Light-responsive peptide [2]rotaxanes as gatekeepers of mechanised nanocontainers

Article abstract of DOI:10.1039/c5cc04365d

Novel mechanized silica nanoparticles incorporating a peptide-based molecular shuttle as a photo-responsive interlocked gatekeeper of nanocontainers are described including the uptake and delivery studies of a model cargo.

Full text of DOI:10.1039/c5cc04365d

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Light-responsive peptide [2]rotaxanes as
gatekeepers of mechanised nanocontainers†
Cite this:DOI: 10.1039/c5cc04365d
A. Martinez-Cuezva, S. Valero-Moya, M. Alajarin and J. Berna*
Received 28th May 2015,
Accepted 6th August 2015
DOI: 10.1039/c5cc04365d
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Novel mechanized silica nanoparticles incorporating a peptide- the positional switching of benzylic amide rings has never been
based molecular shuttle as a photo-responsive interlocked gate- tested as an open/close mechanism for controlling the release
keeper of nanocontainers are described including the uptake and and capture of cargoes from MSNs.
delivery studies of a model cargo.
Among the [2]rotaxanes containing a benzylic amide macro-
cycle pioneered by Leigh,7b–e the subset of the peptide-based
Since the beginning of this century the use of mesoporous structures14–17 are considered excellent scaffolds for the building
materials for the smart delivery of cargoes has been an appealing of a broad range of molecular shuttles,14 logic gates,15 informa-
research topic.1,2 In these studies systems devoted to the tion storage devices16 and enzymatic delivery systems of bioactive
controlled release of drugs have a singular significance due to compounds.17
their promising therapeutic use.3 In this arena, mesoporous
Herein, we describe the preparation of novel mechanized
silica nanoparticles (MSNs) have become outstanding materials silica nanoparticles having a peptide-based molecular shuttle
for controlled delivery applications due to their exceptional as a photocontrollable gatekeeper and MCM-41 as a meso-
features such as high loading capacity, wide diversity regarding porous support aimed at the construction of light-operated
size, shape and pore diameter, easy functionalization, mechan- nanocontainers. The loading and delivery of rhodamine B
ical and chemical resistance and biocompatibility.4,5 Numerous (RhB) as a model cargo through the mechanism depicted in
stimuli-responsive methods6 have been established to govern Fig. 1 have also been reported.
the trapping and liberation of small molecules from the pores
Our system is based on the light-induced E/Z isomerization of a
of these nanocontainers incorporating different organic or fumaramide-based binding site for shuttling the macrocycle along
inorganic motifs behaving as blockers or gatekeepers. One the thread of a bistable [2]rotaxane18 thus closing and opening a
promising group of these tailor-made doors is based on molecular gate on the surface of a mesoporous silica support. We
threaded/interlocked structures,7 giving rise to the materials placed a peptide station (green cylinder, Fig. 1a) near the silica
known as mechanized silica nanoparticles8 which have been surface and connected to a fumaramide station (red cylinder) by
seen as intelligent materials with excellent potential for the an alkyl chain. In the open-pore state, the tetralactame ring is
advancement of novel nanodosifiers.9 Typically, the benefits of located on the fumaramide station allowing the free diffusion of
the MSNs and the well-known templating method to assemble the cargo RhB molecules (purple blocks) toward the void of
MCM-41 make this silica support the preferred choice for the pores. The photoisomerization of the olefin affording the
probing the ability of [2]pseudorotaxanes or bistable [2]rotax- maleamide derivative (pink cylinder) alters the binding affinity
anes to act as controllable gates of their pores. In this regard, of the unsaturated station by several kilocalories per mole19
a variety of mechanized silica having different macrocyclic and promotes the ring translocation towards the peptide-based
components, including cyclophanes,10 crown ethers,11 cucurbi- binding site for entrapping the cargo (Fig. 1a). A cis-to-trans olefin
turils12 and cyclodextrins,13 as gatekeepers of these nanocon- isomerization shuttles back the ring to the fumaramide station,
tainers, has been investigated. To the best of our knowledge, thus opening the pores for enabling the release of the RhB mole-
cules and allowing the reusability of these nanocontainers.
The matching of the porous mesostructure of the silica
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Departamento de Quımica Organica, Facultad de Quımica, Regional Campus of
International Excellence ‘‘Campus Mare Nostrum’’, Universidad de Murcia,
E-30100, Murcia, Spain. E-mail: ppberna@um.es
nanoparticles (ca. 100–200 nm diameter) containing hexagon-
ally arranged pores (ca. 2 nm diameter) and the relative sizes20
of the model cargo (RhB: 1.0 Â 1.5 nm) and the ring (benzylic
tetralactame: 0.8 Â 1.7 nm) supports the ability of the latter for
† Electronic supplementary information (ESI) available: Synthetic procedures,
experimental details and characterization. See DOI: 10.1039/c5cc04365d
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Scheme 1 Synthesis of the mesoporous silica nanoparticles MSN-E-6
functionalized with a photocontrollable peptide [2]rotaxane.
continuous extraction in a Soxhlet apparatus with hot ethanol.
Finally, the nucleophilic substitution of the bulky 2,6-diphenyl-4-
nitrophenoxy stopper17a of the fumaramide rotaxane S2 (see the
ESI†) by the amino groups of the latter silica particles yielded the
target MSN-E-6 with a surface gated with a two-station peptide
[2]rotaxane (Scheme 1).
Non-mechanized nanoparticles MSN-7 bearing an identical
linear fragment to that of MSN-E-6 were also prepared according
to the synthetic route outlined in Scheme 2. In this regard, the
amine 2 was prepared through a two consecutive amide coupling-
Boc deprotection protocol for incorporating the fumaramide and
peptide binding sites tethered by a dodecyl alkyl chain. Next,
the carbodiimide-mediated amide formation between the acid-
terminated surface of MSN-3 and the amine 2 led to silica
nanoparticles MSN-7 which were used as non-threaded model
materials, lacking the benzylic amide macrocycle.
The structure determination and characterization of the com-
pounds and materials shown in the Schemes 1 and 2 were accom-
plished by means of their analytical and spectral data (see the ESI†).
Although intense bands of the Si–O–Si stretching and bending
vibrations at 1080 and 800 cmÀ1 are present in the FTIR spectra
of all the silica materials shown in these schemes (see Fig. S3 and S4,
ESI†) the functional groups incorporated in each stage are also
evidenced in these spectra. Thus, the spectrum of MSN-3 shows a
weak band at 2953 cmÀ1 owing to the C–H stretching and a strong
one at 1726 cmÀ1 corresponding to the CQO stretching vibration of
Fig. 1 (a) Uptake and release of dye cargo molecules (RhB) from the pores of a
MCM-41 silica functionalized with a light-responsive peptide [2]rotaxane.
The movable lid is a tetralactame which locates on the preferred station
(fumaramide, red cylinder, or peptide, green cylinder) depending on its affinity
order. (b) Relative distance of the silicon atom to the first HB acceptor of the
stations that are connected by the thread, illustrating the feasibility of the RhB
loading. Cross dimensions (in nm) of the sealing tetralactame (blue ring) and the
RhB cargo molecule (purple block) showing up the size matching with the
average diameter (ca. 2 nm) of nanopores of the silica support. Molecular
modeling structures of the macrocycle and the RhB cation are shown.
Distances values were obtained from the CCDC database (see ref. 20).
keeping the cargo molecules inside the pores (Fig. 1b). In
addition, the relative distance of each station of the [2]rotaxane
with respect to the porous surface regulates the position of the
moveable lid and, consequently, it determines the limiting
cross-dimensions of the loading cargo molecules to be longer
than 0.7 nm but shorter than 2.7 nm.
Tetraethylorthosilicate as the silicon source and cetyltri-
methylammonium bromide (CTAB) as the template were used
in a base-catalyzed sol–gel protocol21 for affording the meso-
structured silica of the MCM-41 type (MSN-1). The size and the
mesoporous structure of the nanoparticles were studied by
scanning electron and transmission electron microscopy,
respectively (see Fig. S1a and b, ESI†).
The final MSN-E-6 system was assembled in a stepwise synthesis
from the thermoactivated22 silica nanoparticles (Scheme 1). First,
the spherical surface of MSN-1 was functionalized with nitrile
functions affording MSN-2 by heating with 2-cyanoethyltriethoxy-
silane in toluene. Further refluxing with 50% sulfuric acid provided
the surface-bound carboxylic acid MSN-3. Next, amide bond for-
mation between the carboxy groups of MSN-3 with the glycylglycine
building block S1 (see the ESI†) in the presence of N,N-dicyclo-
hexylcarbodiimide afforded the corresponding phthalimide-
functionalized particles MSN-4. Subsequent hydrazinolysis23 of the
preceding silica provided the amino-functionalized MSN-5 which
was completely separated from the phthalhydrazide byproduct by
Scheme 2 Synthesis of the mesoporous silica nanoparticles MSN-7
functionalized with the two-binding site thread precursor 2.
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the carboxy group. At the end of the transformations outlined in
Scheme 1, the FTIR spectrum of the interlocked MSN-E-6 shows two
intense CQO bands at 1646 and 1540 cmÀ1 corresponding to the
CQO stretching vibrations of the different amido groups of the
gatekeeper, also displaying intense bands in the range of 2983 and
2894 cmÀ1 due to the methylene groups present in this motif. 29Si
and 13C cross-polarization magic-angle spinning solid-state (SS)
NMR spectroscopies were also used to examine the grafting and
attachment of the different organic fragments into MCM-41. The 29Si
SSNMR spectrum (see Fig. S5, ESI†) of the silica MSN-2 shows two T
signals at À54.8 and À61.9 ppm corresponding to the silicon atoms
directly connected to the organic fragments and a Q signal at
À109.5 ppm ascribed to the rest of silicon atoms [Si(OSi)n(OH)4Àn
;
n = 2–4]. The measurement of the 13C SSNMR spectrum of each of
the new synthesized material confirmed the successive chemical
transformations toward the final mechanized silica (see the ESI†).
The spectrum of the targeted MSN-E-6 shows several sets of signals
at different chemical shift ranges: at 174.1–163.3 ppm appear those
corresponding to the carbon atoms of the carbonyl groups of the
amide functions, at 144.8–116.4 ppm those of the aromatic carbon
atoms and in the region between 70 and 10 ppm come out those of
the aliphatic carbon atoms (see Fig. S7, ESI†). The comparison of
Fig. 2 Comparison of the release profiles of RhB from MSN-Z-6 in
dichloromethane solution (a and c) and aqueous solution (b and d). These
experiments were carried out at 25 1C under light irradiation at 365 nm
(a and b) and without photoactivation (c and d). The inset displays the
absorption spectral change at 553 nm after the irradiation with 365 nm
light of a suspension of RhB-loaded MSN-Z-6.
this 13C SSNMR spectra with the one of the non-interlocked MSN-7 most energetically favorable binding site that, in this case, is the
materials displays noticeable differences evidencing the lack of the resulting fumaramide station far away from the surface of the
tetralactame in this latter material (see Fig. S7, ESI†) further proving nanoparticulate silica. Consequently, this latter irradiation pro-
the functionalization of MSN-E-6. Finally, TGA and elemental analy- motes the opening of the pores and the release of RhB, which
sis showed the rough estimation of the maximum amount of these was monitored by measuring the absorbance spectrum at different
interlocked motifs on the surface of MSN-E-6 to be approximately times (Fig. 2, inset). The obtained profile for the light-driven open-
0.30 mmol per gram of silica.
ing of the gatekeepers of this silica in dichloromethane shows a
Next the light-responsive gating behavior of MSN-E-6 was progressive delivery of the cargo reaching 50% of the maximum
investigated. The diffusion of the RhB cargo into the pores of this delivery in 50 min and needing 30 min more to reach a liberation of
light-responsive silica was carried out by soaking the mechanized 80% of the cargo (Fig. 2a). Using Beer–Lambert’s law, the RhB
nanoparticles in a stirred aqueous solution of the guest compound loading was calculated revealing that, for 3 mg of RhB-loaded
for 24 h. The surface-adsorbed excess of the cargo was thoroughly MSN-Z-6, 0.175 mmol (2.8 wt%) of the cargo was released (see ESI†).
washed and the resulting material was carefully dried. Then the
When the release experiment was carried out in water, the
pores of the material were sealed by means of a trans-to-cis photo- discharge of half the load lasted 200 min and the release profile
isomerization of the olefin station14c,18,24 by irradiation at 254 nm of the rest is extended for more than 5 h (Fig. 2b). Consequently
promoting the shifting of the tetralactame ring toward the peptide the remarkable positional integrity of the ring after photo-
station close to the surface of the nanoparticulate silica. This isomerization of the maleamide binding site to its trans isomer
operation kinetically entraps the guest molecules into the MSN-Z- promotes the expected release of the cargo in dichloromethane,
6 container and, then, the RhB loaded silica is thoroughly washed and less quickly in water due to the decrease of the ring
and dried. Although the accessibility of the cargo to the pores of discrimination. At this point it is convenient to remark that
MSN-1 decreased after its functionalization with the rotaxane, as it slow dynamics release profiles as that shown in Fig. 2b are
was confirmed by the TEM observation (see Fig. S14, ESI†); the desirable in therapeutic treatments as they allow a moderated
openings of the gated material still permitted the entrance of liberation of potent (and/or short half-life) drugs.2,3
enough RhB for carrying out the study of its controlled release.
It should also be noted that the interlocked nanogates of
The delivery of RhB from the nanopores of MSN-Z-6 was this container prevent significant premature release of the cargo
investigated in two different solvents, dichloromethane and water. dye molecules as revealed by the flat region (0–10 min) of the
For closely related interlocked systems18 it is known that the polarity profiles in both solvents (Fig. 2a and b). We also carried out
of the solvent affects the position of the ring over the peptide control experiments by monitoring the absorbance of RhB-
binding site. Thus, whereas in non-disrupting hydrogen bond loaded MSN-Z-6 in the absence of light in both studied solvents
solvents such as dichloromethane the ring is mainly located on (Fig. 2c and d), showing the absence of leaking processes under
the peptide station, in polar solvents the alkyl chain would act as a such conditions. Incidentally, these latter results also give an
second solvophobic station.18 For this purpose, a stirred suspension idea of the positional integrity of the ring over the peptide-based
of RhB-loaded MSN-Z-6 was irradiated at 365 nm for promoting the binding site in MSN-Z-6 (see ESI†). Release control experiments
cis-to-trans isomerization which triggers the ring translocation to the with the non-mechanized material RhB-loaded MSN-7 disclosed
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In summary, we have demonstrated the feasibility of building
mechanized silica nanoparticles using a peptide-based molecular
shuttle and MCM-41 as a mesoporous support. We have shown
the efficiency of this particular functionalization in actuating as
gatekeepers upon exposure to visible light irradiation displaying
different dosages depending on the working conditions. The
unprecedented integration of a benzylic tetralactame as a movable
lid allows a proficient uptake and release of RhB employed as the
model cargo. This mechanized material must be included in the
yet scarce number of described light-operated molecular nano-
valves and opens stimulating opportunities for the development
of a novel generation of smart nanocontainers by anchoring
amide-based interlocked compounds, which could be used as
controlled delivery systems.
This work was supported by the MINECO (CTQ2009-12216/
BQU and CTQ2014-56887-P) and the Fundacion Seneca-CARM
(Project 19240/PI/14). A.M.-C. thanks the Marie Curie COFUND/
U-IMPACT programs and the MINECO for postdoctoral contracts.
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´
We also thank Prof. Jose M. Gonzalez and Dr Almudena Torres of
the National Center for Electron Microscopy (UCM, Madrid) for
their helpful assistance with the TEM observations.
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