Article pubs.acs.org/cm
Multifunctional Vehicle of Amphiphilic Calix[4]arene Mediated by Liposome Yi-Xuan Wang, Ying-Ming Zhang, Yan-Lin Wang, and Yu Liu* Department of Chemistry, State Key Laboratory of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, People’s Republic of China S Supporting Information *
ABSTRACT: The fabrication of highly efficient nanovehicles represents one of the significant topics in biomedical and pharmaceutical fields. In this work, a perfect combination has been achieved between naturally occurring liposome and artificially macrocyclic receptor. Possessing long alkyl chains at lower rims, the amphiphilic p-sulfonatocalix[4]arenes (SC4As) can be readily embedded in the liposomal bilayers of zwitterionic phosphoglyceride, making the mixed liposomes a particularly appealing candidate for live cell imaging and targeted delivery. The obtained multifunctional vesicles possess several requisite characteristics for drug delivery purpose: (a) the negatively charged outer shell originating from SC4A that can lead to long-term colloidal stabilization in aqueous solution; (b) facile, nondestructive, noncovalent, and modular surface modification using specific host−guest interaction; (c) fluorescent imaging properties through the noncovalent linkage of fluorophores onto the lipid surface; and (d) surface decoration with biologically active ligands capable of specific targeting. Therefore, we believe that the unique structure and activity of self-assembled binary liposomes can be utilized to design smart multifunctional materials for wider application.
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detoxification, and stimulus-responsive drug releasing.18−24 In particular, when modified by hydrophilic groups at one rim and hydrophobic groups at the other rim, the cooperativity of amphiphilicity and its intrinsically cone-shaped cavity is beneficial to stabilize and regulate the relative orientations and aggregation of calixarene-based amphiphiles.25−29 Therefore, combining the structural features of natural liposomes with amphiphilic calixarenes, the strategy of calixarene-coassembled vesicles is proposed to reduce the electrostatic repulsion between amphiphilic calixarenes, thus leading to ample nanostructures and broad applications. For example, some modified calixarenes with different conformations were reported to embed into the bilayer membranes and regulate the transport of ions through barriers.30−32 In addition, calixarenes are regarded as a desired multivalent scaffold, where functional groups are anchored at the rims of macrocyclic calixarenes and present enhanced bioactivities, such as lectin recognition, antimicrobial activity, and targeting property.33−35 Schrader et al. constructed a chromatic vesicle by the incorporation of amphiphilic phosphonate and ammonium calixarene modules with phospholipids and polydiacetylene, which could be used to specifically recognize proteins through electrostatic interactions.36 Ungaro et al. reported that when co-assembled with phospholipid, the DNA condensation properties of amphiphilic
INTRODUCTION Multifunctional vesicles and liposomes, constructed from a wide variety of amphiphiles, have provoked an upsurge of interest, mainly due to their similarity to cell membranes and remarkable ability to accommodate substrates in the internal aqueous compartment and hydrophobic membrane volume.1−4 For the diagnostic and therapeutic purpose, various functional tags, including imaging probes, targeting ligands, and treating modules, have been covalently and noncovalently conjugated to bilayer membranes for the construction of highly efficient drug delivery systems.5−7 Gratifyingly, it should be noteworthy that some liposomal formulations of conventional chemotherapeutic drugs have received approval for clinical use, e.g., Doxil and Caelyx,8 the brand names of liposomal doxorubicin nanodrug for the treatment of cancer. With the development of artificially self-assembled vesicles, researchers are becoming increasingly conscious of the importance of the surface functionalization, by which those supramolecular entities can be endowed with desirable modularity, reversibility, and stimuli-responsiveness.9,10 Among numerous different approaches that are commonly employed in the surface modification of vesicles, supramolecular methodology has emerged as a more advantageous alternative to fabricate multifunctional vesicles via noncovalent interactions.11−17 Meanwhile, with the advances in macrocyclebased superamphiphiles, calixarene, a representative class of synthetic receptors, has been proven as an appealing candidate in fluorescence sensing, enzymatic tandem assays, pesticide © XXXX American Chemical Society
Received: December 17, 2014 Revised: April 7, 2015
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Figure 1. Optical transmittance changes of lipid vesicle solution upon addition of (a) SC4AH from 0 to 40 mol % and (b) SC4AB from 0 to 20 mol % in water at 25 °C. Inset: Dependence of the optical transmittance at 450 nm on the amphiphilic calixarene concentration at 25 °C. The lipid concentration of DPPC was fixed at 0.5 mM.
Figure 2. Average diameters of lipid vesicle upon addition of (a) SC4AH from 0 to 40 mol % and (b) SC4AB from 0 to 20 mol % in water at 25 °C. The lipid concentration of DPPC was fixed at 0.5 mM.
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RESULTS AND DISCUSSION Amphiphilic p-sulfonatocalixarenes, concurrently appended with the hydrophilic sulfonate groups at the upper rim and the hydrophobic alkyl chains at the lower rim, were defined as “surfactants with a host−guest recognition site” applicable to the fabrication of highly ordered nanoarchitectures.38 In our case, two kinds of SC4A derivatives possessing different alkyl chains in length, named SC4A tetrabutyl ether (SC4AB) and tetrahexyl ether (SC4AH), were employed to construct the robust binary supramolecular lipids with 1,2-dihexadecanoyl-snglycero-3-phosphocholine (DPPC). Benefiting from their amphiphilic nature, it can be found that the mixture of DPPC with SC4AH and SC4AB could form lipid bilayer membranes, and the SC4A cavities are still available as the potential host−guest binding sites for the further surface modification. The critical micelle concentrations (CMCs) of these two SC4As were measured by fluorescence spectra using nile red as a hydrophobic probe. As shown in Figure S1 (Supporting Information), the fluorescence of nile red increased in the presence of SC4A, indicating that SC4As possess a micelle-like aggregation, in which the hydrophobic domains formed by alkyl chains could serve as a binding site for hydrophobic probes. The CMCs are obtained as 0.53 mM for SC4AH and 1.10 mM for SC4AB, respectively, which are in the same order of magnitude as described in the literature.39,40 Considering that the interaction of surfactants with liposomes can dissolve the phospholipid components and then destroy the liposome structures,41,42 it is a prerequisite to evaluate the optimal surfactant-to-liposome molar ratio, at which the lipid bilayer should be saturated by surfactant molecules without any
guanidinium calixarene and the corresponding transfection efficiency ability would be increased to a great extent.37 Nevertheless, calixarenes acted only as functional scaffolds in these previous works, and the cavities were not fully exploited. Inspired by these fascinating results, in this work, we have successfully fabricate a nanoplatform by using amphiphilic psulfonatocalix[4]arenes (SC4A) embedded in the bilayer of liposomes, with the aim to explore the potential ability as a multifunctional drug delivery vehicle. Benefiting from high water solubility, excellent biocompatibility, and abundant binding sites toward organic cations of SC4As, our obtained binary lipids possess a negative charged outer shell originating from sulfonate sites at upper rim, which could significantly enhance the colloidal stabilization of liposomes. Moreover, such a phospholipid−calixarene vehicle could be easily functionalized through specific host−guest interaction without any negative effect on the intrinsic vesicular structures and properties. After being decorated with fluorescence imaging probe and targeting ligand, it is found that the multifunctional vesicles can serve as an efficient diagnostic and therapeutic tool. As investigated by the confocal laser scanning microscopic experiments, the mixed lipids can be transferred into targeted cancer cells through receptor-mediated internalization, thus showing the great potential application in targeted drug delivery. To the best of our knowledge, the calixarene− liposome approach has not been exploited in construction of multifunctional drug delivery vehicle so far. B
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Figure 3. TEM images of (a, b) DPPC−SC4AH liposomes and (c, d) DPPC−SC4AB liposomes. (e) Geometry structure of the DPPC−SC4AH lipid membrane optimized by the molecular mechanics method with a Dreiding force field.
on the basis of all of the morphological information discussed previously, we can deduce the intermolecular assembly behaviors in phospholipid−SC4A systems, as illustrated in Scheme 1.
undesirable morphological disruption. Taking the DPPC− SC4AH system as an example, the optical transmittance beyond 450 nm, where neither DPPC nor SC4A shows appreciable absorption, first remained constant at a lower concentration of SC4AH and then sharply increased in the presence of an excess amount of SC4AH, indicating the transformation from the bilayer lipid vesicles to the phospholipid−surfactant mixed micelles (Figure 1a).43 Similarly, an obvious inflection point was also observed in the DPPC−SC4AB system (Figure 1b). Therefore, according to the plot of transmittance at 450 nm as a function of the concentration of SC4A, the optimal surfactant-to-liposome molar ratios for SC4AH and SC4AB were obtained as 5 and 10 mol %, respectively (Figure 1, inset). Dynamic light scattering (DLS) and high-resolution transmission electron microscopy (TEM) experiments were further performed to identify the assembly size and morphology of the resultant mixed lipid. As shown in Figure 2, when an appropriate amount of SC4As was embedded in the DPPC liposome, the resultant mixed lipids gave an average hydrodynamic diameter (Dh) of about 100 nm at a scattering angle of 90°. Comparatively, after increasing the content of SC4As, the corresponding Dh values pronouncedly deceased to 20 and 60 nm, respectively, accompanied by the disappearance of turbidity of phospholipid−SC4A solutions (Figure S2 in the Supporting Information). These phenomena jointly demonstrate that the large-sized particles were converted to small-sized ones as soon as the supramolecular lipid was disrupted from vesicles to micelles upon further addition of SC4A. Moreover, it is found that the optimal surfactant-to-liposome molar ratios obtained from DLS measurements are well consistent with the optical transmittance results, and thus, the SC4A contents of 5 and 10 mol % were employed to construct the robust amphiphilic DPPC−SC4AH and DPPC−SC4AB assemblies, respectively, in the subsequent measurements. Along with the DLS investigation results in solution, the spherical morphology with a diameter ranging from 50 to 100 nm was also found in the TEM images, and these diameters exceed far beyond the extended molecular length (5.9 nm), here again suggesting that the spherical aggregates are originated from the vesicular entities rather than simple micelles (Figure 3). In addition, by comparing the contrast of the dark periphery with the light central area, the thickness of the obtained bilayer membrane could be readily distinguished and measured as 5.1 nm, which is comparable to the length of the phospholipid−SC4A amphiphiles (Figure 3e). Therefore,
Scheme 1. Schematic Illustration of Multifunctional Liposome and the Noncovalent Surface Modification via Host−Guest Interaction
After constructing these bilayer vesicles, we proceeded to investigate the host−guest interaction on the surface of mixed vesicles. Benefiting from the exceptional binding affinity of amphiphilic SC4A with organic cations,44 the surface of phospholipid−SC4A supramolecular vesicles can be conveniently decorated with various functional groups via a nondestructive and noncovalent approach. In our case, some typical pyridinium derivatives with different linkers and terminal groups were chosen to comprehensively study the significance of cooperative noncovalent interactions in the surface modification of these binary lipids. The selected guest molecules, including the singly charged pyridinium and doubly charged bispyridinium salts, are shown in Scheme 1. Since pyridinium derivatives can form stable 1:1 inclusion complexes with amphiphilic SC4As, it is believed that the introduction of positively charged guests could dramatically affect the surface charge of mixed vesicles and, particularly, methyl viologen dimer (bis-MV) would lead to the agglutination of the vesicles. C
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Figure 4. (a) ζ potential of DPPC, DPPC + MV ([MV] = 0.05 mM), DPPC−SC4AH, DPPC−SC4AH + MV ([MV] = 0.05 mM), DPPC−SC4AH + BtPy ([BtPy] = 0.05 mM), and DPPC−SC4AH + BtPy + FITCPy ([BtPy] = 0.015 mM, [FITCPy] = 0.01 mM). The lipid concentration of DPPC was fixed at 0.5 mM. (b) Optical transmittance of DPPC−SC4AH ([DPPC] = 0.5 mM) with and without bis-MV (0.0125 mM). (c) Optical transmittance of DPPC−SC4AB ([DPPC] = 0.5 mM) with and without bis-MV (0.0125 mM). (d) Dependence of the percent of released FITCPy in dialysis media on dialysis time after incubation with DPPC, DPPC−SC4AH, and DPPC−SC4AB, respectively ([FITCPy] = 0.05 mM, [DPPC] = 2.5 mM). Size distribution of (e) DPPC−SC4AH and (f) DPPC−SC4AB with and without BtPy and FITCPy determined by DLS ([DPPC] = 0.5 mM, [FITCPy] = 0.01 mM, and [BtPy] = 0.015 mM).
As expected, ζ potential results showed that the surface charge was slightly changed upon addition of methyl viologen (MV) into pure lipid, probably due to the interaction between cationic moieties of MV and the phosphate groups of DPPC molecules at a water−membrane interface (Figure 4a).29,45 Comparatively, ζ potentials for DPPC−SC4AH and DPPC− SC4AB liposomes showed negative values of −40.8 and −20.4 mV, respectively, clearly corroborating that amphiphilic SC4As can successfully distribute in the outer leaflets of lipid vesicles. The obtained negatively charged particles are favorable for drug delivery, because it is believed that they can exhibit enhanced stability in further application.46 Accordingly, long-term stability was assessed in water. It was found that both DPPC−SC4AH and DPPC−SC4AB liposomes showed only a negligible deviation in size at room temperature for 6 months, whereas the pure lipid solution became turbid and then seriously precipitated in only 7 days even at 0 °C (Table S1 in the Supporting Information). This large difference in long-term stability is mainly attributed to the existence of negatively charged SC4As embedded into the surface of mixed liposomes, by which the strong electrostatic repulsions occurred between neighboring bilayers and then avoided the undesirable aggregation to a great extent. Furthermore, it can be seen that ζ potentials of the resultant lipids pronouncedly increased in the presence of MV, suggesting that MV was successfully introduced onto the surface of supramolecular vesicles via host−guest interaction (Figure 4a and Figure S3 in the Supporting Information). Subsequently, the agglutination behaviors of mixed lipids were monitored by optical transmittance measurements. As discerned from Figure 4b,c, a significant decrease of optical transmittance was found, indicating that the mixed vesicles can be further cross-linked upon addition of bis-MV. Comparatively, there was no agglutination of pure lipid vesicles, excluding the possibility that the aggregation is a result of weak interaction between pyridinium moiety and DPPC (Figure S4 in the Supporting Information). These phenomena
jointly demonstrate that the specific host−guest interaction between bis-MV and SC4A cavity on the liposome surface is the decisive factor to induce agglutination. Next, we used FITC-conjugated pyridinium (FITCPy) as a fluorescent probe and biotinylated pyridinium (BtPy) as a targeting ligand47 to further modify the surface of mixed liposomes, with the goal to ensure the feasibility in construction of liposome-based multifunctional delivery systems (Scheme 1). Considering that the high toxicity of bispyridinium salts may involve considerable risk to human health,48 a singly charged pyridinium group was selected as the binding site to interact with SC4AH. 1H NMR measurements were preliminarily performed to explore the binding geometries the complex structure. The proton signals of pyridinium exhibited visible upfield shifts and became broadened originating from the ring current effect of the aromatic nuclei of calixarene, while the NMR signals of functional tags were almost unchanged (Figure S5 in the Supporting Information).49 Meanwhile, there was no fluorescence quenching of FITCPy upon complexation with amphiphilic SC4As (Figure S6a in the Supporting Information). These results reveal that the pyridinium moietiy could be encapsulated in the cavity of calix[4]arene, whereas the tags stayed outside and retained its original functions. When FITCPy was incubated with pure DPPC and SC4Adecorated mixed lipids, respectively, the dependence of the fluorescence on time was monitored in dialysis media at 515 nm, showing that the fluorescence intensity reached a plateau in about 4 h (Figure 4d). Moreover, compared to free liposome DPPC, most of FITCPy molecules could be bound on the surface of mixed lipids via host−guest interaction, and there were less free dye molecules that could leak from the dialysis bag, thus leading to a slight increase in the fluorescence intensity in dialysis media. When the giant mixed vesicles were incubated with FITCPy, bright green fluorescent spheres were observed by confocal laser scanning microscopy (CLSM), further indicative of the successful surface modification (Figure S7 in the Supporting Information). Moreover, the ζ potentials D
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Figure 5. Confocal laser scanning microscopy images of MCF7 cells incubated with (a) biotin-functionalized DPPC−SC4AB liposome, (b) nonfunctionalized DPPC−SC4AB liposome, (c) biotin-functionalized DPPC−SC4AB liposome with excess of biotin, (d) biotin-functionalized DPPC−SC4AH liposome, (e) nonfunctionalized DPPC−SC4AH liposome, and (f) biotin-functionalized DPPC−SC4AH liposome with excess of biotin for 6 h at 37 °C: [liposome] = 0.5 mM, [FITCPy] = 0.01 mM, and [BtPy] = 0.015 mM. The scale bar is 60 μm.
liposomes, the cell fluorescence intensity seriously decreased, further proving that the biotinylated mixed liposomes were internalized into the cancer cells via receptor-mediated endocytosis (Figure 5). Additionally, the fluorescent imaging properties of SC4A-mediated liposomes in PBS (10 mM, pH 7.2) were examined in vitro. After incubation with FITCPy, giant mixed liposomes in PBS were observed as bright green fluorescent spheres by CLSM, indicative of the successful surface modification (Figure S12 in the Supporting Information). SC4A-mediated nanoliposomes possessing Dh of about 100 nm in PBS can efficiently be internalized into the targeted cancer cells with good fluorescence imaging capacity, also indicating that the functional tags were successfully decorated on the surface of liposomes through noncovalent interaction (Table S3 and Figure S13 in the Supporting Information). Comparing with the assembly size and the imaging property in water and PBS, we can deduce that the solution pH and ionic salt concentration in aqueous medium would not pronouncedly affect the SC4A-mediated liposome.
for mixed liposomes also showed remarkable increase after incubation with pyridinium guest instead of MV, indicating that these pyridinium guests could be introduced to the surface of mixed liposomes by a noncovalent method (Figure 4a and Figure S3 in the Supporting Information). After loading fluorescent probe and targeting ligand, it was also confirmed that no apparent change in the morphology or size was observed in DLS and high-resolution TEM experiments, indicating that the noncovalent surface modification by using host−guest interaction is a facile and nondestructive approach to maintain the original structure and physicochemical property of mixed lipids (Figure 4e,f and Figure S8 and Table S1 in the Supporting Information). To explore the potential application of mixed lipids as multifunctional drug delivery carriers, we investigated the tumor targeting ability of the FITC- and biotin-decorated DPPC−SC4AH and DPPC−SC4AB liposomes. The complex stability constant (KS) between SC4AB and BtPy was determined as 7.37 × 104 M−1 by the method of isothermal titration calorimetry, which was comparable to the one between amphiphilic SC4As and classic pyridinium derivatives (Figure S9 and Table S2 in the Supporting Information).44 In our case, these functionalized vesicles were added to targeted cancer cells, which were then collected for observation of FITC fluorescence by CLSM after incubation with functionalized liposome for 6 h at 37 °C. Gratifyingly, in contrast to free FITCPy and the nonfunctionalized mixed liposomes, the biotinylated ones displayed a much better targeting activity toward MCF7 cancer cells, a type of human breast adenocarcinoma cells with overexpression of biotin receptors on their surfaces (Figure 5 and Figure S10 in the Supporting Information).47 A control experiment was performed with 1methylpyridinium (Py) instead of BtPy, and the fluorescence was much weaker than that of biotinylated mixed liposomes (Figure S10 in the Supporting Information), which excludes a ζ-potential effect on the cell uptake. Importantly, as can be seen in Figure S11 (Supporting Information), neither SC4AH nor SC4AB exhibited overt cytotoxicity at the same concentrations. When MCF7 cells were first incubated with an excess amount of free biotin molecules to saturate the corresponding receptors on the cancer cell surface before addition of biotinylated
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CONCLUSION
In conclusion, we have designed and fabricated multifunctional liposomes consisting of phospholipids and two kinds of amphiphilic SC4As as operational targeted drug delivery carriers. Due to the electrostatic repulsion from the negatively charged SC4As located on the outer shell of liposomes, the mixed vesicle displayed a better long-term stability in aqueous media compared to original liposome. Furthermore, benefiting from the dynamic equilibrium characteristics of noncovalent interactions, the obtained multicomponent vesicles can be successfully functionalized with imaging probe and targeting ligand in a nondestructive, facile, and modular manner. More significantly, the functionalized vesicles could be efficiently internalized into targeted cancer cells, which may hold great promise for substantial therapeutic and diagnostic applications. We also envision that this strategy based on supramolecular methodology can be readily optimized by altering its functional tags responding to an external request and will be utilized to create new multifunctional materials in miscellaneous fields. E
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ASSOCIATED CONTENT
S Supporting Information *
Experimental procedures, CMCs of SC4As, additional DLS data, CLSM images, optical transmittance and UV/vis curves, binding behaviors of SC4As with guests, cytotoxicity of SC4As, and imaging properties of SC4A-mediated liposomes in PBS. This material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the “973” Program (Grant No. 2011CB932502) and NNSFC (Grant Nos. 91227107, 21432004, and 21472100) for financial support.
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ABBREVIATIONS USED SC4A = p-sulfonatocalix[4]arene SC4AB = amphiphilic p-sulfonatocalix[4]arenes bearing tetrabutyl chains SC4AH = amphiphilic p-sulfonatocalix[4]arenes bearing tetrahexyl chains CMC = critical micelle concentration DPPC = 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine BtPy = biotinylated pyridinium FITCPy = fluorescein-conjugated pyridinium MV = methyl viologen Py = 1-methylpyridinium
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