Phosphonated Pillar[5]arene-Valved Mesoporous Silica Drug Delivery

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Phosphonated Pillar[5]arene-Valved Mesoporous Silica Drug Deliv-ery Systems Xuan Huang, Shanshan Wu, Xiaokang Ke, Xueyuan Li, and Xuezhong Du ACS Appl. Mater. Interfaces, Just Accepted Manuscript • Publication Date (Web): 22 May 2017 Downloaded from http://pubs.acs.org on May 23, 2017

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ACS Applied Materials & Interfaces

Phosphonated Pillar[5]arene-Valved Mesoporous Silica Drug Delivery Systems Xuan Huang, Shanshan Wu, Xiaokang Ke, Xueyuan Li, and Xuezhong Du* Key Laboratory of Mesoscopic Chemistry (Ministry of Education), State Key Laboratory of Coordination Chemistry, Collaborative Innovation Center of Chemistry for Life Sciences, and School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, P. R. China ABSTRACT: To explore the diversity and promising applications of pillararene-based molecular machines, phosphonated pillar[5]arenes (PPA[5]) were synthesized to construct novel supramolecular nanovalves for the first time, based on mesoporous silica nanoparticles (MSNs) functionalized with choline and pyridinium moieties, respectively. PPA[5] encircled the choline or pyridinium stalks to construct supramolecular nanovalves for encapsulation of drugs within the MSN pores. PPA[5] showed a high binding affinity for the quaternary ammonium stalks through the host−guest interactions primarily via ion pairing between the phosphonate and quaternary ammonium moieties, in comparison to carboxylated pillar[5]arene (CPA[5]), to minimize premature drug release. The specific ion pairing between the phosphonate and quaternary ammonium moieties was elaborated for the first time to construct supramolecular nanovalves. The supramolecular nanovalves were activated by low pH, Zn2+ coordination, and competitive agents for controlled drug release, and release efficiency and antitumor efficacy were further enhanced when gold nanorod (GNR)embedded MSNs (GNR@MSNs) were used instead under illumination of near infrared (NIR) light, attributed to the synergistic effect of photothermo-chemotherapy. The constructed PPA[5]-valved GNR@MSN delivery system has promising applications in tumor photothermo-chemotherapy. KEYWORDS: drug delivery system, host−guest interaction, ion pairing, mesoporous silica nanoparticle, photothermal effect, phosphonated pillararene, supramolecular nanovalve

INTRODUCTION Stimuli-responsive nanoparticle delivery systems are very promising in precise tumor therapy for the enhancement of therapeutic efficacy and the minimization of side effects of drugs.1 Mesoporous silica nanoparticles (MSNs) have been proved to be excellent drug carriers for stimuli-responsive controlled release of encapsulated drugs,2−15 in contrast to polymeric micelles and liposomes for sustained release of drugs. Mechanized MSNs conjugated with supramolecular nanovalves, based on the macrocyclic host−guest chemistry, are endowed with the controlled release of drugs from the MSN pores under endogenous and exogenous stimuli.16 Supramolecular nanovalves are rotaxane/pseudorotaxane-based molecular machines constructed from macrocyclic hosts encircling and removing from stalk-like molecules functionalized on the MSN surfaces to modulate the access of drugs to and from the MSN pores. Many efforts have been devoted to the constructions of MSN-based supramolecular nanovalves, including cyclodextrins,17−19 calixarenes,20 and cucurbiturils,21−28 in response to pH,18,21−23,26,27 redox,18 competitors,23,24 lights,25,28 and enzymes.17,19,20,24 Pillararenes are new cylinder-shaped macrocyclic hosts composed of 1,4-dialkoxyphenyl rings linked by methylene bridges at the para positions and are readily modified with a diverse of functional groups,29−31 in contrast to calixarenes with basket-shaped structures linked by methylene bridges at the meta positions. Recently, water-soluble carboxylated pillar[n]arenes (CPA[n]) have been used to construct CPA[5]32−38

and CPA[6]39 supramolecular nanovalves for controlled drug release in response to pH, divalent metal ions, and competitive molecules. Du and co-workers reported CPA[6] supramolecular nanovalves in response to metal (Zn2+, Ni2+, Cu2+, Ca2+, and Mg2+) coordination for controlled drug release for the first time in 2014,39 and recently constructed CPA[6]-based supramolecular vesicles for quintuple-stimuli-responsive controlled drug release.40 Chart 1. Synthetic Route to Phosphonated Pillar[5]arene (PPA[5]) HO

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Scheme 1. Illustration of PPA[5]-Valved MSN and GNR@MSN Drug Delivery Systems Functionalized with Choline or Pyridinium Moieties for Stimuli-Responsive Controlled Release

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mance could be also realized because the phosphonates of PPA[5] were coordinated by Zn2+ ions for the weakening of the host−guest interactions. In the presence of highly symmetric methyl viologen (MV) as a competitive agent, PPA[5] could be removed from the two stalks by competitive binding for controlled drug release. It is known that near infrared (NIR) lights are noninvasive to biological tissues and can penetrate deep tissues.45−48 Upon embedding of gold nanorods (GNRs) within MSNs, the photothermal effect of GNR@MSNs generated under irradiation of NIR light weakened the host−guest interactions of the supramolecular nanovalves, resulting in the controlled release of encapsulated drugs. It is obvious that the stimuli-responsive PPA[5]-valved MSN drug delivery systems have promising applications in tumor photothermochemotherapy.

RESULTS AND DISCUSSION

To explore the diversity and promising applications of pillararene-based molecular machines, phosphonated pillar[5]arenes (PPA[5]) were synthesized (Chart 1, synthesis details and Figures S1−S9 in the Supporting Information) in our laboratory41 to construct novel supramolecular nanovalves for the first time, based on MSN vehicles functionalized with choline and pyridinium moieties as stalks, respectively (Scheme 1). Phosphonic acids have two protons that can be dissociated (pKa1, ∼2.4; pKa2, ∼8.0).42 At neutral pH, the phosphonates of PPA[5] preferentially carried single negative charges, thus the phosphonates might be weakly hydrated similar to sulfonates in contrast to the strongly hydrated carboxylates of CPA[5] (Chart S1). Specific ion pairing could be formed between the weakly hydrated single-charged phosphonates and the weakly hydrated quaternary ammoniums, such as choline and pyridinium, on the basis of the Hofmeister effect,43,44 for the strong host−guest interactions between PPA[5] and choline/pyridinium (tight supramolecular nanovalves), which means that the premature release of drugs from the PPA[5]-valved MSN vehicles could be almost inhibited favorable to in vivo circulation of the drug delivery systems. The specific ion pairing between the phosphonate and quaternary ammonium moieties was elaborated for the first time. Under the acidic intracellular microenvironments of tumor tissues, pH-responsive controlled drug release could be realized because PPA[5] was protonated and removed from the functionalized stalks owing to the weakening of the host−guest interactions of the supramolecular nanovalves. In the presence of abnormally enriched Zn2+ ions, the controlled release perfor-

Construction of PPA[5]-Valved MSNs. The synthesized MCM-41 type MSNs showed the spherical-like morphologies with a mean size of 115 nm from transmission electron microscope (TEM) and scanning electron microscope (SEM) images (Figure S10a,b). The TEM image clearly displayed parallelarranged cylindrical nanopores, and the corresponding smallangle powder X-ray diffraction (XRD) patterns further demonstrated the two-dimensional hexagonal arrays of cylindrical pores with three well-resolved (100), (110), and (200) reflections49 (Figure S10c). The nitrogen adsorption– desorption measurements of MCM-41 type MSNs exhibited a typical curve of type IV with a specific surface area of 1041 m2/g and a mean pore diameter of 2.7 nm (Figure S10d). MSNs were functionalized with choline and pyridinium moieties and characterized using FTIR spectroscopy (Figure S11). After MCM-41 type MSNs were modified with iodine propyltriethoxysilane (IPTS) (I-MSNs), a peak at 955 cm−1, due to the Si−OH bending vibration, decreased in intensity. Upon further modification of 3-mercaptopropionic acid (SPA) (SPA-MSNs), a shoulder around 1710 cm−1, assigned to the C=O stretching vibrations of carboxylic acids, was observed, which was overlapped with the 1634 cm−1 band, and two peaks around 1550 and 1390 cm−1 were present due to the antisymmetric and symmetric stretching vibrations of carboxylate groups, respectively. After SPA-MSNs were functionalized with choline chloride (Figure S12) (Ch-MSNs), a peak at 1477 cm−1 emerged due to the antisymmetric bending vibrations of methyl groups of choline. On the other hand, after SPA-MSNs were functionalized with 1-(2hydroxyethyl)pyridinium chloride (HEPC, Figure S13) (PyMSNs), a peak at 1490 cm−1 appeared owing to the skeletal stretching vibrations of pyridine rings, and a peak at 681 cm−1 was observed due to the C−H out-of-plane bending modes of pyridine rings.


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Figure 1. Solid-state 13C NMR spectra of (a) Ch-MSNs and (b) Py-MSNs and solid-state 31P NMR spectra of (c) PPA[5]-valved Ch-MSNs and (d) PPA[5]-valved Ch-MSNs without cargo loading.

The functionalizations of choline and pyridinium moieties were further characterized using solid-state 13C NMR spectroscopy (Figure 1a,b). The appearance of the resonances at 173 ppm verified the formation of ester linkages. The resonance at 54 ppm was assigned to the methyl groups of choline, and the resonances at 145 and 128 ppm were ascribed to the carbon atoms of pyridine rings. The 13C NMR spectral results indicated that MSNs were functionalized with choline and pyridinium moieties via the ester linkages, respectively. After capping of PPA[5], a single resonance at ca. 19 ppm was clearly observed in the corresponding solid-state 31P NMR spectra, due to the phosphonates of PPA[5] (Figure 1c,d), which indicates that the supramolecular nanovalves were developed by encircling of PPA[5] around the choline/pyridinium stalks. To gain a deep insight into the development of the supramolecular nanovalves, the model guests of choline and pyridinium stalks, hexyltrimethylammonium bromide (GCh, Figures S14 and S15) and N-hexylpyridinium bromide (GPy, Figures S16 and S17), were synthesized, and the 1H NMR spectra of PPA[5] and the guest (GCh/GPy) in D2O were investigated. Almost all of proton resonances of GCh/GPy were shifted upfield, moreover, some of hexyl proton resonances were even shifted to negative values (ppm) (Figures S18−S21), as a consequence of the shielding effect of electron-rich PPA[5] cavities. Meanwhile, some of PPA[5] proton resonances also underwent an obvious change in peak profile. These spectral changes confirm that GCh/GPy were encapsulated within the PPA[5] cavities for the strong host−guest interactions. Furthermore, the association constants of PPA[5] and the guests were determined using isothermal titration calorimetry (ITC) to be (3.63 ± 0.12) × 105 M−1 for GCh and (5.50 ± 0.98) × 105 M−1 for GPy at 25 °C (Figures S22 and S23).

The zeta potential of MCM-41 type MSNs was −31.6 mV, and the zeta potentials of Ch-MSNs and Py-MSNs were increased to 6.3 and 7.7 mV, respectively. After capping of PPA[5] on Ch-MSNs or Py-MSNs, the zeta potentials were abruptly decreased to −36.5 or −34.5 mV, respectively (Figure S24). These results indicate that the PPA[5]-valved Ch-MSNs and Py-MSNs were constructed and well dispersed in aqueous solutions, which were further confirmed by dynamic light scattering (DLS) measurements (Figure S25). MCM-41 type MSNs had an average hydrodynamic diameter of 142 nm, and Ch-MSNs and Py-MSNs showed the hydrodynamic diameters of 146 and 154 nm, respectively. The constructed PPA[5]valved Ch-MSNs and Py-MSNs displayed the hydrodynamic diameters of 160 and 164 nm, respectively. In addition, thermogravimetric analysis (TGA) was used to study the functionalizations of MSNs with choline or pyridinium moieties and subsequent PPA[5] capping dependent on the change of weight loss (Figures S26 and S27). The weight losses of these nanomaterials in the range of 100−200 °C were due to desorption of adsorbed water. Further weight losses at elevated temperatures resulted from the oxygenolysis of organic scaffolds modified/capped on the MSN surfaces and probably from further dehydration condensation of silanols. To avoid the interference from the silanol condensation, the weight losses in the same temperature ranges were compared. In the range of 230−620 °C, the weight loss was 9.8% in the case of SPA-MSNs. The weight losses were increased to 12.3% and 12.5% for Ch-MSNs and Py-MSNs, respectively, and further increased to 13.3% after capping of PPA[5] in the two cases. Ch-MSNs and Py-MSNs showed the similar XRD patterns to MCM-41 type MSNs (Figure S28), which indicates that the mesoporous structures of MSNs remained almost unchanged upon functionalization of choline or pyridinium moieties, but the (100) reflections showed the decrease of intensity in the cases of PPA[5]-valved MSNs with cargo (Ru(bipy)3Cl2) loading. Ch-MSNs and Py-MSNs showed the similar TEM images of mesoporous structures to MCM-41 type MSNs, but the mesoporous structures of the two PPA[5]-valved MSNs with cargo loading were blurred (Figure S29). The specific surface areas of Ch-MSNs and Py-MSNs were decreased respectively to 835 and 827 m2/g from 1041 m2/g before modification (i.e., MCM-41 type MSNs), and the corresponding pore sizes were reduced to 2.2 nm from 2.7 nm (Figures S30 and Table S1). The specific surface areas of the PPA[5]-valved Ch-MSNs and Py-MSNs with Ru(bipy)3Cl2 loading were dramatically diminished to 138 and 200 m2/g, respectively. These results indicate that the Ru(bipy)3Cl2loaded, PPA[5]-valved Ch-MSNs and Py-MSNs were constructed. The loading capacities of Ru(bipy)3Cl2 were determined using UV-vis spectroscopy to be 0.242 mmol/g ChMSNs and 0.245 mmol/g Py-MSNs for the two PPA[5]-valved MSNs, respectively, which were much larger than the cargo residues of 0.050 mmol/g Ch-MSNs and 0.054 mmol/g PyMSNs without PPA[5] capping after copious washing. These results indicate that the PPA[5] supramolecular nanovalves played a crucial role in drug loading and stimuli-responsive controlled release. pH-Responsive Controlled Release. The controlled release of Ru(bipy)3Cl2 from the PPA[5]-valved Ch-MSNs and PyMSNs was monitored using UV-vis spectroscopy (Figures S31 and S32). At pH 7.4, the two delivery systems showed small premature release of cargo, even less than 7% (Ch-MSNs) and


ACS Applied Materials & Interfaces 5% (Py-MSNs) after 8 h (Figure 2a,b). Upon decrease of pH, the phosphonates of PPA[5] were further protonated, resulting in the weakening of the electrostatic interactions between PPA[5] and the choline/pyridinium moieties and the removal of PPA[5] from the stalks. The supramolecular nanovalves were activated for the release of loaded cargo, and the release efficiencies increased with the decrease of pH. The loading capacities of cargo for the two delivery systems were almost identical, but the release efficiencies of the PPA[5]-valved ChMSNs were higher than those of the PPA[5]-valved Py-MSNs at the same pH values. This is because the host−guest interactions between PPA[5] and the pyridinium moieties (including π−π interactions as well as the primary electrostatic interactions) were stronger than those between PPA[5] and the choline moieties, which is in agreement with the association constants of PPA[5] and GPy/GCh. Furthermore, the 1H NMR spectra in D2O showed that the PPA[5]−GCh and PPA[5]−GPy inclusion complexes underwent a disassembly upon decrease of pH, owing to the weakening of the host−guest interactions, so that the resonance signals of PPA[5] could hardly be observed and the proton resonances of GCh and GPy got back to those of individual guests but with broad peak profiles upon further decrease of pH to 3.0 (Figures S33 and S34). PPA[5] was almost completely protonated, resulting in a decrease in solubility and precipitation from aqueous solution. After the cargo was released from the two PPA[5]-valved delivery systems at pH 3.0, the specific surface areas were increased from 138 to 476 m2/g (Ch-MSNs) and from 200 to 493 m2/g (Py-MSNs), respectively, and the corresponding pore sizes were recovered to 1.9 and 2.0 nm, respectively (Figure S30 and Table S1). Under the same conditions, the CPA[5]-valved Ch-MSNs and Py-MSNs were constructed for comparison (Figure 2c,d), with the loading capacities of Ru(bipy)3Cl2 of 0.248 mmol/g ChMSNs and 0.269 mmol/g Py-MSNs. The release efficiencies of the two PPA[5]-valved delivery systems were lower than those of the CPA[5] counterparts.

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ly interact with weakly hydrated soft counterions, and strongly hydrated hard ions preferentially interact with strongly hydrated hard counterions. The anionic headgroups from strongly hydrated hard ions to weakly hydrated soft ones are in the order of carboxylate (R−COO−, R = alkyl), monovalent phosphate (R2PO4−), sulfate (RSO4−), and sulfonate (RSO3−).43,44 However, phosphonate has not been reported yet in the Hofmeister series so far. Referring to the order of sulfate and sulfonate in the Hofmeister series,43,44 it is most likely that monovalent phosphonate (RPO3H− or R2PO3−) is a weakly hydrated soft ion similar to sulfonate. Obviously, the monovalent phosphonates of PPA[5] were weakly hydrated in contrast to the strongly hydrated carboxylates of CPA[5], thus specific ion pairing could be developed between the weakly hydrated monovalent phosphonates and the weakly hydrated choline/pyridinium moieties for the strong host−guest interactions, which might be similar to the interactions between adjacent phosphatidylcholine moieties of zwitterionic phospholipids to some degree. The specific ion pairing between the phosphonate and quaternary ammonium moieties was elaborated for the first time. On the other hand, phosphonic acids have smaller pKa than carboxylic acids, so that the degree of protonation of the PPA[5] phosphonates was smaller at the same pH values and the release efficiencies of the PPA[5]-valved delivery systems were lower. It is known that the intracellular environments of tumors have low pH values, down to pH 6.0−5.0 in the endosomes and pH 5.0−4.0 in the lysosomes,50,51 in comparison to blood and normal tissues. Furthermore, the antitumor drug doxorubicin (DOX) was used to investigate controlled drug release of the PPA[5]-valved Ch-MSNs and Py-MSNs for potential practical applications (Figure S35). The loading capacities of DOX were determined using UV-vis spectroscopy to be 0.101 mmol/g Ch-MSNs and 0.093 mmol/g Py-MSNs for the two delivery systems, respectively. At pH 7.2, the two delivery systems showed minimal premature release of drugs less than 3% after 8 h (Figure 3). At pH 5.0, a significant controlled release of DOX from the two delivery systems was observed, and the release efficiencies were further increased upon decrease of pH to 4.0.

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Figure 2. pH-responsive controlled release of Ru(bipy)3Cl2 from (a) PPA[5]-valved Ch-MSNs, (b) PPA[5]-valved Py-MSNs, (c) CPA[5]-valved Ch-MSNs, and (d) CPA[5]-valved Py-MSNs.

On the basis of the Hofmeister effect and extended computation study by Kunz and co-workers,43,44 ion pairs are formed preferentially between oppositely charged ions with comparable water affinities, i.e., weakly hydrated soft ions preferential-

Figure 3. pH-responsive controlled release of DOX from (a) PPA[5]-valved Ch-MSNs and (b) PPA[5]-valved Py-MSNs.

Zn2+-Triggered Controlled Release. Zinc ranks the second place in the trace elements of human body and plays an important role in a variety of physiological processes, such as tissue regeneration, gene expression, enzyme regulation, immune maintenance, myocardial protection, protein transport, and neuroendocrine.52 It is found that the formation of amyloid


plaques relevant to Alzheimer’s disease is associated with abnormally enriched Zn2+ ions in the brains.50 The phosphonates of PPA[5] could be coordinated with Zn2+ ions via multivalent chelating, leading to the weakening of the host−guest interactions between PPA[5] and the choline/pyridinium moieties, thus the PPA[5] supramolecular nanovalves were activated and the loaded cargo was released (Figures 4 and S36). Similarly, the 1H NMR spectra of the PPA[5]−GCh and PPA[5]−GPy inclusion complexes in D2O in the presence of Zn2+ ions (Figures S37 and S38) displayed obvious changes as occurred at low pH. It is confirmed that the coordination of Zn2+ ions with the phosphonates of PPA[5] resulted in a decrease in the host−guest interactions between PPA[5] and the choline/pyridinium moieties for cargo release. The release efficiencies of the PPA[5]-valved Ch-MSNs at the same concentrations of Zn2+ ions were higher than those of the PPA[5]valved Py-MSNs. The Zn2+-triggered controlled drug release of the two PPA[5]-valved delivery systems has promising applications in the diseases associated with the nervous system.

demonstrated the competitive binding of MV to PPA[5]. The highly symmetric MV had large probability of competitive binding in comparison to lowly symmetric acetylcholine, especially in the cases of the PPA[5] supramolecular valves mounted on the MSN surfaces, through either end of MV. In general, the release efficiencies of the PPA[5]-valved ChMSNs in response to pH, Zn2+, and MV were higher than those of the PPA[5]-valved Py-MSNs, owing to the strong host−guest interactions between PPA[5] and the pyridinium moieties.

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Figure 4. Zn2+-triggered controlled release of Ru(bipy)3Cl2 from (a) PPA[5]-valved Ch-MSNs and (b) PPA[5]-valved Py-MSNs at pH 7.4.

Competitor-Triggered Controlled Release. The PPA[5] supramolecular nanovalves could be activated by competitive agents for the controlled release of encapsulated cargo. Acetylcholine is a common neurotransmitter in the central and peripheral nervous systems and plays key roles in learning and memory. It is currently believed that high level of acetylcholine is related to significant improvement of Alzheimer’s disease. In fact, acetylcholine could hardly trigger cargo release from the two PPA[5]-vavled delivery systems up to 1.0 mM (Figure S39). It is important that the two PPA[5]-vavled delivery systems could be well resistant to physiological acetylcholine levels. However, MV could trigger the removal of PPA[5] from the choline/pyridinium stalks and the release of loaded cargo (Figures 5 and S40). The association constant of PPA[5] and MV was determined using ITC to be (2.35 ± 0.22) × 105 M−1 (Figure S41), comparable to the association constants of PPA[5]−GCh and PPA[5]−GPy inclusion complexes. The addition of MV to the PPA[5]−GCh and PPA[5]−GPy solutions gave rise to a series of changes in the 1H NMR spectra in D2O (Figures S42 and S43). The proton resonances of GCh and GPy were basically restored to those of individual guests, concomitant with the sharpening of the resonance peaks. In other words, the 1H NMR spectrum of the ternary solution of PPA[5], GCh/GPy, and MV was more like the spectrum of PPA[5]−MV inclusion complexes than the spectra of PPA[5]−GCh or PPA[5]−GPy inclusion complexes. These spectral changes

NIR Light-Triggered Controlled Release. GNRs have an absorption maximum in the NIR region and show the photothermal effect upon illumination of NIR light. The assynthesized GNRs had a longitudinal axis of 66 nm and a transversal axis of 18 nm with an aspect ratio of ca. 3.7 (Figure 6a) and showed an NIR absorption maximum at 823 nm (Figure 6c). The GNR-embedded MSNs (GNR@MSNs) were ellipsoidal (long axis of about 145 nm and short axis of about 101 nm) with an average silica shell of 40 nm (Figure 6b) and displayed an NIR absorption maximum at 814 nm (Figure 6c). The specific surface area of GNR@MSNs was 664 m2/g, and the average pore size was 3.0 nm (Figure S44). Upon illumination of NIR light at 808 nm, GNR@MSNs showed the photothermal effect dependent on power density of laser (Figure 6d). The variable temperature 1H NMR spectra of the PPA[5]−GCh and PPA[5]−GPy inclusion complexes in D2O were investigated (Figures S45 and S46). At elevated temperatures, the proton resonance peaks of two ends of the guest molecules were sharpened, while the other resonance peaks of the guests were flattened and even disappeared. These spectral changes might be due to the acceleration of assembly and disassembly of the hosts and guests, concomitant with a decrease in binding affinity at elevated temperatures. The association constants of PPA[5] and the guests were further determined using ITC to be (3.81 ± 0.41) × 104 M−1 for GCh and (1.35 ± 0.21) × 105 M−1 for GPy at 75 °C (Figures S47 and S48). It is clear that the host−guest interactions between PPA[5] and GCh/GPy were weakened at elevated temperatures owing to the thermal effect.



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Similarly, GNR@MSNs were successively functionalized with choline moieties (GNR@MSNs-Ch), loaded with DOX, and capped with PPA[5]. The photothermal effect generated from GNR@MSNs could weaken the host−guest interactions between PPA[5] and the choline moieties for the activation of supramolecular nanovalves. The PPA[5]-valved GNR@MSNs-Ch delivery system showed the controlled release of DOX upon intermittent illumination (ON/OFF) of NIR light (Figure S49), and the release efficiency increased with the increase of power density of laser and was further enhanced under combined stimuli of NIR light and acidic pH, due to the synergistic effect of photothermo-chemotherapy (Figure 7). The combination of NIR light-based thermotherapy and chemotherapy (photothermo-chemotherapy) would provide enhanced therapeutic efficacy.

the PPA[5]-valved GNR@MSNs-Ch with DOX loading showed significant cytotoxicity, due to the pH-responsive controlled drug release in the weakly acidic environments of tumor cells. The illumination of NIR light at 808 nm could not cause apoptosis of the A549 cells in the absence of GNR@MSNbased delivery system. Upon illumination of NIR light, the A549 cells incubated with the PPA[5]-valved GNR@MSNsCh without drug loading displayed the obvious decrease of cell viability (Figure 8B). It is clear that the cell apoptosis resulted from the photothermal effect of GNRs upon illumination of NIR light. The cell viability was further diminished when the A549 cells incubated with the PPA[5]-valved GNR@MSNs-Ch with DOX loading were illuminated with NIR light. On the one hand, the photothermal effect of GNRs could cause cell apoptosis (photothermal therapy); on the other hand, the controlled release of DOX, triggered both by low pH in the tumor cells (chemotherapy) and by photothermal activation of the supramolecular nanovalves, considerably inhibited proliferative activity of the tumor cells. The enhanced antitumor efficacy of the PPA[5]-valved GNR@MSNs-Ch with DOX loading upon illumination of NIR light was attributed to the synergistic effect of photothermo-chemotherapy.

Cell viability / %

Figure 6. (a) TEM image of GNRs. (b) TEM image of GNR@MSNs. (c) UV-vis spectra of GNRs and GNR@MSNs. (d) Photothermal effects of GNR@MSNs (0.3 mg/mL) upon irradiation of 808 nm NIR light at different power densities for 15 min.

Cumulative release / %

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Figure 8. (A) Cell viability of PPA[5]-valved GNR@MSNs-Ch without and with DOX loading after 24 h of incubation with A549 cells. (B) Cell viability of drug delivery systems (40 µg/mL) after 24 h of incubation with A549 cells: (a) blank control under illumination of NIR light (808 nm, 3 W/cm2); (b) PPA[5]-valved GNR@MSNs-Ch without drug loading; (c) PPA[5]-valved GNR@MSNs-Ch without drug loading under illumination of NIR light; (d) DOX-loaded, PPA[5]-valved GNR@MSNs-Ch; (e) DOX-loaded, PPA[5]-valved GNR@MSNs-Ch under illumination of NIR light.

CONCLUSION

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Figure 7. NIR light (808 nm)-triggered and/or pH-responsive controlled release of DOX from PPA[5]-valved GNR@MSNs-Ch.

Cytotoxicity and Antitumor Efficacy. Cell viability and antitumor efficacy of the PPA[5]-valved GNR@MSNs-Ch without and with DOX loading were first tested by the sulforhodamine B (SRB) assay after 24 h of incubation with A549 cells (Figure 8A). The PPA[5]-valved GNR@MSNs-Ch without drug loading almost showed no cytotoxicity; however,

In summary, PPA[5] was synthesized to construct novel supramolecular nanovalves for the first time, based on MSNs functionalized with choline or pyridinium moieties with high binding affinity through the host-guest interactions primarily via ion pairing, which resulted in the minimization of premature release of encapsulated drugs. The specific ion pairing between the phosphonate and quaternary ammonium moieties was elaborated for the first time to construct supramolecular nanovalves.

The PPA[5] supramolecular nanovalves were activated by low pH, Zn2+ coordination, and competitive agents for controlled drug release, and the release efficiency and antitumor efficacy were further enhanced when GNR-embedded MSNs were used to construct the PPA[5]-valved GNR@MSN drug delivery system under illumination of NIR light, attributed to the


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synergistic effect of photothermo-chemotherapy. The PPA[5]valved GNR@MSN delivery system has promising biological applications in tumor photothermo-chemotherapy.

ASSOCIATED CONTENT Supporting Information. Experimental details, synthesis details and characterizations, SEM and TEM images, XRD patterns, nitrogen adsorption−desorption isotherm and pore size distributions, FTIR spectra, 1H NMR spectra, ITC plots and fitted parameters, zeta potentials, dynamic light scattering data, thermogravimetric analysis, time-dependent UV-vis spectra of cargo release, and relevant release profiles. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * E-mail: [email protected].

Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT This work was supported by National Natural Science Foundation of China (21273112).

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