Peptide-Decorated Gold Nanoparticles as ... - ACS Publications

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Peptide Decorated Gold Nanoparticles as Functional Nano-Capping Agent of Mesoporous Silica Container for Targeting Drug Delivery Ganchao Chen, Yusheng Xie, Raoul Peltier, Haipeng Lei, Ping Wang, Jun Chen, Yi Hu, Feng Wang, Xi Yao, and Hongyan Sun ACS Appl. Mater. Interfaces, Just Accepted Manuscript • DOI: 10.1021/acsami.6b02594 • Publication Date (Web): 22 Apr 2016 Downloaded from http://pubs.acs.org on April 24, 2016

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ACS Applied Materials & Interfaces

ABSTRACT:

A stimuli-responsive drug delivery system (DDS) with bio-active surface is constructed by end-capping mesoporous silica nanoparticles (MSNs) with functional peptide-coated gold nanoparticles. MSNs are first functionalized with acid-labile α-amide-β-carboxyl groups to carry negative charges, and then capped with positively charged GNPs that are decorated with oligo-lysine-containing peptide. The resulting hybrid delivery system exhibits endo/lysosomal pH triggered drug release, and the incorporation of RGD peptide facilitates targeting delivery to αvβ3 integrin over-expressing cancer cells. The system can serve as a platform for preparing diversified multi-functional nanocomposites using various functional inorganic nanoparticles and bioactive peptides.

Nanomaterial-based drug delivery systems (NDDS) have shown to be increasingly promising and useful as tools in cancer therapy. To overcome the challenges in conventional chemotherapy, an ideal nano-carrier should possess desirable properties, including minimal toxicity towards healthy cells, controlled release of payload, the ability to target cancer cells, etc.1 Integrating all these properties into one “magic bullet”, however, remains a challenge today, thereby raising the urge to design novel NDDS that offer new perspectives to achieve this goal. Over the past decades, much effort has been devoted for the development of porous inorganic nanoparticles as a general drug delivery platform, including mesoporous silica nanoparticles (MSNs),2 titanium3 and hydroxyapatite nanoparticles.4 Among these widely reported

2 ACS Paragon Plus Environment


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nano-carriers, MSNs have attracted substantial attention due to its high porosity, good tunability and ease of functionalization.2 In particular, end-capped MSNs have attracted strong interest in the scientific field. This carrier has the potential to display “zero premature release” prior to reaching target tissues or cells while controlled cargo release when exposed to specific stimuli. These prominent properties of end-capped MSNs are highly desirable as they can help to improve of biocompatibility as well as overall selectivity towards cancer cells. Numerous MSN-based controlled release systems have been developed by utilizing a wide variety of pore-blocking agents such as macromolecules,5 nucleic acid,6 polymers,7 inorganic nanoparticles (INPs),8 proteins,9 or peptides.10 Once the drug loaded containers reach their target, control of the payload release is usually achieved via specific stimuli, either internal stimuli such as the presence of certain biomolecules (e.g. ATP6 or enzymes11), redox potential,12 pH,13 or external stimuli such as light,14 or temperature.15 Among all the “gate-keepers”, INPs can be facilely integrated into the system to produce multi-functional nano-carriers with unique features. For example, Fe3O4 nanoparticles capped MSNs were found to be responsive to an external magnetic field, resulting in a system that exhibited both controlled release profile and magnetic resonance imaging (MRI) contrast enhancement properties.16 Another study utilized ZnO quantum dots to seal the pores of MSN. As release of the drug was triggered by changes in pH, the decomposition of the quantum dots also exhibited cytotoxicity at their destination, thus giving a synergistic effect towards destruction of cancer cells.8


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Despite notable success in utilizing INPs as capping agents, their wider application in cancer therapy is hampered by a few factors, including a lack of efficient targeting property. On one hand, the intrinsic ability of nanoparticles to discriminate between inflammatory and healthy tissues based on enhanced permeation and retention (EPR) effect is insufficient to specifically target tumor tissues.17 On the other hand, though active targeting has been demonstrated to be an effective strategy for improving the specificity of NPs towards tumor cells via receptor-mediated endocytosis, incorporation of active targeting ligands into INPs-capped MSNs is still challenging due to tedious synthesis, undesirable influence on colloidal stability, and limited reaction site for anchoring the ligand grafted INPs onto MSNs.8,18 To this end, peptides have emerged as an attractive biocompatible ligands for nanoparticles. Compared to conventional ligands, peptide ligands could not only improve colloidal stability under biophysical condition and biocompatibility, render tunable physicochemical properties for flexible conjugation, but also provide the particles with desirable biological functions, e.g. cell/organelle targeting or cell membrane penetrating function. Herein we describe a hierarchically constructed pH-responsive nano-carrier utilizing peptide functionalized gold nanoparticles (GNPs@peptide) as the gate-keeper for targeting drug delivery (Scheme 1). GNPs are chosen as pore capping agents due to their good biocompatibility, facile modification with thiol containing ligands or peptides, and desirable physicochemical features for constructing multi-functional nano-carriers.19 In our design, MSNs are functionalized with carboxyl groups to carry



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Scheme 1. (a) Schematic illustration of the GNPs coated with mixed peptides and the drug loaded and end–capped MSN with RGD peptide residue for cancer cell targeting. (b) The cellular uptake and intra-organelle removal of the gate-keeping GNPs due to charge reversal under acidic condition.

negative charges, via an α-amide-β-carboxyl unsaturated bond linker that is sensitive to pH and will degrade in acidic environment in endo/lysosome.20 On the other hand, GNPs are coated with oligo-Lysine containing peptides to hold positive charge. In the meantime, RGD peptide is incorporated to enhance the targeting ability of the system towards cancer cells.21 Under neutral condition, the MSNs can be coated by a layer of GNPs@peptide via electrostatic interaction to cap the pores and prohibit premature leakage. Upon uptake via endocytosis, the acidic environment of the endo/lysosome (pH 4.0-6.0)22 is expected to induce rapid hydrolysis of β-carboxylic amide into corresponding amine and carboxyl groups, resulting in a charge reversal of the MSNs from negative to positive, removal of the nano-capping agent and release of entrapped drug.23


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MSNs were first prepared using established method to obtain spherical nanoparticles with diameter of about 120 nm, as shown by the SEM and TEM images (Figure 1a and b, respectively). The dynamic light scattering (DLS) result indicates a narrow size distribution of as-obtained MSNs, indicating good dispersion in solution (Figure S1, Supporting Information). The highly ordered lattice array in the TEM image indicated a honeycomb-like MCM-41 type mesoporous structure of as-obtained MSN, which was further confirmed by the low angle powder X-Ray diffraction (XRD) (Figure S2, Supporting Information). N2 sorption analysis of the MSN exhibited a Type Ⅳ BET isotherm with a surface area of 1129 m2 g-1 and average pore diameter of about 3.0 nm (Figure S3, Supporting information).

Figure 1. (a) SEM image of MCM-41, (b) TEM image of MCM-41, (c) TEM image of GNPs@peptide and (d) TEM image of the gold nanoparticles capped silica nanoparticles (MSN@GNPs@peptide).



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Surface functionalization of MSN is illustrated in Scheme S1. Briefly, MSN was first modified with (3-aminopropyl)-triethoxysilane (APTES) to obtain MSN-NH2, followed by removal of the template CTAB by ion exchange method. Subsequently, MSN-NH2 were reacted with citraconic anhydride to obtain MSN-NH2(cit). FT-IR spectrum of MSN-NH2 showed new peaks at 1639 cm-1 and 1538 cm-1 compared to the MSNs before APTES modification. The two bands in the peaks at 1639 cm-1 and 1538 cm-1 can be assigned to the stretching vibration of amide I and -NH2 bending, respectively.13 After modification with citraconic anhydride, new peaks at 1670 cm-1, 1626 cm-1 and

1562 cm-1

were observed, which could be attributed to functional

groups of amide and carboxylic acid (Figure S4, supporting information).24 Zeta potential of the samples in PBS increased from -33 mV to +15 mV upon grafting of amine. And it decreased to about -30 mV after reacting with citraconic anhydride to produce carboxyl groups on the surface (Figure S5, supporting information). Both FT-IR spectrum and zeta potential of the obtained MSNs after each step suggested successful incorporation of primary amine and subsequent citraconic amide. The resulting β-carboxylic amide was reported to be acid-labile and could hydrolyze rapidly into amine and carboxyl groups, resulting in the charge reversal to positive.20 As implied by Figure 2, the MSN-NH2(cit) was stable in PBS, with a zeta potential of about -35 mV. At pH 5.0, it increased gradually, reaching 0 mV after incubation for about 2.5 h, and finally to about +18 mV as incubation time increased to 24 h. As anticipated, regeneration of primary amines after hydrolysis of citraconic amides at low pH induced a charge reversal of the MSNs. As a control, MSN-NH2(suc)


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obtained by functionalizing MSN-NH2 with succinic anhydride did not show the charge reversion when incubated in acidic buffer, further demonstrating that the charge reversion was resulted from hydrolysis of α-amide-β-carboxyl bond. This is expected to facilitate removal of positively charged nano-capping agent via electrostatic repulsion.20,23,25

Figure 2. Zeta potential of (a) GNPs@peptide in acetate buffer (10 mM, pH 5.0); (b) MSN-NH2(cit) incubated in acetate buffer (10 mM, pH 5.0); (c) GNPs@peptide in PBS (10 mM, pH 7.4); (d) MSN-NH2(cit) incubated in PBS (10 mM, pH 7.4); (e) MSN-NH2(suc) incubated in acetate buffer (10 mM, pH 5.0) and (f) MSN-NH2(suc) incubated in PBS (10 mM, pH 7.4) for different time.

GNPs with diameter of about 4 nm (Figure S6a, Supporting Information) were synthesized by reduction of HAuCl4 with sodium borohydride.26 Two cationic



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peptides CALNNKKKK and CALNNKKKKGRGD were synthesized by the standard Fmoc-chemistry based solid phase synthesis (Figure S7, Supporting Information). A mixture of CALNNKKKK and CALNNKKKKGRGD at the ratio of 4/1 was used to functionalize GNPs to obtain GNPs@peptide. On contrary to original citrate stabilized GNPs which could not disperse in PBS buffer or re-disperse in water after lyophilization, as-obtained GNPs@peptide was found to disperse well after ligand exchange and lyophilization, as revealed by the TEM image (Figure 1c) and DLS (Figure S6b, supporting information). This clearly signified that peptide could act as good ligands for GNPs, imparting enhanced colloidal stability, which is vital for biological applications. The increase in hydrodynamic diameter of the GNPs from 4.0 to 6.7 nm after ligand exchange confirmed the presence of an extending peptide layer.27 Upon coating with peptides, zeta potential of the GNPs was switched from -32 mV to about +14 mV. And it could be maintained in PBS or acidic buffer for 24 h, implying that as-obtained GNPs@peptide could act as gate-keeper for the negatively charged MSN-NH2(cit) though electrostatic interaction. This was further verified by the TEM image shown in Figure 1d, in which lots of dark dots (GNPs) on the surface of MSNs were observed. The pH triggered release property of this hybrid nano-carrier was characterized using doxorubicin (DOX) as a model drug. Drug loading was carried out by soaking MSN-NH2(cit) in DOX solution in 10 mM PBS (pH 7.4) for one day, followed by capping with GNPs@peptide for another 24 h. Then the obtained end-capped MSNs (MSN@GNPs@peptide) were extensively washed with PBS to remove any DOX that


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Figure 3. Release profile of DOX from GNPs@peptide capped MSNs (MSN@GNPs@peptide) under different pH’s. a) MSN-NH2(suc), pH 7.4; b)MSN-NH2(suc), pH 5.0; c) MSN-NH2 (cit), pH 7.4; d) MSN-NH2(cit), pH 5.0; e) MSN-NH2(cit), pH 3.0.

adsorbed on the surface. The drug loading capacity was determined to be approximately 37 mg g-1 by fluorescence spectroscopy method. The resulting MSN@GNPs@peptide was then suspended in buffers of either pH=5.0 or 3.0 and TEM was used to evaluate the detachment of GNPs@peptide over time directly. As implied in Figure S8, the hexagonally packed porous channels of the MSNs could be observed again after incubation in pH 5.0 buffer for 3 h, suggesting partial detachment of GNPs@peptide on the surface. Most of the GNPs@peptide detached from MSNs when incubation time was prolonged to 5 h. In contrast, incubation in pH



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3.0 buffer induced a faster removal of those GNPs@peptide from the surface of MSNs, with over 90% of GNPs@peptide detached after incubation for 3h. The release profile of loaded DOX was then monitored via fluorescence spectroscopy. As shown in Figure 3, only limited DOX was released at pH 7.4, indicating efficient confinement of DOX in the pores by capping with GNPs@peptides. In accordance with the TEM results described above, a faster release profile of loaded DOX was observed in acidic buffers. Approximately 40% and 75% of DOX was released after incubation for 24 h at pH 5.0 and 3.0, respectively. The incomplete release might be due to electrostatic interaction between protonated DOX and the silanol groups inside the pores.8 On the contrary, no such acidic pH triggered release of loaded DOX was observed for MSN-NH2(suc), which did not possess the pH induced charge reversion property (Curve (a) and (b) in Figure 3). To integrate active targeting function into the present nano-carrier, RGD peptide was incorporated onto GNPs as model ligand. Cellular uptake and intracellular release behavior of the resulting system was tested on two cell lines: αvβ3 integrin over-expressed U87 MG cells (human glioblastoma cells) and αvβ3 integrin negative HEK 293 cells (human embryonic kidney cells). Confocal laser scanning microscopy (CLSM) images revealed that U87 MG cells exhibited stronger red fluorescence than that in HEK 293 cells after 4 h incubation with DOX-loaded MSNs (Figure 4), indicating an enhanced uptake of the DOX loaded nanoparticles for αvβ3 integrin over-expressing cells.


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Figure 4. Confocal laser scanning microscopy (CLSM) images of (a-c) U87 MG cells and (d-f) HEK 293 cells after incubation with DOX loaded and GNPs@peptide capped MSNs for 4 h. (a, d) red fluorescence of DOX; (b, e) blue fluorescence of Hoechst 33342; (c, f) overlap of confocal fluorescence and bright field images. Scale bar: 40 µm.

As a control, free RGDS peptide was pre-incubated with the cells before DOX loaded MSNs. The free RGDS peptide will compete with RGD peptide present on the GNPs for binding to the αvβ3 integrin, resulting in attenuated internalization of nano-carriers.28 CLSM images indicated that the fluorescence of DOX in U87 MG cells decreased upon incubation with RGDS peptide (Figure 5a and 5d). On the contrary, the fluorescence of DOX observed in HEK 293 cells exhibited negligible difference for cells incubated in presence or absence of free RGDS peptide (Figure 5g and 5j). These results clearly indicated that the presence of RGD peptide on the surface of the GNPs@peptide capped MSNs systems can facilitate the binding to αvβ3 integrin over-expressing cancer cells, and subsequent internalization via 12 ACS Paragon Plus Environment


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Figure 5. Confocal laser scanning microscopy (CLSM) images of (a-f) U87 MG cells and (g-l) HEK 293 cells after incubation with DOX loaded and GNPs@peptide capped MSNs for 4 h, in presence (d-f, and j-l) and absence (a-c and g-i) of free RGDS peptide. (a,d,g,j) red fluorescence of DOX; (b,e,h,k) blue fluorescence of Hoechst 33342; and (c,f,i,l) overlap of confocal fluorescence and bright field images. Scale bar: 40 µm.


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receptor-mediated endocytosis.29 In contrast, cells that express αvβ3 integrin in low level showed limited internalization due to a lack of cell recognition and possible presence of repulsion between the negatively charged cell membrane and the slightly negatively charged nanoparticles (Figure S9, supporting information). In order to further investigate the function of the nano-vectors, free DOX was introduced as a control. It was reported that free DOX could show even stronger fluorescence than that loaded in NPs due to different cellular uptake mechanisms.30 Similar result was observed in HEK 293 cells, which might be due to limited cellular uptake of RGD-conjugated MSNs in these αvβ3 integrin negative cells. However, for αvβ3 integrin over-expressed U87 MG cells, the fluorescence intensity did not show noticeable decrease when incubated with DOX loaded MSNs@GNPs@peptide, due to enhanced uptake of the nano-carrier (Figure S10, supporting information). The results above clearly indicated that RGD peptides decorated on NPs contributed to selective delivery of DOX into αvβ3 integrin over-expressing cancer cells. Finally, biocompatibility of the bare and DOX loaded MSNs@GNPs@peptide, and its targeting therapeutic efficiency was quantitatively evaluated using MTT assay on both U87 MG cells and HEK 293 cells. As shown in Figure 6, the cell viability for both cells co-incubated with bare hybrid nanoparticles remained over 80%, even for concentration of as high as 150 µg mL-1, indicating a good biocompatibility of the blank MSNs@GNPs@peptide. After co-incubating with 100 µg mL-1 of DOX loaded MSNs@GNPs@peptide for 24 h, the cell viability decreased dramatically to about 40 % for U87 MG cells while remained at around 75% for the control HEK 293 cells. It should be noted that U87 MG cells were found to be intrinsically more resistant to DOX than HEK 293 cells (Figure S11, supporting information). Taking this into account, the results further indicate that such MSNs@GNPs@peptide hybrid nano-carrier is capable of targeting to cells that over-express αvβ3 integrin. 14 ACS Paragon Plus Environment


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Figure 6. Cell viability of (a) U87 MG cells and (b) HEK 293 cells incubated for 24 h with GNPs@peptide capped MSNs with or without DOX at different concentrations.

In addition, the effect of RGD peptide on the enhanced apoptosis of U87 MG cells was further investigated by control experiments performed by pre-incubating the U87 MG cells with 50 µM free RGDS peptide for 30 min, followed by incubating for 24 h with DOX loaded MSNs@GNPs@peptide. As shown in Figure S12 in supporting information, the MTT assay indicated higher cell viability when free RGDS peptide was introduced to bind with the integrin on cell membrane and compete with the RGD peptide on GNPs, resulting in inhibition of RGD mediated enhanced uptake of MSNs@[email protected],29 The result supports the conclusion that RGD peptide resulted in an enhanced NPs-mediated apoptosis of αvβ3 integrin over-expressing cancer cells. In summary, we have constructed a new pH-responsive drug delivery carrier by capping MSNs with GNPs@peptide. Such obtained hybrid nanoparticles showed good confinement efficiency of loaded cargoes with a burst release upon exposure to acidic environment. Incorporation of RGD peptide facilitated targeting delivery of the


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hybrid nanoparticles to cancer cells. So far as we know, this is the first report of equipping active targeting ligands onto INPs end-capped MSNs for targeting drug delivery. This facile route will provide new strategy to design and construct diverse multi-functional drug delivery carriers by combining various desirable INPs and different biologically active peptides.

ASSOCIATED CONTENT

Supporting Information. Detailed experimental section, XRD, dynamic light scattering, zeta potential, nitrogen sorption isotherms, FT-IR spectrum, ESI-MS of peptides.

This material is available free of charge via the internet at

http://pubs.acs.org.

AUTHOR INFORMATION

Corresponding Author * Dr. Hongyan Sun, E-mail: [email protected].

* Dr. Hu Yi, E-mail: [email protected]

Author Contributions The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

Notes The authors declare no competing financial interest.



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ACKNOWLEDGMENT We thank Prof. Shuk Han Cheng from Department of Biomedical Science, City University of Hong Kong for providing the U87 MG cell line. This work was supported by the Research Grants Council of Hong Kong (No. 21300714 and 11302415) and the National Natural Science Foundation of China (No. 21202137, 21572190 and 21390411).

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Table of Contents

A new pH-responsive drug delivery carrier is constructed by end-capping mesoporous silica nanoparticles with gold nanoparticles functionalized by bio-active peptides.


Peptide-Decorated Gold Nanoparticles as ... - ACS Publications

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