivery System

Synthesis of Janus Nanocomposites for Drug Delivery System Over the past few decades, drug delivery systems have been well developed and studied to improve the curative effect of drugs.[1–4] Drug delivery systems can ameliorate the problems of conventional administration by prolonging duration time, enhancing drug solubility, retaining drug bioactivity, reducing side effect, and so on.[5, 6] A variety of carriers such as lipids,7, 8 polymer gels,[9,10] especially nanoparticles,11, 12 have been studied in drug delivery systems. At present, stimuli sensitive drug delivery systems have been an attractive theme for controlled release. The release behaviors of drugs can be easily controlled by surrounding properties, such as temperature,13, 14 pH,15,16 electric field,[17 ionic strength,[18 and so on. Recently, combined therapy with dual-drugs of different therapeutic effects shows excellent performance in treatment of diseases.19, 20 In order to optimize therapeutic effects, the doses and species of drugs should be optimized at different c linical manifestations and periods in the treatment. One of the main challenges of combined therapy is to control the release behavior of each drug independently. However, simple drug delivery systems cannot fulfill the needs of such therapy, because the most widely used carriers are normally possess single symmetrical geometry with single-surface. Even the dual-drugs are loaded on the single-surface carrier at same time, the delivery systems are designed only for the simultaneous release of two different drugs, and the release of each drug cannot be controlled. Furthermore, the multi-conjugates or loadings can interact with each other leading to undesired adverse effects. Therefore, developing independent multi-surface nanostructures for combination or loading of multiple drugs is critically desired. Janus nanoparticles possess multiple surface structures are anisotropic in composition, shape, and surface chemistry.[21] The structural asymmetry is ideally suited for dual-drug conju gations or loadings on different sections of a single Janus particle.[22] Furthermore, functionally distinct surfaces of the Janus particle can be used to selectively conjugate with specific chemical moieties for controlling the dual-drug loading or releasing, respectively.[23-25] During the past decades, considerable efforts have been made on the fabrication of Janus particles.[26-30] For instance, a monolayer of spherical particles such as those of polystyrene (PS) or silica colloidal nanospheres are spread on a solid substrate.[31-33] Thus, the functionalization could take place only on the top surfaces of the anchored particles. Because the low yield of the Janus particles result from the limited surface area of the bulk substrates, a modified method was later developed by using colloidal particles as the supporting substrates.[34-38] Another method for fabricating Janus particles was carried out at interfaces: a particle partially contacted with reactive medium and generated different surface functionalities from the opposite surface.36 With the development of microfluidic technique, Janus particles could also be fabricated by solidifying droplets composed of immiscible components.[39, 40] Other methods such as controlled surface nucleation, phase separat ion, and controllable polymer attachment,[41-54] have been also developed to synthesize the Janus particles. But the Janus particles reported previously were often close to micrometer in size and typically involved various types of polymers, which could induced poor biocompatibility, the fabrication of small Janus nanoparticles with inorganic materials is still a greater challenge.[48-54] On the other hand, the widely used silica is an useful material for building concentric [emailprotected] structures by using metallic or magnetic nanoparticles or quantum dots as cores,[55-57] but there have been few reports about silica based Janus nanoparticles. Due to the amorphous nature of silica, it is difficult to fine-tune the surface tension or lattice mismatch between silica and these core materials to form the Janus nanostructure. Feasibility for the synthesis of Janus nanocomposites As mentioned above, it is difficult to fine-tune the surface tension or lattice mismatch between silica and these core materials to form the Janus nanostructure due to the amorphous nature of silica. But for mesoporous silica materials, it has attracted a great deal of attention because of their versatility in surface tension and pore lattice parameters.[58, 59] In order to realize the formation of silica based Janus nanoparticles, the solution-grown synthesis route for the fabrication of inorganic nanocrystals based Janus (such as Au-Fe3O4,[60] Au-CdSe,[61] CdS-FePt,[62] Ag-Fe3O4,[63] CdSe-Fe3O4,[64] and so on) provides a possible clue to the creation of the silica based Janus nanoparticles by using the mesoporous silica as a structural subunit. The inorganic nanocrystals may have polymorphic atomic structures that are epitaxially attached at the interface from a core, leading to specific inorganic nanostructures with well-defined and characteristic shapes such as dimmers or trimers .[65, 66] For the growth of the ordered mesoporous structures, it is partly analogous to the growth of inorganic nanocrystals. Rather than epitaxy from atomic structures, the mesostructures can also be oriented by surfactants micelle and further induced the epitaxy growth of the mesoporous silica. So, compared with the formation of the inorganic nanocrystals Janus nanostructures, the silica based Janus nanocomposites would also be fabricated under the direction of the epitaxially growing properties of the mesoporous silica. Project proposal Focusing on the issues faced by the synthesis of the silica-based Janus nanocomposites and corresponding applications, this proposed project concerns the development of a novel anisotropic growth induced route for the synthesis of Janus core-shell mesoporous silica nanocomposites [[emailprotected]2@mSiO2-PMO (NCs = Functional nanocrystals; mSiO2= mesoporous silica; PMO= periodic mesoporous organosilicas)] by using the mesoporous silica as a structural subunit, and the obtained Janus nanocomposites can be used for dual-control drug release (ibuprofen and doxorubicin). As shown in Scheme 1, inorganic functional nanocrystals, including upconversion nanoparticles (UCNPs), magnetic nanoparticles (Fe3O4) and quantum dots (QDs), are firstly synthesized by using solvothermal approaches at a high temperature. Then, the [emailprotected]2 [emailprotected] nanoparticles, including [emailprotected]2, Fe3O4@SiO2, [emailprotected]2, will be synthesized with the reverse micro-emulsion method. Duo to the hydrophobic surface property of the obtained NCs, this hydrophilic SiO2 layer is very necessary for the following syntheses and applications. Furthermore, SiO2 layer can also serve as protective cover for the physical properties of the inorganic functional NCs, such as the fluorescences of UCNPs and QDs. Subsequently, the radial mesoporous SiO2 will be synthesized to form [emailprotected]2@mSiO2 [emailprotected]@shell nanostructures with the Stà ¶ber method in the presence of structure-directing agent (CTAB). The radial mesoporous layer of the obtained [emailpro tected]2@mSiO2 can accommodate the guest drug molecules (doxorubicin), the channel can also be easily modified with light sensitive switch molecules (azobenzene) by using post-modification method to realize the controllable release of doxorubicin. Finally, the Janus core-shell mesoporous silica nanocomposites of [emailprotected]2@mSiO2-PMO can be fabricated through a surfactant-templating approach by using cationic surfactant CTAB as a structure-directing agent and organic silica precursor as a source. At the very beginning, mesostructured CTAC/PMO composites can be assembled and deposited on the [emailprotected]2@mSiO2 nanoparticles surfaces. Then, through an anisotropic growth, the mesostructured shells finally develop into mesoscale single-crystals coated on the spherical [emailprotected]2@mSiO2 cores and form Janus nanocomposites. The mesoporous of PMO section of Janus nanocomposites can also accommodate the guest drug molecules (ibuprofen). By introducing the heat sensitive pha se-change material (1-tetradecanol) as switch molecules, it will realize the dual-control release of the guest species. As shown in Scheme 2, the dual-control (heat and NIR light) drug release (ibuprofen and doxorubicin) can be realized as following. Drug molecule (doxorubicin) loading in the [emailprotected]2@mSiO2 domains of the Janus nanocomposites: In this procedure, the inorganic functional nanocrystals are specified as NaGdF4:Yb, Tm UCNPs, which can emit photons in both UV (~ 350 nm) and Visible (~ 470 nm) region under NIR (980 nm) excitation. The mesopores of the [emailprotected]2@mSiO2 nanoparticles are modified with azobenzene molecules by using the post-modification method firstly. Both the loading and release of doxorubicin are regulated by the trans–cis photoisomerization of the azobenzene molecules. Specifically, the trans isomer of the azobenzene molecules will transform into the cis isomer under UV light irradiation, and in contrast the cis isomer will form the trans isomer under irradiation of visible light. The installing â€Å"photomechanical† azobenzene groups in the m esopores of silica are act as â€Å"stirrer† in the mesoporous silica, which can be used to control the loading and release of the drug. So, not only the release but also the loading of doxorubicin should be processed under the UV and visible light at the same time, and the drug will be locked in the mesopores of the [emailprotected]2@mSiO2 domains in the Janus structures after the UV and visible light are removed. The doxorubicin molecules absorb on the surface and mesopores of PMO domains in the Janus can be washed off with water. Drug molecule (ibuprofen) loading in the PMO section of the Janus nanocomposites and heat control release: After ibuprofen molecules are absorbed into the mesopores of PMO, the mesopores can be blocked with a phase-change material (1-tetradecanol), which has a melting point of 38 – 39 à ¯Ã¢â‚¬Å¡Ã‚ °C. Below 1-tetradecanol’s melting point, it will be in a solid state to completely block the passing of encapsulated ibuprofen. When the temperature is raised beyond its melting point, it will quickly melt to release the encapsulated ibuprofen (heat control release). NIR light control release of doxorubicin in the [emailprotected]2@mSiO2 section of the Janus nanocomposites: Upon absorption of NIR light (980 nm), the UCNPs can emit photons in the UV/Vis region, which are absorbed immediately by the photo responsive azobenzene molecules. The reversible photoisomerization by simultaneous UV and visible light emitted by the UCNPs creates a continuous rotation–inversion movement, and the doxorubicin molecules can be released from the mesopores of [emailprotected]2@mSiO2. Novelty of the project proposal: The anisotropic growth induced route for the synthesis of silica based multi-functional Janus core-shell mesoporous silica nanocomposites is proposed for the first time. Varieties of inorganic nanocrystals, including upconversion nanoparticles (UCNPs), magnetic nanoparticles (Fe3O4), quantum dots (QDs), can be introduced to further functionalize the Janus nanocomposites. Dual-control drug relase system based on mesoporous silica is proposed for the first time. The mesopore channels of [emailprotected]2@mSiO2 domains and PMO domains in multi-functional Janus nanocomposites can accommodate two kinds of drug molecules independently at the same time. Two kinds of switch molecules are design to realize dual-control release of the drug molecules independently for the first time. Task 1: Synthesis of the inorganic functional nanocrystals (NCs), including upconversion nanoparticles (UCNPs), magnetic nanoparticles (Fe3O4), quantum dots (QDs), and so on. The synthesis of the inorganic nanocrystals will be carried out at organic solvent with high boiling point solvents such as 1-octadecylen via a solvothermal approach at a high temperature (~ 300 à ¯Ã¢â‚¬Å¡Ã‚ °C for UCNPs, ~ 270 à ¯Ã¢â‚¬Å¡Ã‚ °C for Fe3O4 NCs, ~ 240 à ¯Ã¢â‚¬Å¡Ã‚ °C for QDs) in presence of the surfactants (oleic acid, oleylamine, etc.). Some simple inorganic salts such as rare earth chloride, iron acetylacetonate, iron oleate, cadmium oleate, zinc oleate, etc. will be used as the inorganic precursors. The necessary characterization (i.e. TEM, XRD, PL, UV-Vis, VSM) will be used in the experiments. Task 2: Fabrication of the [emailprotected]2 [emailprotected] nanoparticles, including [emailprotected]2, Fe3O4@SiO2, [emailprotected]2 and so on. Duo to the hydrophobic surface property of the obtained NCs, the [emailprotected]2 [emailprotected] nanoparticles will be synthesized with the reverse micro-emulsion method. The hydrophilic SiO2 layers in this objective are very necessary for the following syntheses and applications. Furthermore, SiO2 layers can also serve as a protective cover for the physical properties of the inorganic functional NCs, such as the fluorescences of UCNPs and QDs. Typically, the obtained inorganic NCs are dispersed in cyclohexane. Then polyoxyethylene (5) nonylphenyl ether (CO-520) and NH3.H2O are introduced to form reverse micro-emulsion. Finally, TEOS is introduced and hydrolysized at room temperature to form the [emailprotected]2 [emailprotected] nanoparticles. The necessary characterization (i.e. SEM and TEM) will be used in the experiments. Task 3: Fabrication of the [emailprotected]2@mSiO2 [emailprotected]@shell nanoparticles. In this step, the radial mesoporous SiO2 will be synthesized with the Stà ¶ber method in the presence of cationic surfactant such as CTAB. TEOS is used as a silica sources and hydrolysis in ethanol/water solution under alkaline condition (NH3.H2O) at room temperature. The necessary characterization (i.e. BET, SEM, and TEM) will be used in the experiments. Task 4: Fabrication of the Janus core-shell mesoporous silica nanocomposites ([emailprotected]2@mSiO2-PMO). The orientation growth of the cubic mesostructure of mesoporous organosilica (PMO) materials is the key factor for the formation of the silica-based Janus nanocomposites. In this step, organic silica precursors, such as bis(trieth-oxysilyl)benzene (BTEB), 1,2-bis(triethoxysilyl)ethane (BTEE), bis(triethoxysilyl) ethylene (BTEEE), are used as the silica sources and hydrolysis in ethanol/water solution under alkaline condition (NH3.H2O) at room temperature in the presence of CTAB templates. By adjusting experimental parameters, the organic silica precursors can cooperative self-assembly with surfactant CTAB to form the ordered cubic mesostructured PMO crystals. Because the different mesostructures between [emailprotected]2@mSiO2 (radial) and PMOs (cubic), the PMOs will epitaxy growth to form the [emailprotected]2@mSiO2-PMO Janus structure instead of the [emailprotected]2@mSiO2@PM O [emailprotected]@[emailprotected] structure. The necessary characterization (i.e. BET, XRD, SEM, FL, VSM and TEM) will be used in the experiment. Task 5: The design and evaluation of the dual-control drug release by using the obtained Janus core-shell mesoporous silica nanocomposites. The dual-control drug release can be realized as following. Drug molecule (doxorubicin) loading in the [emailprotected]2@ mSiO2 section of the Janus nanocomposites: In this procedure, the inorganic functional nanocrystals are specified as NaGdF4:Yb, Tm, UCNPs, which can emit photons in both UV (~ 350 nm) and Visible (~ 470 nm) region under NIR (980 nm) excitation. The mesopores of the [emailprotected]2@mSiO2 nanoparticles are post-modified with azobenzene molecules by using N-(3-triethoxysilyl)propyl-4-phenylazobenzamide in ethanol at 80 à ¯Ã¢â‚¬Å¡Ã‚ °C firstly. Both the loading and release of doxorubicin are regulated by the trans–cis photoisomerization of the azobenzene molecules. So, not only the release but also the loading of doxorubicin should be processed under the UV and visible light at the same time, and the drug will be locked in the mesopores of [emailprotected]2@mSiO2 domains in the Janus after the UV and visible light are removed. The doxorubicin molecules absorb on the surface and mesopores of PMO domains in the Janus can be washed off with water. Drug molecule (ibuprofen) loading in the PMO domains in the Janus nanocomposites and heat control release: After the ibuprofen molecules are absorbed into the mesopores of PMO, the mesopores can be blocked with a phase-change material (1-tetradecanol), which has a melting point of 38 – 39 à ¯Ã¢â‚¬Å¡Ã‚ °C. Below 1-tetradecanol’s melting point, it will be in a solid state to completely block the passing of encapsulated ibuprofen. When the temperature is raised beyond its melting point, it will quickly melt to release the encapsulated ibuprofen (heat control release). NIR light control release of doxorubicin in the [emailprotected]2@mSiO2 domains in the Janus nanocomposites: Upon absorption of NIR light (980 nm), the UCNPs emit photons in the UV/ Vis region, which can be absorbed immediately by the photo responsive azobenzene molecules. The reversible photoisomerization by simultaneous UV and visible light emitted by the UCNPs creates a continuous rotation–inversion movement, and the doxorubicin molecules can be released from the mesopores of [emailprotected]2@mSiO2. The necessary characterization (i.e. UV-Vis, FTIR, SEM, and TEM) will be used in the experiments.