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WO2009097439A1 - Nano-devices having valves for controlled release of molecules - Google Patents

Nano-devices having valves for controlled release of molecules Download PDF

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Publication number
WO2009097439A1
WO2009097439A1 PCT/US2009/032451 US2009032451W WO2009097439A1 WO 2009097439 A1 WO2009097439 A1 WO 2009097439A1 US 2009032451 W US2009032451 W US 2009032451W WO 2009097439 A1 WO2009097439 A1 WO 2009097439A1
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WO
WIPO (PCT)
Prior art keywords
nanodevice
nanoparticles
chem
valve assembly
nanoparticle
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PCT/US2009/032451
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French (fr)
Inventor
Jeffrey I. Zink
Jie Lu
Fuyuhiko Tamanoi
Sarah Angelos
Fraser Stoddart
Qiaolin Chen
Andre Nel
Tian Xia
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The Regents Of The University Of California
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Publication of WO2009097439A1 publication Critical patent/WO2009097439A1/en
Priority to US12/841,331 priority Critical patent/US20100310465A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5115—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0097—Micromachined devices; Microelectromechanical systems [MEMS]; Devices obtained by lithographic treatment of silicon; Devices comprising chips
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/40—Cyclodextrins; Derivatives thereof

Definitions

  • the current invention relates to nano-devices, and more specifically to nano- nano-devices that have valves for controlled release of molecules contained therein.
  • Control of molecular transport in, through, and out of mesopores has important potential applications in nanoscience including fluidics and drug delivery.
  • Surfactant-templated silica (Kresge, C. T.; Leonowicz, M. E.; Roth, W. J.; Vartuli, J. C; Beck, J. S. Nature 1992, 359, 710-712) is a versatile material in which ordered arrays of mesopores can be easily synthesized, providing a convenient platform for attaching molecules that undergo large amplitude motions to control transport.
  • Mesostructured silica is transparent (for photocontrol and spectroscopic monitoring), and can be fabricated into useful morphologies (thin films (Lu, Y.
  • nanovalves in therapeutic applications, for example, it is imperative that they not only employ biocompatible components but that they also operate under physiological conditions.
  • a recognition and binding motif which operates in aqueous media has to be identified, tried and tested. Consequently, there remains a need for improved nano-devices.
  • a nanodevice has a containment vessel, defining a storage chamber therein and defining at least one port to provide transfer of matter to or from the storage chamber, and a valve assembly attached to the containment vessel.
  • the valve assembly is operable in an aqueous environment.
  • the nanodevice comprises biocompatible materials and has a maximum dimension of less than about 1 ⁇ m and greater than about 50 nm.
  • a composition of matter according to some embodiments of the current invention has a plurality of nanoparticles, each defining a storage chamber therein, and a guest material contained within the storage chambers defined by the nanoparticles, the guest material being substantially chemically non-reactive with the nanoparticles.
  • Each nanoparticle of the plurality of nanoparticles has a valve assembly to allow the guest material contained within the storage chambers to be selectively released, and each nanoparticle of the plurality of nanoparticles comprises biocompatible materials in a composition thereof and has a maximum dimension of less than about 1 ⁇ m and greater than about 50 run.
  • a method of administering at least one of a biologically active substance, a therapeutic substance, a neutraceutical substance, a cosmetic substance or a diagnostic substance includes administering a composition to at least one of a person, an animal, a plant, or an organism, the composition comprising nanoparticles therein.
  • the nanoparticles contain the at least one of the biologically active substance, therapeutic substance, neutraceutical substance, cosmetic substance or diagnostic substance therein
  • the method also includes selectively opening a valve in each of the nanoparticles to allow the at least one of the biologically active substance, therapeutic substance, neutraceutical substance, cosmetic substance or diagnostic substance to escape from the nanoparticles.
  • FIGS 1A-1C provide schematic illustrations of a nano-device and methods of production/operation according to an embodiment of the current invention.
  • the alkyne-functionalized mesoporous silica nanoparticles MCM-41 are loaded (a— >b) with Rhodamine B (RhB) molecules, and capped (a ⁇ b) with CB[6] during the CB[6]-catalyzed alkyne-azide 1,3-dipolar cycloadditions, followed by washing away the excess of substrates.
  • RhB molecules are released (b— >c) by switching off the ion-dipole interactions between the CB[6] rings and the bisammonium stalks upon raising the pH.
  • Figure 2 is schematic illustration to help explain additional embodiments of the current invention.
  • Figure 3 shows (a) The XRD pattern and (b) SEM image of mesoporous silica nanoparticles ⁇ 3 c CB[6] ⁇ produced according to an embodiment of the current invention.
  • Figures 4A and 4B illustrate synthetic routes to mesoporous silica nanoparticles functionalized with CB [6] / dialkylammonium pseudorotaxanes according to some embdiments of the current invention, i) and iv) propargyl bromide, MeOH, 50 0 C, overnight; ii) and v) 0.5 mM RhB, H 2 O, RT, 5 h; then CB[6], 2N HCl, RT, 3 d; iii) NaNH 2 , PhMe, heat under reflux, 12 h.
  • Figures 5A and 5B provide data taken for the release of the RhB guest molecules monitored by following the luminescence intensity of the solution of (a) nanoparticles with longer linkers ⁇ 3 c CB[6] ⁇ and (b) nanoparticles with shorter linkers ⁇ 6 c CB[6] ⁇ (upper trace) according to two embodiments of the current invention. Control experiments without changing pH (lower trace), with respect to time were also performed. Whereas (a) exhibits substantial leakage, as indicated by the premature rise in luminescence intensity, (b) shows no leakage.
  • FIG. 6 is a schematic representation of a cucurbit[6]uril-based pH-driven molecular nanovalve system according to an embodiment of the current invention in which the cucurbituril at the pore openings gate the release of material (e.g., drug molecules), i) PhN(Boc)(CH 2 ) 6 N(Boc)(CH 2 ) 4 NH 2 , Methanol, reflux; Trifluoroacetic acid; adjust pH to larger than 6.73; ii) loading drug / dye; capping with cucurbit[6]uril; iii) adjust pH to acidic less than 6.73 to release the trapped molecules.
  • material e.g., drug molecules
  • FIG. 1A is a schematic illustration of a nanodevice 100 according to an embodiment of the current invention.
  • the nanodevice 100 has a containment vessel 102 defining a storage chamber 104 therein and defining at least one port 106 to provide access for the transfer of material 108 into and/or out of the storage chamber 104.
  • the containment vessel 102 can be a mesoporous silica nanopaiticle in some embodiments of the current invention.
  • the material 108 can be molecules which are sometimes also referred to as guest molecules herein.
  • the Rhodamine B molecules illustrated schematically in Figures 1 A-IC are only one example of a very wide range of possible materials 108 that can be selected based on the desired application.
  • the material 108 is not limited to this example.
  • the material 108 does not always have to be in the form of molecules in some embodiments of the current invention.
  • the material 108 is also referred to as cargo herein since it can be loaded into the nanodevice 100.
  • the nanodevice 100 also has a valve assembly 110 attached to the containment vessel 102.
  • the valve assembly 110 has a valve 112 arranged proximate the at least one port 106 and has a structure suitable to substantially prevent material 108 after being loaded into the storage chamber 104 from being released while the valve 112 is arranged in a blocking configuration.
  • the valve assembly 110 is responsive to a change in pH such that the valve 112 moves in the presence of the change in pH to allow the material 108 to be released from the storage chamber 104.
  • the nanodevice 100 has a maximum dimension of less than about 1 ⁇ m and greater than about 50 nm in some embodiments.
  • the nanodevice 100 has a maximum dimension of less than about 400 nm and greater than about 50 nm.
  • the nanodevice 100 is greater than about 400 nm, it becomes too large to enter into biological cells.
  • the nanodevice 100 is less than about 50 nm, it becomes less able to contain a useful number of molecules therein.
  • the nanodevices are less than about 300 nm, they become more useful in some applications to biological systems.
  • nanodevices having a maximum dimension in the range of about 50 nm to about 150 nm are suitable.
  • the containment vessel can be, but is not limited to, a mesoporous silica nanoparticle according to some embodiments of the current invention.
  • the material or molecules of interest to be stored in and released from the containment vessels 102 can include, but are not limited to, biologically active substances.
  • biologically active substance as used herein is intended to include all compositions of matter that can cause a desired effect on biological material or a biological system and may include in situ and in vivo biological materials and systems.
  • the biologically active substance may be selected from such substances that have molecular sizes such that they can be loaded into the nanodevices, and can also be selected from such substances that don't react with the nanodevices.
  • a biological system may include a person, animal or plant, for example.
  • Bioly active substances may include, but are not limited to, the following:
  • Small molecule drugs for anticancer treatment such as camptothecin, paclitaxel and doxorubicin;
  • Ophthalmic drugs such as flurbiprofen, levobbunolol and neomycin
  • Nucleic acid reagents such as siRNA and DNAzymes
  • Small molecule drugs for immune suppression such as rapamycin, FK506, cyclosporine;
  • any pharmacological compound that can fit into the nanodevice e.g., analgesics, NSAIDS, steroids, hormones, anti-epileptics, anti-arrythmics, anti-hypentensives, antibiotics, antiviral agents, anticoagulants, platelet drugs, cardiostimulants, cholesterol lowering agents, etc.
  • Molecules of interest can also include imaging and/or tracking substances.
  • Imaging and/or tracking substances may include, but are not limited to, dye molecules such as propidium iodide, fluorescein, rhodamine, green fluorescent protein and derivatives thereof.
  • Figure 2 is a schematic illustration to facilitate the explanation of additional embodiments of the current invention.
  • Figure 2 does not show storage chambers, such as a plurality of pores of a mesoporous silica nanoparticle, and does not show valve assemblies.
  • the nanodevices can include a plurality of anionic molecules attached to the surface of the nanodevice as is illustrated schematically in Figure 2.
  • the anionic molecules can be phosphonate moieties attached to the outer surface of the nanodevice to effectively provide a phosphonate coating on the nanodevice.
  • the anionic molecules can be trihydroxysilylpropyl methylphosphonate molecules according to an embodiment of the current invention.
  • This phosphonate coating can provide a negative zeta potential that is responsible for electrostatic repulsion to keep such submicron structures dispersed in an aqueous tissue culture medium, for example.
  • This dispersion can also be important for keeping the particle size limited to a size scale that allows endocytic uptake (i.e., hinders clumping).
  • the negative zeta potential may play a role in the formation of a protein corona on the particle surface that can further assist cellular uptake in some applications. It is possible that this could include molecules such as albumin, transferrin or other serum proteins that could participate in receptor-mediated uptake.
  • the nanodevice 100 can also be functionalized with molecules in addition to anionic molecules according to some embodiments of the current invention.
  • a plurality of folate ligands can be attached to the outer surface of the containment vessel 102 according to some embodiments of the current invention, as is illustrated schematically in Figure 2 (valve assemblies are not shown for clarity).
  • the nanodevice 100 can also include fluorescent molecules contained in or attached to the containment vessel 102.
  • fluorescent molecules may be attached inside the pores of mesoporous silica nanoparticles according to some embodiments of the current invention.
  • the fluorescent molecules can be an amine-reactive fluorescent dye attached by being conjugated with an amine-functionalized silane according to some embodiments of the current invention.
  • some fluorescent molecules without limitation, can include fluorescein isothiocyanate, NHS-fluorescein, rhodamine B isothiocyanate, tetramethylrhodamine B isothiocyanate, and/or Cy5.5 NHS ester.
  • the nanodevices 100 may further comprise one or more nanoparticle of magnetic material formed within the containment vessel 102, as is illustrated schematically in Figure 2 for one particular embodiment.
  • the nanoparticles of magnetic material can be iron oxide nanoparticles according to an embodiment of the current invention.
  • the broad concepts of the current invention are not limited to only iron oxide materials for the magnetic nanoparticles.
  • Such nanoparticles of magnetic material incorporated in the submicron structures can permit them to be tracked by magnetic resonance imaging (MRI) systems and/or manipulated magnetically, for example.
  • MRI magnetic resonance imaging
  • the nanodevices 100 may further comprise one or more nanoparticle of a material that is optically dense to x-rays.
  • gold nanoparticles may be formed within the containment vessel 102 of the nanodevice 100 according to some embodiments of the current invention.
  • CB[6] cucurbit[6]uril
  • CB[6] a pumpkin-shaped polymacrocycle with D ⁇ h symmetry consisting of six glycouril units strapped together by pairs of bridging methylene groups between nitrogen atoms ((a) J. Lagona, P. Mukhopadhyay, S. Chakrabarti, L. Isaacs, Angew. Chem. 2005, 117, 4922 ⁇ 949; Angew. Chem. Int. Ed.
  • CB[6] Another important characteristic of CB[6] is its ability (a) W. L. Mock, T. A. Irra, J. P. Wepsiec, T. L.
  • the silica supports employed were ⁇ 400 run diameter spherical particles which contain ordered 2D hexagonal arrays of tubular pores ( ⁇ 2 nm pore diameters with ⁇ 4 nm lattice spacing) prepared using a base-catalyzed sol-gel method (a) S. Huh, J. W. Wiench, J.-C. Yoo, M. Pruski, V. S.-Y. Lin, Chem. Mater. 2003, 15, 4247 ⁇ 256; b) M. Grun, I. Laner, K. K. Unger, Adv. Mater. 1997, 9, 254-257; c) Y. Lu, R. Ganguli, C A. Drewien, M. T. Anderson, C. J.
  • FIG. 4A This system was designed ( Figure 4A) such that the valve assembly components can be assembled in a stepwise, divergent manner from the nanoparticle surface outwards according to an embodiment of the current invention.
  • the nanoparticles were heated under reflux in an aminopropyl-triethoxysilane (APTES) solution, resulting in the amino-modif ⁇ ed nanoparticles 1.
  • APTES aminopropyl-triethoxysilane
  • the empty nanopores in 2 were loaded with fluorescent guest molecules by soaking the nanoparticles in a 0.5 mM solution of Rhodamine B (RhB) for 5 h.
  • RhB Rhodamine B
  • the preparation of the valve systems was completed by means of an interfacial CB[6]-catalyzed 1,3- dipolar cycloaddition of the silica-supported alkyne function and 2-azidoethylamine to yield CB[6] / 1,3-disubstituted triazole [2]pseudorotaxanes ⁇ 3 cz CB[6] ⁇ spread all over the silica surface.
  • RhB RhB-capped nanoparticles were washed extensively with MeOH and H 2 O to remove adsorbed molecules from the surface. A portion of the washed nanoparticles (-15 mg) was placed in the bottom corner of a cuvette, and H 2 O (12 mL) was added carefully. A 10 mW, 514 nm probe beam, directed into the water above the nanoparticles, was used to excite the dye molecules as they are released from the nanoparticles. The emission spectrum of RhB was recorded as a function of time at 1 -second intervals.
  • valve systems were opened by adjusting the pH of the solution to 10 through the addition of 2M NaOH. Plots of the dissolved dye intensities as functions of time - the release profiles shown in Figure 5 - indicate an increase in the amount of dye released upon base activation, demonstrating that the valve systems do indeed open at high pH values.
  • valve assembly activation includes (i) the size of the valve assembly components, (ii) the positioning of the valve systems relative to the orifices of the nanopores and (iii) the length of the linker.
  • the outer diameter of the CB[6] ring (a) J. Lagona, P. Mukhopadhyay, S. Chakrabarti, L. Isaacs, Angew. Chem. 2005, 117, 4922- 4949; Angew. Chem. Int. Ed.
  • CMTES chloromethyl-triethoxysilane
  • the use of the shorter linker curtails the length of the stalk of the pseudorotaxane in ⁇ 6 c CB[6] ⁇ such that the CB[6] ring is positioned ⁇ 0.2 nm closer to the surface of the silica nanoparticle. This subtle change in linker length tightens up the valve systems sufficiently to prevent leakage and the release profile illustrated in Figure 5B is observed.
  • a concern regarding the operation of these valve systems is the stability of the silica supports under the high pH conditions required for the valve assembly to function.
  • Activation of the valve systems relies on deprotonation of the primary alkylammonium and secondary dialkylammonium centers (p ⁇ T a ⁇ 10) so as to disrupt the ion-dipole interactions responsible for binding of the CB[6] rings.
  • base NaOH
  • SEM images and X-ray diffraction patterns of the functionalized nanoparticles were compared before and after exposure to base. No noticeable differences in either the nanoparticle morphology or mesostructure were observed, indicating that the structure of the nanoparticle supports is preserved during the controlled release process.
  • valve systems based on CB [6] rings as the gatekeepers can play a significant role in the future of functionalized mesoporous silica nanoparticles for biotechnological and medical applications
  • J. Lu M. Liong, J. I. Zink, F.
  • CTAB cetyltrimethyl-ammonium bromide
  • the solvent-extracted nanoparticles were collected by vacuum filtration and washed thoroughly with MeOH.
  • Amino-modification of the silica surface was performed by suspending the nanoparticles (100 mg) in a solution of 3- aminopropyltriethoxy-silane (APTES) (1 mM) in dry PhMe (10 mL) and heating them under reflux for 24 h.
  • the nanoparticles were collected by filtration, washed thoroughly with PhMe, and dried under vacuum.
  • APTES 3- aminopropyltriethoxy-silane
  • [0039] 2 Refluxing aminopropyl-modified MCM-41 nanoparticles 1 in a MeOH solution of propargyl bromide for 24 h under N 2 (1 atm) afforded the alkyne-modif ⁇ ed MCM-41, resulting in silica nanoparticles 2 after washing them extensively with MeOH and drying them under vacuum.
  • the nanoparticles were characterized by means of FTIR, XRD, SEM, and DLS.
  • CMTES chloromethyl- triethoxysilane
  • Nanoparticles 5 were first modified with propargyl bromide by heating under reflux in MeOH under N 2 for 24 h to obtain the alkyne-terminated silica nanoparticles. Loading with RhB and completion of the valve assembly synthesis was achieved as described for valve assembly ⁇ 3 c CB [6] ⁇ . They were characterized by means of FT-IR, XRD and SEM.
  • a bistable CB[6]/triamine pseudorotaxane-based nanodevice having a valve assembly can be operated under mildly acidic conditions (Figure 6).
  • the important feature of the triamine thread functionalized onto the silica surface is that the pair of nitrogen atoms not connected directly to the benzene ring ought to be 10 6 -fold more basic than the one which is, so the pH changes will result in changes in the protonation state of the aniline N atom, which provides the possibility of the relocation of CB[6] host molecule.
  • CB[6] will move to the protonated diaminohexane site forming a more stable complex than with diprotonated diaminobutane, thus open the pores and release the drug/dye molecules trapped in the pores. This process is reversible due to the relocation of CB [6] when the pH is changed back to 6.73.

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Abstract

A nanodevice has a containment vessel, defining a storage chamber therein and defining at least one port to provide transfer of matter to or from the storage chamber, and a valve assembly attached to the containment vessel. The valve assembly is operable in an aqueous environment. The nanodevice comprises biocompatible materials and has a maximum dimension of less than about 1 μm and greater than about 50 nm.

Description

NANO-DEVICES HAVING VALVES FOR CONTROLLED RELEASE OF
MOLECULES
CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to U.S. Provisional Application No. 61/006,725 filed January 29, 2008, the entire contents of which are hereby incorporated by reference.
[0002] The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require that the patent owner license others on reasonable terms as provided for by the terms of Grant Nos. CHE 0507929 and DMR 0346601, awarded by the National Science Foundation, and of Grant No. 32737, awarded by NIH.
BACKGROUND
1. Field of Invention
[0003] The current invention relates to nano-devices, and more specifically to nano- nano-devices that have valves for controlled release of molecules contained therein.
2. Discussion of Related Art
[0004] Control of molecular transport in, through, and out of mesopores has important potential applications in nanoscience including fluidics and drug delivery. Surfactant-templated silica (Kresge, C. T.; Leonowicz, M. E.; Roth, W. J.; Vartuli, J. C; Beck, J. S. Nature 1992, 359, 710-712) is a versatile material in which ordered arrays of mesopores can be easily synthesized, providing a convenient platform for attaching molecules that undergo large amplitude motions to control transport. Mesostructured silica is transparent (for photocontrol and spectroscopic monitoring), and can be fabricated into useful morphologies (thin films (Lu, Y. F.; Ganguli, R.; Drewien, C. A.; Anderson, M. T.; Brinker, C. J.; Gong, W. L.; Guo, Y. X.; Soyez, H.; Dunn, B.; Huang, M. H.; Zink, J. I. Nature 1997, 389, 364-368), particles (Kresge, C. T.; Leonowicz, M. E.; Roth, W. J.; Vartuli, J. C; Beck, J. S. Nature 1992, 359, 710-712; Huh, S.; Wiench, J. W.; Yoo, J. C; Pruski, M.; Lin, V. S. Y. Chem. Mater. 2003, 15, 4247-4256)) with designed pore sizes and structures. [0005] Mesoporous silica nanoparticles coated with molecular valves hold the promise to encapsulate a pay load of therapeutic compounds, to transport them to specific locations in the body, and to release them in response to either external or cellular stimuli. Sequestering drug molecules serves the dual purpose of protecting the payload from enzymatic degradation, while reducing the undesired side-effects associated with many drugs. Although these benefits are common to pro-drug strategies ((a) Hirano, T.; Klesse, W.; Ringsdorf, H. Makromol. Chem. 1979, 180, 1125. (b) Kataoka, K.; Harada, A.; Nagasaki, Y. Adv. Drug Delivery Rev. 2001, 47, 113. (c) Padilla De Jesus, O. L.; Ihre H. R.; Gagne, L.; Frechet, J. M. J.; Szoka, F. C. Jr. Bioconjug Chem. 2002, 13, 453. (d) Denny, W. A. Cancer Invest. 2004, 22, 604. (e) Lee, C. C; MacKay, J. A.; Frechet, J. M. J., et al. Nat. Biotechnol. 2005, 23, 1517. (f) Duncan, R.; Ringsdorf, H.; Satchi-Fainaro, R. J. Drug Target. 2006, 14, 337. (g) Tietze, L. F.; Major, F.; Schuberth, I. Angew. Chem. Int. Ed. 2006, 45, 6574), the nanoparticle-supported nano valve assembly does not require covalent modification of the therapeutic compounds and allows for the release of many drug molecules upon each stimulus event ((a) Duncan, R.; Vicent, M. J.; Greco, F., et al. Endocr-Relat. Cancer. 2005, 12, S189. (b) Pantos, A.; Tsiourvas, D.; Nounesis, G.; Paleos, C. M. Langmuir 2005, 21, 7483. (c) Dhanikula, R. S.; Hildgen, P. Bioconjug. Chem. 2006, 17, 29. (d) Darbre, T.; Reymond, J.-L. Ace. Chem. Res. 2006, 39, 925. (e) Gopin, A.; Ebner, S.; Attali, B.; Shabat, D. Bioconjug. Chem. 2006, 17, 1432). Recently, it was demonstrated that mesoporous silica nanoparticles, not modified with molecular machinery, can deliver the water-insoluble drug camptothecin into human pancreatic cancer cells with very high efficiency (Lu, J. Liong, M.; Zink, J.I.; Tamanoi, F. Small 2007, 3, 1341). For more sophisticated drug delivery applications, the ability to functionalize ((a) Hernandez, R.; Tseng, H.-R.; Wong, J. W.; Stoddart, J. F.; Zink, J. I. J. Am. Chem. Soc. 2004, 126, 3370. (b) Nguyen, T. D.; Tseng, H.-R.; Celestre, P. C; Flood, A. H.; Liu, Y.; Stoddart, J. F.; Zink, J. I. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 10029. (c) Nguyen, T. D.; Leung, K. C-F.; Liong, M.; Pentecost, C. D.; Stoddart, J. F.; Zink, J. I. Org. Lett. 2006, 8, 3363. (d) Leung, K. C-F.; Nguyen, T. D.; Stoddart, J. F.; Zink, J. I. Chem. Mater. 2006, 18, 5919. (e) Nguyen, T. D.; Liu, Y.; Saha, S.; Leung, K. C-F.; Stoddart, J. F.; Zink, J. I. J. Am. Chem. Soc. 2007, 129, 626. (f) Nguyen, T. D.; Leung, K. C F.; Liong, M.; Liu, Y.; Stoddart, J. F.; Zink, J. I. Adv. Fund. Mater. 2007, 17, 2101. (g) Saha, S.; Leung, K. C F.; Nguyen, T. D.; Stoddart, J. F.; Zink, J. 1. Adv. Funct. Mater. 2007, 17, 685. (h) Angelos, S.; Johansson, E.; Stoddart, J. F.; Zink, J. I. Adv. Funct. Mater. 2007, ASAP article) nanoparticles with nanovalvcs and other control led-release mechanisms has become an area of widespread interest ((a) MaI, N. K.; Fujiwara. M.; Tanaka, Y.; Nature 2003, 421, 350. (b) Gin, S.; Trewyn, B. G.; Stellmaker, M. P.; Lin, V. S. Y. Angew. Chem. Int. Ed 2005, 44, 5038. (c) Kocer, A.; Walko, M.; Meijberg, W.; Feringa, B. L. Science 2005, 309, 755.
(d) Angelos, S.; Choi, E.; Vogtle, F.; De Cola, L.; Zink, J. I. J. Phys. Chem. C 2007, 111, 6589.
(e) Slowing, L; Trewyn, B. G.; Giri, S.; Lin, V. S. Y. Adv. Fund. Mater. 2007, 17, 1225). Previously, we have demonstrated the operation of molecular and supramolecular valves in non- biologically relevant contexts using redox (Hernandez, R.; Tseng, H.-R.; Wong, J. W.; Stoddart, J. F.; Zink, J. I. J. Am. Chem. Soc. 2004, 126, 3370. Nguyen, T. D.; Tseng, H.-R.; Celestre, P. C; Flood, A. H.; Liu, Y.; Stoddart, J. F.; Zink, J. I. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 10029. Nguyen, T. D.; Liu, Y.; Saha, S.; Leung, K. C-F.; Stoddart, J. F.; Zink, J. I. J. Am. Chem. Soc. 2007, 129, 626.), pH (Nguyen, T. D.; Leung, K. C-F.; Liong, M.; Pentecost, C. D.; Stoddart, J. F.; Zink, J. I. Org. Lett. 2006, 8, 3363.), competitive binding (Leung, K. C-F.; Nguyen, T. D.; Stoddart, J. F.; Zink, J. I. Chem. Mater. 2006, 18, 5919.), and light (Nguyen, T. D.; Leung, K. C. F.; Liong, M.; Liu, Y.; Stoddart, J. F.; Zink, J. I. Adv. Fund. Mater. 2007, 17, 2101) as actuators. Other controlled release systems include photoresponsive azobenzene-based nanoimpellers (Angelos, S.; Choi, E.; Vogtle, F.; De Cola, L.; Zink, J. I. J. Phys. Chem. C 2007, 111, 6589), chemically removable CdS nanoparticle caps (Giri, S.; Trewyn, B. G.; Stellmaker, M. P.; Lin, V. S. Y. Angew. Chem. Int. Ed. 2005, 44, 5038. Slowing, I.; Trewyn, B. G.; Giri, S.; Lin, V. S. Y. Adv. Fund. Mater. 2007, 17, 1225.), and reversible photo-dimerization of tethered coumarins (MaI, N. K.; Fujiwara, M.; Tanaka, Y.; Nature 2003, 421, 350).
[0006] Since most of the traditional nanovalve designs have been based on
[2]pseudorotaxanes (P. R. Ashton, D. Philp, N. Spencer, J. F. Stoddart, J. Chem. Soc, Chem. Commun. 1991, 1677-1679) and bistable [2]rotaxanes ((a) J. O. Jeppesen, J. Perkins, J. Becher, J. F. Stoddart, Org. Lett. 2000, 2, 3547-3550; b) J. O. Jeppesen, J. Perkins, J. Becher, J. F. Stoddart, Angew. Chem. 2001, 113, 1256-1261; Angew. Chem. Int. Ed. 2001, 40, 1216-1221; c) T. Yamamoto, H.-R. Tseng, J. F. Stoddart, V. Balzani, A. Credi, F. Marchioni, M. Venturi, Collect. Czech. Chem. Commun. 2003, 68, 1488-1514; d) H.-R. Tseng, S. A. Vignon, J. F. Stoddart, Angew. Chem. 2003, /75, 1529-1533; Angew. Chem. Int. Ed. 2003, 42, 1491-1495; e) H.-R. Tseng, S. A. Vignon, P. C. Celestre, J. Perkins, J. O. Jeppesen, A. Di Fabio, R. Ballardini, M. T. Gandolfi, M. Venturi, V. Balzani, J. F. Stoddart, Chem. Eur. J. 2004, 10, 155-172; f) Y. Liu, A. H. Flood, P. A. Bonvallet, S. A. Vignon, B. H. Northrop, H.-R. Tseng, J. O. Jeppesen, T. J. Huang, B. Brough, M. Bailer, S. Magonov, S. D. Solares, W. A. Goddard, C-M. Ho, J. F. Stoddart, J. Am. Chem. Soc. 2005, 127, 9745-9759; g) J. O. Jeppesen, S. Nygaard, S. A. Vignon, J. F. Stoddart, Eur. J. Org. Chem. 2005, 196-220; h) S. Nygaard, K. C-F. Leung, I. Aprahamian, T. Ikeda, S. Saha, B. W. Laursen, S.-Y. Kim, S. W. Hansen, P. C. Stein, A. H. Flood, J. F. Stoddart, J. O. Jeppesen, J. Am. Chem. Soc. 2007, 129, 960-970; i) I. Aprahamian, W. R. Dichtel, T. Ikeda, J. R. Heath, J. F. Stoddart, Org. Lett. 2007, P, 1287-1290; j) I. Aprahamian, T. Yasuda, T. Ikeda, S. Saha, W. R. Dichtel, K. Isoda, T. Kato, J. F. Stoddart, Angew. Chem. 2007, 119, 4759-4763; Angew. Chem. Int. Ed 2007, 46, 4675-4679) that rely upon donor-acceptor and hydrogen bonding interactions between the ring and stalk components, they are limited largely to use in organic solvents (C. Park, K. Oh, S. C. Lee, C. Kim, Angew. Chem. 2007, 119, 1477-1479; Angew. Chem. Int. Ed. 2007, 46, 1455-1457). However, in order to realize the potential of nanovalves in therapeutic applications, for example, it is imperative that they not only employ biocompatible components but that they also operate under physiological conditions. For nanovalves to be viable in biological environments, a recognition and binding motif which operates in aqueous media has to be identified, tried and tested. Consequently, there remains a need for improved nano-devices.
SUMMARY
[0007] A nanodevice according to some embodiments of the current invention has a containment vessel, defining a storage chamber therein and defining at least one port to provide transfer of matter to or from the storage chamber, and a valve assembly attached to the containment vessel. The valve assembly is operable in an aqueous environment. The nanodevice comprises biocompatible materials and has a maximum dimension of less than about 1 μm and greater than about 50 nm.
[0008] A composition of matter according to some embodiments of the current invention has a plurality of nanoparticles, each defining a storage chamber therein, and a guest material contained within the storage chambers defined by the nanoparticles, the guest material being substantially chemically non-reactive with the nanoparticles. Each nanoparticle of the plurality of nanoparticles has a valve assembly to allow the guest material contained within the storage chambers to be selectively released, and each nanoparticle of the plurality of nanoparticles comprises biocompatible materials in a composition thereof and has a maximum dimension of less than about 1 μm and greater than about 50 run.
[0009] A method of administering at least one of a biologically active substance, a therapeutic substance, a neutraceutical substance, a cosmetic substance or a diagnostic substance includes administering a composition to at least one of a person, an animal, a plant, or an organism, the composition comprising nanoparticles therein. The nanoparticles contain the at least one of the biologically active substance, therapeutic substance, neutraceutical substance, cosmetic substance or diagnostic substance therein The method also includes selectively opening a valve in each of the nanoparticles to allow the at least one of the biologically active substance, therapeutic substance, neutraceutical substance, cosmetic substance or diagnostic substance to escape from the nanoparticles.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Further objectives and advantages will become apparent from a consideration of the description, drawings, and examples.
[0011] Figures 1A-1C provide schematic illustrations of a nano-device and methods of production/operation according to an embodiment of the current invention. Graphical representations of operating supramolecular nanovalves {3 c CB [6]} and {6 c CB [6]}. The alkyne-functionalized mesoporous silica nanoparticles MCM-41 are loaded (a— >b) with Rhodamine B (RhB) molecules, and capped (a→b) with CB[6] during the CB[6]-catalyzed alkyne-azide 1,3-dipolar cycloadditions, followed by washing away the excess of substrates. RhB molecules are released (b— >c) by switching off the ion-dipole interactions between the CB[6] rings and the bisammonium stalks upon raising the pH.
[0012] Figure 2 is schematic illustration to help explain additional embodiments of the current invention. [0013] Figure 3 shows (a) The XRD pattern and (b) SEM image of mesoporous silica nanoparticles {3 c CB[6]} produced according to an embodiment of the current invention.
[0014] Figures 4A and 4B illustrate synthetic routes to mesoporous silica nanoparticles functionalized with CB [6] / dialkylammonium pseudorotaxanes according to some embdiments of the current invention, i) and iv) propargyl bromide, MeOH, 50 0C, overnight; ii) and v) 0.5 mM RhB, H2O, RT, 5 h; then CB[6], 2N HCl, RT, 3 d; iii) NaNH2, PhMe, heat under reflux, 12 h.
[0015] Figures 5A and 5B provide data taken for the release of the RhB guest molecules monitored by following the luminescence intensity of the solution of (a) nanoparticles with longer linkers {3 c CB[6]} and (b) nanoparticles with shorter linkers {6 c CB[6]} (upper trace) according to two embodiments of the current invention. Control experiments without changing pH (lower trace), with respect to time were also performed. Whereas (a) exhibits substantial leakage, as indicated by the premature rise in luminescence intensity, (b) shows no leakage.
[0016] Figure 6 is a schematic representation of a cucurbit[6]uril-based pH-driven molecular nanovalve system according to an embodiment of the current invention in which the cucurbituril at the pore openings gate the release of material (e.g., drug molecules), i) PhN(Boc)(CH2)6N(Boc)(CH2)4NH2, Methanol, reflux; Trifluoroacetic acid; adjust pH to larger than 6.73; ii) loading drug / dye; capping with cucurbit[6]uril; iii) adjust pH to acidic less than 6.73 to release the trapped molecules.
DETAILED DESCRIPTION
[0017] Some embodiments of the current invention are discussed in detail below. In describing embodiments, specific terminology is employed for the sake of clarity. However, the invention is not intended to be limited to the specific terminology so selected. A person skilled in the relevant art will recognize that other equivalent components can be employed and other methods developed without departing from the broad concepts of the current invention. All references cited herein are incorporated by reference as if each had been individually incorporated. [0018] Figure IA is a schematic illustration of a nanodevice 100 according to an embodiment of the current invention. The nanodevice 100 has a containment vessel 102 defining a storage chamber 104 therein and defining at least one port 106 to provide access for the transfer of material 108 into and/or out of the storage chamber 104. The containment vessel 102 can be a mesoporous silica nanopaiticle in some embodiments of the current invention. The material 108 can be molecules which are sometimes also referred to as guest molecules herein. The Rhodamine B molecules illustrated schematically in Figures 1 A-IC are only one example of a very wide range of possible materials 108 that can be selected based on the desired application. The material 108 is not limited to this example. In addition, the material 108 does not always have to be in the form of molecules in some embodiments of the current invention. The material 108 is also referred to as cargo herein since it can be loaded into the nanodevice 100. The nanodevice 100 also has a valve assembly 110 attached to the containment vessel 102. The valve assembly 110 has a valve 112 arranged proximate the at least one port 106 and has a structure suitable to substantially prevent material 108 after being loaded into the storage chamber 104 from being released while the valve 112 is arranged in a blocking configuration. The valve assembly 110 is responsive to a change in pH such that the valve 112 moves in the presence of the change in pH to allow the material 108 to be released from the storage chamber 104.
[0019] The nanodevice 100 has a maximum dimension of less than about 1 μm and greater than about 50 nm in some embodiments. For some embodiments, the nanodevice 100 has a maximum dimension of less than about 400 nm and greater than about 50 nm. When the nanodevice 100 is greater than about 400 nm, it becomes too large to enter into biological cells. On the other hand, when the nanodevice 100 is less than about 50 nm, it becomes less able to contain a useful number of molecules therein. Furthermore, when the nanodevices are less than about 300 nm, they become more useful in some applications to biological systems. For some embodiments of the current invention, nanodevices having a maximum dimension in the range of about 50 nm to about 150 nm are suitable. The containment vessel can be, but is not limited to, a mesoporous silica nanoparticle according to some embodiments of the current invention.
[0020] The material or molecules of interest to be stored in and released from the containment vessels 102 can include, but are not limited to, biologically active substances. The term "biologically active substance" as used herein is intended to include all compositions of matter that can cause a desired effect on biological material or a biological system and may include in situ and in vivo biological materials and systems. The biologically active substance may be selected from such substances that have molecular sizes such that they can be loaded into the nanodevices, and can also be selected from such substances that don't react with the nanodevices. A biological system may include a person, animal or plant, for example.
[0021] Biologically active substances may include, but are not limited to, the following:
(1) Small molecule drugs for anticancer treatment such as camptothecin, paclitaxel and doxorubicin;
(2) Ophthalmic drugs such as flurbiprofen, levobbunolol and neomycin;
(3) Nucleic acid reagents such as siRNA and DNAzymes;
(4) Small molecule antioxidants such as n-acetylcysteine, sulfurophane, vitamin E, vitamin C, etc.;
(5) Small molecule drugs for immune suppression such as rapamycin, FK506, cyclosporine; and
(6) Any pharmacological compound that can fit into the nanodevice, e.g., analgesics, NSAIDS, steroids, hormones, anti-epileptics, anti-arrythmics, anti-hypentensives, antibiotics, antiviral agents, anticoagulants, platelet drugs, cardiostimulants, cholesterol lowering agents, etc.
[0022] Molecules of interest can also include imaging and/or tracking substances.
Imaging and/or tracking substances may include, but are not limited to, dye molecules such as propidium iodide, fluorescein, rhodamine, green fluorescent protein and derivatives thereof.
[0023] Figure 2 is a schematic illustration to facilitate the explanation of additional embodiments of the current invention. For the sake of clarity, Figure 2 does not show storage chambers, such as a plurality of pores of a mesoporous silica nanoparticle, and does not show valve assemblies. However, it should be understood that they can be present in addition to the features illustrated in Figure 2. According to some embodiments of the current invention, the nanodevices, such as nanodevice 100, can include a plurality of anionic molecules attached to the surface of the nanodevice as is illustrated schematically in Figure 2. For example the anionic molecules can be phosphonate moieties attached to the outer surface of the nanodevice to effectively provide a phosphonate coating on the nanodevice. For example, the anionic molecules can be trihydroxysilylpropyl methylphosphonate molecules according to an embodiment of the current invention.
[0024] A phosphonate coating on the containment vessel, such as containment vessel
102, can provide an important role in some biological applications according to some embodiments of the current invention. This phosphonate coating can provide a negative zeta potential that is responsible for electrostatic repulsion to keep such submicron structures dispersed in an aqueous tissue culture medium, for example. This dispersion can also be important for keeping the particle size limited to a size scale that allows endocytic uptake (i.e., hinders clumping). In addition to size considerations, the negative zeta potential may play a role in the formation of a protein corona on the particle surface that can further assist cellular uptake in some applications. It is possible that this could include molecules such as albumin, transferrin or other serum proteins that could participate in receptor-mediated uptake. In addition to the role of the phosphonate coating for drug delivery, it can also provide beneficial effects for molecule loading according to some embodiments of the current invention. (See co-pending application number PCT/US08/13476, co-owned by the assignee of the current application, the entire contents of which are incorporated by reference herein.)
[0025] The nanodevice 100 can also be functionalized with molecules in addition to anionic molecules according to some embodiments of the current invention. For example, a plurality of folate ligands can be attached to the outer surface of the containment vessel 102 according to some embodiments of the current invention, as is illustrated schematically in Figure 2 (valve assemblies are not shown for clarity).
[0026] In some embodiments of the current invention, the nanodevice 100 can also include fluorescent molecules contained in or attached to the containment vessel 102. For example, fluorescent molecules may be attached inside the pores of mesoporous silica nanoparticles according to some embodiments of the current invention. For example, the fluorescent molecules can be an amine-reactive fluorescent dye attached by being conjugated with an amine-functionalized silane according to some embodiments of the current invention. Examples of some fluorescent molecules, without limitation, can include fluorescein isothiocyanate, NHS-fluorescein, rhodamine B isothiocyanate, tetramethylrhodamine B isothiocyanate, and/or Cy5.5 NHS ester. [0027] In further embodiments of the current invention, the nanodevices 100 may further comprise one or more nanoparticle of magnetic material formed within the containment vessel 102, as is illustrated schematically in Figure 2 for one particular embodiment. For example, the nanoparticles of magnetic material can be iron oxide nanoparticles according to an embodiment of the current invention. However, the broad concepts of the current invention are not limited to only iron oxide materials for the magnetic nanoparticles. Such nanoparticles of magnetic material incorporated in the submicron structures can permit them to be tracked by magnetic resonance imaging (MRI) systems and/or manipulated magnetically, for example.
[0028] In further embodiments of the current invention, the nanodevices 100 may further comprise one or more nanoparticle of a material that is optically dense to x-rays. For example, gold nanoparticles may be formed within the containment vessel 102 of the nanodevice 100 according to some embodiments of the current invention.
EXAMPLE 1
[0029] We now describe some examples of nanodevices according to some embodiments of the current invention that have a pH-responsive valve assembly that relies on the ion-dipole interaction between cucurbit[6]uril (CB[6]) and bisammonium stalks, and that can operate in water. CB[6], a pumpkin-shaped polymacrocycle with D^h symmetry consisting of six glycouril units strapped together by pairs of bridging methylene groups between nitrogen atoms ((a) J. Lagona, P. Mukhopadhyay, S. Chakrabarti, L. Isaacs, Angew. Chem. 2005, 117, 4922^949; Angew. Chem. Int. Ed. 2005, 44, 4844-4870; b) S. Liu, C. Ruspic, P. Mukhopadhyay, S. Chakrabarti, P. Y. Zavalij, L. Isaacs, J. Am. Chem. Soc. 2005, 727, 15959- 15967; c) J. W. Lee, S. Samal, N. Selvapalam, H.-J. Kim, K. Kim, Ace. Chem. Res. 2003, 36, 621-630; d) K. Kim, Chem. Soc. Rev. 2002, 31, 96-107; e) A. Day, A. P. Arnold, R. J. Blanch, B. Snushall, J. Org. Chem. 2001, 66, 8094-8100; f) W. L. Mock, Top. Curr. Chem. 1995, 175, 1-24; g) R. Hoffmann, W. Knoche, C. Fenn, H.-J. Buschmann, J. Chem. Soc. Faraday Trans. 1994, 90, 1507-1511; h) W. A. Freeman, W. L. Mock, N.-Y. Shih, J. Am. Chem. Soc. 1981, 103, 7367-7368; i) R. Behrend, E. Meyer, F. Rusche, Justus Liebigs Ann. Chem. 1905, 339, 1- 37), has received considerable attention because of its highly distinctive range of physical and chemical properties. Of particular interest in the field of supramolecular chemistry is the ability of CB[6] to form inclusion complexes with a variety of polymethylenc derivatives, especially diaminoalkanes: the stabilities of these 1:1 complexes are highly pH-dependent ((a) C. Marquez, R. R. Hudgins, W. M. Nau, J. Am. Chem. Soc. 2004, 126, 5806-5816; b) C. Marquez, W. M. Nau, Angew. Chem 2001, 113, 3248-3254; Angew. Chem. Int. Ed. 2001, 40, 3155-3160. c) J.
W. Lee, K. Kim, K. Kim, Chem. Commun. 2001, 1042-1043; d) D. Tuncel, J. H. G. Steinke,
Chem. Commun. 2001, 253-254; e) C. Meschke, H.-J. Buschmann, E. Schollmeyer, Polymer
1999, 40, 945-949; f) W. L. Mock, J. Pierpont, J. Chem. Soc, Chem. Commun. 1990, 1509-
1511). The pll-dependent complexation-decomplexation behavior of CB [6] with diaminoalkanes has enabled the preparation of dynamic supramolecular entities which can be controlled by pH (C. Park, K. Oh, S. C. Lee, C. Kim, Angew. Chem. 2007, 119, 1477-1479;
Angew. Chem. Int. Ed. 2007, 46, 1455-1457; a) J. Lagona, P. Mukhopadhyay, S. Chakrabarti, L.
Isaacs, Angew. Chem. 2005, 117, 4922-4949; Angew. Chem. Int. Ed. 2005, 44, 4844-4870; b) S.
Liu, C. Ruspic, P. Mukhopadhyay, S. Chakrabarti, P. Y. Zavalij, L. Isaacs, J. Am. Chem. Soc.
2005, 127, 15959-15967; c) J. W. Lee, S. Samal, N. Selvapalam, H.-J. Kim, K. Kim, Ace.
Chem. Res. 2003, 36, 621-630; d) K. Kim, Chem. Soc. Rev. 2002, 31, 96-107; e) A. Day, A. P.
Arnold, R. J. Blanch, B. Snushall, J. Org. Chem. 2001, 66, 8094-8100; f) W. L. Mock, Top.
Curr. Chem. 1995, 175, 1-24; g) R. Hoffmann, W. Knoche, C. Fenn, H.-J. Buschmann, J.
Chem. Soc. Faraday Trans. 1994, 90, 1507-1511; h) W. A. Freeman, W. L. Mock, N.-Y. Shih,
J. Am. Chem. Soc. 1981, 103, 7367-7368; i) R. Behrend, E. Meyer, F. Rusche, Justus Liebigs
Ann. Chem. 1905, 339, 1-37. a) C. Marquez, R. R. Hudgins, W. M. Nau, J. Am. Chem. Soc.
2004, 126, 5806-5816; b) C. Marquez, W. M. Nau, Angew. Chem 2001, 113, 3248-3254;
Angew. Chem. Int. Ed. 2001, 40, 3155-3160. c) J. W. Lee, K. Kim, K. Kim, Chem. Commun.
2001, 1042-1043; d) D. Tuncel, J. H. G. Steinke, Chem. Commun. 2001, 253-254; e) C.
Meschke, H.-J. Buschmann, E. Schollmeyer, Polymer 1999, 40, 945-949; f) W. L. Mock, J.
Pierpont, J Chem. Soc, Chem. Commun. 1990, 1509-1511. a) D. Tuncel, O. Ozsar, H. B. Tiftik,
B. Salih, Chem. Commun. 2007, 1369-1371; b) D. Tuncel, H. B. Tiftik, B. Salih, J. Mater.
Chem. 2006, 16, 3291-3296; c) D. Tuncel, J. H. G. Steinke, Chem. Commun. 2002, 496-497; d)
T. C. Krasia, J. H. G. Steinke, Chem. Commun. 2002, 22-23; e) D. Tuncel, J. H. G. Steinke,
Chem Commun. 1999, 1509-1510. K. Kim, W. S. Jeon, J.-K. Lee, S. Y. Jon, T. Kim, K. Kim.
Angew. Chem. 2003, 115, 2395-2398; Angew. Chem. Int. Ed. 2003, 42, 2293-2296). Another important characteristic of CB[6] is its ability (a) W. L. Mock, T. A. Irra, J. P. Wepsiec, T. L.
Manimaran, J. Org. Chem. 1983, 48, 3619-3620; b) W. L. Mock, A. Irra, J. P. Websiec, M.
Adhya, J. Org. Chem. 1989, 54, 5302-5308) to catalyze 1,3-dipolar cycloadditions (See: a) R.
Huisgen, G. Szeimies, L. Mδbius, Chem. Ber. 1967, 100, 2494-2507; b) J. Bastide, J. Hamelin,
F. Texicr, V. Q. Ven, Bull. Chem. Soc. Fr. 1973, 2555-2579; c) J. Bastide, J. Hamelin, F.
Texier, V. Q. Ven, Bull. Chem. Soc. Fr. 1973, 2871-2887; d) W. Lwowski in 1,3-Dipolar Cycloaddition Chemistry, Vol. 1 (Ed. A. Padwa), Wiley, New York, 1984, Chapter 5; e) R. Huisgen, Pure Appl. Chem. 1989, 61, 613-628; f) H. C. KoIb, M. G. Finn, K. B. Sharpless, Angew. Chem 2001, 113, 2056-2075; Angew. Chem. Int. Ed. 2001, 40, 2004-2021; g) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew. Chem 2002, 114, 2708-2711 ; Angew. Chem. Int. Ed. 2002, 41, 2596-2599; h) C. W. Tornoe, C. Christensen, M. Meldal, J. Org. Chem. 2002, 67, 3057-3064; i) W. R. Dichtel, O. S. Miljaniό, J. M. Spruell, J. R. Heath, J. F. Stoddart, J. Am. Chem. Soc. 2006, 128, 10388-10390; j) O. S. Miljaniό, W. R. Dichtel, S. Mortezaei, J. F. Stoddart, Org. Lett. 2006, 8, 4835-4838; k) A. B. Braunschweig, W. R. Dichtel, O. S\ Miljanic, M. A. Olson, J. M. Spruell, S. I. Khan, J. R. Heath, J. F. Stoddart, Chem. Asian J. 2007, 2, 634-647; 1) O. S. Miljanic, W. R. Dichtel, S. I. Khan, S. Mortezaei, J. R. Heath, J. F. Stoddart, J. Am. Chem. Soc. 2007, 129, 8236-8246; m) V. Aucagne, K. D. Hanni, D. A. Leigh, P. J. Lusby, D. B. Walker, J. Am. Chem. Soc. 2006, 128, 2186-2187; n) P. Mobian, J.-P. Collin, J.-P. Sauvage, Tetrahedron Lett. 2006, 47, 4907-4909), such that the reaction between an azide- substituted ammonium ion and an alkyne-containing ammonium ion yields a 1,3-triazole derivative encircled by a CB[6] ring. The Huisgen 1,3-dipolar cycloaddition, in particular the Cu(I)-catalyzed stepwise variant, is often referred to simply as the "click reaction". This "click chemistry" has already been applied successfully in the efficient and convergent template- directed synthesis of mechanically interlocked molecules by our and other groups. In view of these particular properties of CB[6], we employ it as a catalyst for the formation of monolayers of [2]pseudorotaxanes on the surfaces of mesoporous silica nanoparticles so as to generate pH- responsive, biocompatible valve systems capable of executing different missions according to some embodiments of the current invention.
[0030] Mesoporous silica has proven ((a) M. Vallet-Regi, A. Ramila, R. P. del Real,
J. Perez-Pariente, Chem. Mater. 2001, 13, 308-311; b) J. M. Xue, M. Shi, J. Controlled Release 2004, 98, 209-217; c) C. Barbέ, J. Bartlett, L. Kong, K. Finnie, H. Q. Lin, M. Larkin, S. Calleja, A. Bush, G. Calleja, Adv. Mater. 2004, 16, 1959-1966; d) Q. Yang, S. Wang, P. Fan, L. Wang, Y. Di, K. Lin, F.-S. Xiao, Chem. Mater. 2005, 17, 5999-6003; e) F. Balas, M. Manzano, P. Horcajada, M. Vallet-Regi, J. Am. Chem. Soc. 2006, 128, 8116-8117; f) M. Arruebo, M. Galan, N. Navascues, C. Tellez, C. Marquina, M. R. Ibarra, J. Santamaπa, Chem. Mater. 2006, 18, 191 1-1919; g) S. Angelos, E. Choi, F. Vδgtle, L. De Cola, J. I. Zink, J. Phys. Chem. C 2007, 111, 6589-6592; h) I. I. Slowing, B. G. Trewyn, V. S.-Y. Un, J. Am. Chem. Soc. 2007, 129, 8845-8849; i) B. Dunn, J. I. Zink, Ace. Chem. Res. 2007, 40, 747-755. T. D. Nguyen, K. C-F. Leung, M. Liong, C. D. Pentecost, J. F. Stoddart, J. I. Zink, Org. Lett. 2006, 8, 3363-3366. K. C-F. Leung, T.D. Nguyen, J. F. Stoddart, J. I. Zink, Chem. Mater. 2006, 18, 5919-5928. a) N. K. MaI, M. Fujiwara, Y. Tanaka, Nature 2003, 421, 350-353; b) N. K. MaI, M. Fujiwara, Y. Tanaka, T. Taguchi, M. Matsukata, Chem. Mater. 2003, 15, 3385-3394; c) N. Liu, D. R. Dunphy, P. Atanassov, S. D. Bunge, Z. Chen, G. P. Lopez, T. J. Boyle, C. J. Banker, Nano Lett. 2004, 4, 551-554; d) R. Hernandez, H.-R. Tseng, J. W. Wong, J. F. Stoddart, J. I. Zink, J. Am. Chem. Soc. 2004, 126, 3370-3371; e) T. D. Nguyen, K. C-F. Leung, M. Liong, Y. Liu, J. F. Stoddart, J. I. Zink, Adv. Fund. Mater. 2007, 17, 2101-2110. a) R. Hernandez, H.-R. Tseng, J. W. Wong, J. F. Stoddart, J. I. Zink, J. Am. Chem. Soc. 2004, 126, 3370-3371; b) T. D. Nguyen, H.-R. Tseng, P. C Celestre, A. H. Flood, Y. Liu, J. F. Stoddart, J. I. Zink, Proc. Natl. Acad. ScL USA 2005, 102, 10029-10034; c) T. D. Nguyen, Y. Liu, S. Saha, K. C-F. Leung, J. F. Stoddart, J. I. Zink, J. Am. Chem. Soc. 2007, 129, 626-634. For recent reviews on nanovalves, see: a) S. Saha, K. C-F. Leung, T. D. Nguyen, J. F. Stoddart, J. I. Zink, Adv. Funct. Mater. 2007, 17, 685- 693; b) S. Angelos, E. Johansson, J. F. Stoddart, J. I. Zink, Adv. Funct. Mater. 2007, 17, 2261- 2271. a) P. N. Minoofar, B. S. Dunn, J. I. Zink, J. Am. Chem. Soc. 2005, 127, 2656-2665; b) E. Johansson, J. I. Zink, J. Am. Chem. Soc. 2007, ASAP Article.) to be an excellent support for the formation of dynamic nanosystems, including valve systems, because it is chemically stable and optically transparent. In this present research, [2]pseudorotaxanes having bisammonium stalks and CB[6] rings, were constructed (Figures IA, IB) on the surface of mesoporous silica nanoparticles, and the pH-dependent binding of CB[6] with the bisammonium stalks is exploited to control the release of guest molecules from the pores of the silica nanoparticles. At neutral and acidic pH values, the CB[6] rings encircle the bisammonium stalks tightly, blocking the nanopores efficiently when employing suitable lengths of tethers. Deprotonation of the stalks upon addition of base results in spontaneous dethreading (Figures IB, 1C) of the CB[6] rings and unblocking of the silica nanopores.
[0031] The silica supports employed were ~400 run diameter spherical particles which contain ordered 2D hexagonal arrays of tubular pores (~2 nm pore diameters with ~4 nm lattice spacing) prepared using a base-catalyzed sol-gel method (a) S. Huh, J. W. Wiench, J.-C. Yoo, M. Pruski, V. S.-Y. Lin, Chem. Mater. 2003, 15, 4247^256; b) M. Grun, I. Laner, K. K. Unger, Adv. Mater. 1997, 9, 254-257; c) Y. Lu, R. Ganguli, C A. Drewien, M. T. Anderson, C. J. Brinker, W. Gong, Y. Guo, H. Soyez, B. Dunn, M. H. Huang, J. I. Zink, Nature 1997, 389, 364- 368; d) C T. Kresge, M. E. Leonowicz, W. J. Roth, J. C Vartuli, J. S. Beck, Nature 1992, 359, 710-712). The nanopores were templated by cetyltrimethylammonium bromide (CTAB) surfactants, and tetraethylorthosilicate (TEOS) was used as the silica precursor. Empty nanopores were obtained after removal of the templating agents by solvent extraction. The ordered structure and particle morphology were confirmed (Figure 3) by X-ray diffraction and scanning electron microscopy.
[0032] This system was designed (Figure 4A) such that the valve assembly components can be assembled in a stepwise, divergent manner from the nanoparticle surface outwards according to an embodiment of the current invention. Following solvent extraction, the nanoparticles were heated under reflux in an aminopropyl-triethoxysilane (APTES) solution, resulting in the amino-modifϊed nanoparticles 1. These nanoparticles were recovered by vacuum filtration and washed and dried extensively, before being resuspended in MeOH in the presence of propargyl bromide and heated under reflux overnight to obtain the alkyne-terminated nanoparticles 2. Next, the empty nanopores in 2 were loaded with fluorescent guest molecules by soaking the nanoparticles in a 0.5 mM solution of Rhodamine B (RhB) for 5 h. The preparation of the valve systems was completed by means of an interfacial CB[6]-catalyzed 1,3- dipolar cycloaddition of the silica-supported alkyne function and 2-azidoethylamine to yield CB[6] / 1,3-disubstituted triazole [2]pseudorotaxanes {3 cz CB[6]} spread all over the silica surface.
[0033] The surface functionalization of silica nanoparticles and the construction of the
CB [6] -capped valve systems was monitored by FT-IR spectroscopy. The FT-IR spectrum of the nanoparticle 2 showed new absorption peaks at 2131 cm"1 and 3296 cm"1, resulting from the alkyne CsC and C-H stretching modes, respectively. In the FT-IR spectrum of the nanoparticles {3 c CB[6]}, the peak at 1632 cm"1 corresponding to the CB[6] C=O stretching mode, confirms the attachment of monolayers of [2]pesudorotaxanes to the surfaces of the silica nanoparticles. The existence of the alkyne C≡C stretching mode at 2131 cm'1 infers that not all of the tethered alkyne groups are involved in CB[6]-catalyzed 1,3-cycloadditions, presumably because of the steric hindrance between the [2]pseudorotaxanes congregated on the surface of the silica nanoparticle.
[0034] Real-time measurements on the release of RhB have been made in order to monitor the valve system's operation. Dye-loaded, CB[6]-capped nanoparticles were washed extensively with MeOH and H2O to remove adsorbed molecules from the surface. A portion of the washed nanoparticles (-15 mg) was placed in the bottom corner of a cuvette, and H2O (12 mL) was added carefully. A 10 mW, 514 nm probe beam, directed into the water above the nanoparticles, was used to excite the dye molecules as they are released from the nanoparticles. The emission spectrum of RhB was recorded as a function of time at 1 -second intervals. The valve systems were opened by adjusting the pH of the solution to 10 through the addition of 2M NaOH. Plots of the dissolved dye intensities as functions of time - the release profiles shown in Figure 5 - indicate an increase in the amount of dye released upon base activation, demonstrating that the valve systems do indeed open at high pH values.
[0035] In keeping with the development of prototypical valve systems, optimization of the design components to achieve the best possible performance is usually required. The situation is no different with the [2]pseudorotaxane {3 c CB[6]}. The release profile (Figure 5A) reveals that {3 <z CB [6]} exhibits appreciable leakiness prior to base activation. We suspected that the CB [6] rings in the [2]pseudo-rotaxanes do not reside close enough to the surface of the mesoporous silica nanoparticles when the valve systems are closed, making it possible for the RhB molecules to escape prior to base activation. Previous research (T. D. Nguyen, Y. Liu, S. Saha, K. C-F. Leung, J. F. Stoddart, J. I. Zink, J. Am. Chem. Soc. 2007, 129, 626-634) revealed that the critical factors affecting valve assembly activation include (i) the size of the valve assembly components, (ii) the positioning of the valve systems relative to the orifices of the nanopores and (iii) the length of the linker. The outer diameter of the CB[6] ring (a) J. Lagona, P. Mukhopadhyay, S. Chakrabarti, L. Isaacs, Angew. Chem. 2005, 117, 4922- 4949; Angew. Chem. Int. Ed. 2005, 44, 4844-4870; b) S. Liu, C. Ruspic, P. Mukhopadhyay, S. Chakrabarti,- P. Y. Zavalij, L. Isaacs, J. Am. Chem. Soc. 2005, 127, 15959-15967; c) J. W. Lee, S. Samal, N. Selvapalam, H.-J. Kim, K. Kim, Ace. Chem. Res. 2003, 36, 621-630; d) K. Kim, Chem. Soc. Rev. 2002, 31, 96-107; e) A. Day, A. P. Arnold, R. J. Blanch, B. Snushall, J. Org. Chem. 2001, 66, 8094-8100; f) W. L. Mock, Top. Curr. Chem. 1995, 175, 1-24; g) R. Hoffmann, W. Knoche, C. Fenn, H.-J. Buschmann, J. Chem. Soc. Faraday Trans. 1994, 90, 1507-1511; h) W. A. Freeman, W. L. Mock, N.-Y. Shih, J. Am. Chem. Soc. 1981, 103, 7367- 7368; i) R. Behrend, E. Meyer, F. Rusche, Justus Liebigs Ann. Chem. 1905, 339, 1-37) which is 1.4 nm, might be expected to be large enough to gate the ~2 nm-diameter pore and thus prevent RhB molecules from escaping. In the synthetic approach summarized in Figure 4A, solvent extraction of the sol-gel prior to amino-modification of the silica nanoparticles enables the linkers to bind to the pore interiors as well as to the surfaces of the nanoparticles. We suspect, nonetheless, that the bulky CB[6] rings in {3 c CB|6|} do not penetrate deep enough inside the nanopores, leaving the valve systems prone to leakage. Thus, in order to seal the valve systems, a shorter linker was employed so that the CB [6] rings would be positioned closer to the surface of the mesoporous silica and so block the nanopore orifices more efficiently. A shorter linker was attached to the silica surface in two steps (Figure 4B). The nanoparticles were first of all derivatized with chloromethyl-triethoxysilane (CMTES) to afford the nanoparticle 4 and then they were treated with NaNH2 to produce the amino-modifϊed nanoparticles 5. The remaining steps of the synthesis of the valve assembly with the shorter linkers were similar to those described earlier (Figure 4A) for the nanoparticles with the longer linkers. The use of the shorter linker curtails the length of the stalk of the pseudorotaxane in {6 c CB[6]} such that the CB[6] ring is positioned ~0.2 nm closer to the surface of the silica nanoparticle. This subtle change in linker length tightens up the valve systems sufficiently to prevent leakage and the release profile illustrated in Figure 5B is observed.
[0036] A concern regarding the operation of these valve systems is the stability of the silica supports under the high pH conditions required for the valve assembly to function. Activation of the valve systems relies on deprotonation of the primary alkylammonium and secondary dialkylammonium centers (pΛTa ~ 10) so as to disrupt the ion-dipole interactions responsible for binding of the CB[6] rings. In order to verify that the silica mesostructure and particle morphology are able to withstand the exposure to base (NaOH) that is required for the activation of the valve systems, SEM images and X-ray diffraction patterns of the functionalized nanoparticles were compared before and after exposure to base. No noticeable differences in either the nanoparticle morphology or mesostructure were observed, indicating that the structure of the nanoparticle supports is preserved during the controlled release process.
[0037] The above provides an example of the production of CB[6]-based valve systems, which employ biocompatible components and operate in water. The valve systems rely on the ion-dipole interactions between the CB [6] rings and the bisammonium stalks attached to the mesoporous silica nanoparticles and can be operated quite simply by raising and lowering the pH according to some embodiments of the current invention. A modular approach has been developed that relies on the interfacial CB[6]-catalyzed 1,3-cycloaddition of alkyne- and azide- terminated subunits in the final steps of the syntheses of the valve systems. Now that the validity of exploiting ion-dipole interactions for valve assembly design has been established, we anticipate that valve systems based on CB [6] rings as the gatekeepers can play a significant role in the future of functionalized mesoporous silica nanoparticles for biotechnological and medical applications ((a) F. Torney, B. G. Trewyn, V. S.-Y. Lin, K. Wang, Nature Nanotech. 2007, 2, 295-300; b) B. G. Trewyn, S. Giri, 1. 1. Slowing, V. S.-Y. Lin, Chem. Commun. 2007, 3236- 3245; c) J. Lu, M. Liong, J. I. Zink, F. Tamanoi, Small 2007, 3, 1341-1346; d) B. G. Trewyn, I. I. Slowing, S. Giri, H.-T. Chen, V. S.-Y. Lin, Ace. Chem. Res. 2007, 40, 846-853). Furthermore, it is expected that these pH-responsive supramolecular valve systems can be tuned to operate under gentler pH stimulation by identifying bisammonium ion centers with pKa values that will enable the development of CB[6]-based valve systems for in vivo applications using the natural variations in pH that exist (a) N. Raghunand, R. Martinez-Zaguilan, S. H. Wright, R. J. Gillies, Biochem. Pharmacol. 1999, 57, 1047-1058; b) S. D. Webb, J. A. Sherratt, R. G. Fish, J. Theor. Biol. 1999, 196, 237-250; c) R. Becelli, G. Renzi, R. Morello, F. Altieri, J. Craniofac. Surg. 2007, 18, 1051-1054) within healthy and diseased cells in living systems.
Experimental Procedures
[0038] 1 : Bare mesoporous silica nanoparticles templated by cetyltrimethyl-ammonium bromide (CTAB) were synthesized according to a literature procedure (S. Huh, J. W. Wiench, J.- C. Yoo, M. Pruski, V. S.-Y. Lin, Chem. Mater. 2003, 15, 4247-4256). Empty pores were obtained by solvent extraction of the CTAB template: nanoparticles (1.5 g) were suspended in MeOH (160 mL), to which a concentrated aqueous HCl solution (12 M, 9 mL) had been added, and the mixture was heated under reflux for 24 h. The solvent-extracted nanoparticles were collected by vacuum filtration and washed thoroughly with MeOH. Amino-modification of the silica surface was performed by suspending the nanoparticles (100 mg) in a solution of 3- aminopropyltriethoxy-silane (APTES) (1 mM) in dry PhMe (10 mL) and heating them under reflux for 24 h. The nanoparticles were collected by filtration, washed thoroughly with PhMe, and dried under vacuum.
[0039] 2: Refluxing aminopropyl-modified MCM-41 nanoparticles 1 in a MeOH solution of propargyl bromide for 24 h under N2 (1 atm) afforded the alkyne-modifϊed MCM-41, resulting in silica nanoparticles 2 after washing them extensively with MeOH and drying them under vacuum. The nanoparticles were characterized by means of FTIR, XRD, SEM, and DLS.
[0040] {3 c= CB[6]}: Loading of the pores with Rhodamine B (RhB) was carried out by soaking the alkyne-modified porous silica nanoparticles 2 in an aqueous solution of RhB (0.5 mM) for 5 h at RT. A concentrated HCl solution (12 M, 15 mL) containing an excess of CB[6] and 2-azidoethylamine was then added to the above mixture. The resulting mixture was stirred for 3 days at RT. The loaded, capped nanoparticles were collected by filtration and washed thoroughly with water to give {3 c CB[6J}, which was characterized by means of FT-IR, XRD and SEM.
[0041] 5: The bare nanoparticle surface was derivatized with chloromethyl- triethoxysilane (CMTES) by suspending nanoparticles (100 mg) in CMTES solution (1 mM) in dry PhMe (10 mL) and heating under reflux for 12h, resulting in the intermediate nanoparticles 4 (T. D. Nguyen, Y. Liu, S. Saha, K. C-F. Leung, J. F. Stoddart, J. I. Zink, J. Am. Chem. Soc. 2007, 129, 626-634). After adding NaNH2 (0.02 mmol), the reaction mixture was heated at reflux for another 12 h. The aminomethyl-modified nanoparticles 5 were collected by filtration, washed thoroughly with PhMe, and dried under vacuum. They were characterized by means of FT-IR, XRD, SEM, and DLS.
[0042] {6 c CB[6]}: Nanoparticles 5 were first modified with propargyl bromide by heating under reflux in MeOH under N2 for 24 h to obtain the alkyne-terminated silica nanoparticles. Loading with RhB and completion of the valve assembly synthesis was achieved as described for valve assembly {3 c CB [6]}. They were characterized by means of FT-IR, XRD and SEM.
[0043] Controlled Release Experiments: The dye-loaded, CB [6] -capped nanoparticles
(15 mg) were placed in the corner of a cuvette, and distilled H2O (12 mL) was added carefully. A lO mW, 514 nm excitation beam was directed into the solution above the nanoparticles, and the RhB emission spectrum was recorded as a function of time. Release profiles were obtained by plotting the luminescence intensity of RhB at the emission maximum (578 nm) as a function of time. Activation of the valve systems was accomplished by adjusting the pH of the solution to 10 by adding 2M NaOH solution. The solution in the cuvette was stirred gently throughout the controlled release experiment.
EXAMPLE 2
[0044] In the example above, we demonstrated the operation of a CB[6] / diaminoalkane pseudorotaxane-based valve assembly that is activated by base. However, a valve system, which opens under mildly acidic conditions, is desirable for drug delivery and other cellular applications, as the expected route of nanoparticle uptake into cells is via endocytosis into acidic vesicles (pH ~ 5). In 1990, Mock reported a pseudorotaxane-based molecular switch which consists of a CB[6] 'bead' and a triamine 'string' PhNH(CH2)6NH(CH2)4NH2, and demonstrated that CB[6] can reversibly shuttle along the string by changing the pH. According to another embodiment of the current invention, a bistable CB[6]/triamine pseudorotaxane-based nanodevice having a valve assembly can be operated under mildly acidic conditions (Figure 6). First, we can easily functionalize the triamine 'string' onto the surface of mesoporous silica nanoparticles. The important feature of the triamine thread functionalized onto the silica surface is that the pair of nitrogen atoms not connected directly to the benzene ring ought to be 106-fold more basic than the one which is, so the pH changes will result in changes in the protonation state of the aniline N atom, which provides the possibility of the relocation of CB[6] host molecule. Second, we loaded drug/dye molecules in the pores and then capped the pores with CB[6] in basic condition. At pH values above the pΛTa value of the anilinium group (6.73), CB[6] will reside in the fully protonated diaminobutane site blocking the pores due to the 100- fold stronger binding than monoprotonated diaminohexane. Below the pKΑ value, that is, in mildly acidic or acidic conditions, all the nitrogen atoms of the 'string' are protonated, CB[6] will move to the protonated diaminohexane site forming a more stable complex than with diprotonated diaminobutane, thus open the pores and release the drug/dye molecules trapped in the pores. This process is reversible due to the relocation of CB [6] when the pH is changed back to 6.73.
[0045] In describing embodiments of the invention, specific terminology is employed for the sake of clarity. However, the invention is not intended to be limited to the specific terminology so selected. The above-described embodiments of the invention may be modified or varied, without departing from the invention, as appreciated by those skilled in the art in light of the above teachings. It is therefore to be understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

Claims

WE CLAIM:
1. A nanodevice, comprising: a containment vessel defining a storage chamber therein and defining at least one port to provide transfer of matter to or from said storage chamber; and a valve assembly attached to said containment vessel; wherein said valve assembly is operable in an aqueous environment, and wherein said nanodevice comprises biocompatible materials in a composition thereof and has a maximum dimension of less than about 1 μm and greater than about 50 nm.
2. A nanodevice according to claim 1, wherein said nanodevice has a maximum dimension of less than about 400 nm and greater than about 50 nm.
3. A nanodevice according to claim 1, wherein said nanodevice has a maximum dimension of less than about 300 nm and greater than about 50 nm.
4. A nanodevice according to claim 1, wherein said nanodevice has a maximum dimension of less than about 150 nm and greater than about 50 nm.
5. A nanodevice according to any one of claims 1-4, wherein said valve assembly is operable to at least one of open and close in response to a change of pH in a local environment of said valve assembly.
6. A nanodevice according to any one of claims 1-5, wherein said valve assembly is operable to open in response to a change to an acidic local environment and to close in response to a change to a non-acidic local environment of said valve assembly.
7. A nanodevice according to any one of claims 1-6, wherein said nanodevice consists essentially of biocompatible materials in a composition thereof.
8. A nanodevice according to any one of claims 1-7, wherein said containment vessel comprises silica in a material thereof.
9. A nanodevice according to any one of claims 1-7, wherein said containment vessel is a mesoporous silica nanoparticle defining a plurality of substantially parallel pores therein, said storage chamber being one of said plurality of substantially parallel pores.
10. A nanodevice according to any one of claims 1-9, wherein said valve assembly is at least a portion of one of a [2]rotaxane and a [2]pseudorotaxane supramolecular structure.
11. A nanodevice according to claim 10, wherein said at least said portion of one of said [2]rotaxane and said [2]pseudorotaxane comprises a cucurbituril molecule as a moving valve component thereof.
12. A nanodevice according to claim 10, wherein said at least said portion of one of said [2]rotaxane and said [2]pseudorotaxane comprises a cyclodextrin molecule.
13. A nanodevice according to any one of claims 1-12, further comprising a plurality of anionic or electrostatic molecules attached to an outer surface of said containment vessel, wherein said anionic or electrostatic molecules provide hydrophilicity or aqueous dispersability to said nanodevice and are suitable to provide repulsion between other similar nanodevices.
14. A nanodevice according to claim 13, wherein said plurality of anionic molecules comprise a phosphonate moiety.
15. A nanodevice according to claim 13, wherein said plurality of anionic molecules are trihydroxysilylpropyl methylphosphonate.
16. A nanodevice according to any one of claims 1-15, further comprising folate ligands attached to said containment vessel.
17. A nanodevice according to any one of claims 1-16, further comprising a nanoparticle of magnetic material formed within said containment vessel of said nanodevice.
18. A nanodevice according to claim 17, wherein said nanoparticle of magnetic material is an iron oxide nanoparticle.
19. A nanodevice according to any one of claims 1-18, further comprising a nanoparticle of gold formed within said containment vessel of said nanodevice.
20. A composition of matter, comprising: a plurality of nanoparticles, each defining a storage chamber therein; and a guest material contained within said storage chambers defined by said nanoparticles, said guest material being substantially chemically non-reactive with said nanoparticles, wherein each nanoparticle of said plurality of nanoparticles has a valve assembly to allow said guest material contained within said storage chambers to be selectively released, and wherein each nanoparticle of said plurality of nanoparticles comprises biocompatible materials in a composition thereof and has a maximum dimension of less than about 1 μm and greater than about 50 nm.
21. A composition of matter according to claim 20, wherein said valve assembly is operable to at least one of open and close in response to a change of pH in a local environment of said valve assembly. i
22. A composition of matter according to claim 20, wherein said valve assembly is operable to open in response to a change to an acidic local environment and to close in response to a change to a non-acidic local environment of said valve assembly.
23. A composition of matter according to any one of claims 20-22, wherein each nanoparticle of said plurality of nanoparticles comprises silica in a material thereof.
24. A composition of matter according to any one of claims 20-22, wherein each nanoparticle of said plurality of nanoparticles is a mesoporous silica nanoparticle defining a plurality of substantially parallel pores therein, said storage chamber being one of said plurality of substantially parallel pores.
25. A composition of matter according to any one of claims 20-24, wherein said valve assembly is at least a portion of one of a [2]rotaxane and a [2]pseudorotaxane supramolecular structure.
26. A composition of matter according to claim 25, wherein said at least said portion of one of said [2]rotaxane and said [2]pseudorotaxane comprises a cucurbituril molecule.
27. A composition of matter according to any one of claims 20-26, wherein each nanoparticle of said plurality of nanoparticles comprises a surface coating of a hydrophilic group.
28. A composition of matter according to any one of claims 20-27, wherein each nanoparticle of said plurality of nanoparticles comprises folate ligands attached thereto.
29. A method of administering at least one of a biologically active substance, a therapeutic substance, a neutraceutical substance, a cosmetic substance or a diagnostic substance, comprising: administering a composition to at least one of a person, an animal, a plant, or an organism, said composition comprising nanoparticles therein, wherein said nanoparticles contain said at least one of biologically active substance, therapeutic substance, neutraceutical substance, cosmetic substance or diagnostic substance therein; and selectively opening a valve in each of said nanoparticles to allow said at least one of said biologically active substance, therapeutic substance, neutraceutical substance, cosmetic substance or diagnostic substance to escape from said nanoparticles.
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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130046274A1 (en) * 2011-07-14 2013-02-21 The Regents Of The University Of California Method of controlled delivery using sub-micron-scale machines
WO2013095736A3 (en) * 2011-09-27 2014-01-23 The Methodist Hospital Research Institute Gold-in-silicon nanoassembly for thermal therapy and methods of use
CN104447768A (en) * 2013-09-23 2015-03-25 贵州大学 Cucurbit [7] uril [3] rotaxane as well as preparation method and application thereof
US9042765B2 (en) 2012-01-16 2015-05-26 Samsung Electronics Co., Ltd. Image forming apparatus with improved heat transmission
CN105983390A (en) * 2015-01-30 2016-10-05 南京理工大学 Intelligent nano container with pH-stimulated large ring capable of reversibly moving and preparation method thereof
US9993437B2 (en) 2007-12-06 2018-06-12 The Regents Of The University Of California Mesoporous silica nanoparticles for biomedical applications
US10343903B2 (en) 2010-07-13 2019-07-09 The Regents Of The University Of California Cationic polymer coated mesoporous silica nanoparticles and uses thereof
CN114455776A (en) * 2021-12-21 2022-05-10 中煤科工集团杭州研究院有限公司 Stainless steel pickling wastewater treatment method based on biological denitrification

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6929636B1 (en) * 2000-11-08 2005-08-16 Hewlett-Packard Development Company, L.P. Internal drug dispenser capsule medical device
US20060154069A1 (en) * 2003-07-22 2006-07-13 Lin Victor S Capped mesoporous silicates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6929636B1 (en) * 2000-11-08 2005-08-16 Hewlett-Packard Development Company, L.P. Internal drug dispenser capsule medical device
US20060154069A1 (en) * 2003-07-22 2006-07-13 Lin Victor S Capped mesoporous silicates

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9993437B2 (en) 2007-12-06 2018-06-12 The Regents Of The University Of California Mesoporous silica nanoparticles for biomedical applications
US10668024B2 (en) 2007-12-06 2020-06-02 The Regents Of The University Of California Mesoporous silica nanoparticles for biomedical applications
US10343903B2 (en) 2010-07-13 2019-07-09 The Regents Of The University Of California Cationic polymer coated mesoporous silica nanoparticles and uses thereof
US20130046274A1 (en) * 2011-07-14 2013-02-21 The Regents Of The University Of California Method of controlled delivery using sub-micron-scale machines
US10220004B2 (en) 2011-07-14 2019-03-05 The Regents Of The University Of California Method of controlled delivery using sub-micron-scale machines
WO2013095736A3 (en) * 2011-09-27 2014-01-23 The Methodist Hospital Research Institute Gold-in-silicon nanoassembly for thermal therapy and methods of use
US9042765B2 (en) 2012-01-16 2015-05-26 Samsung Electronics Co., Ltd. Image forming apparatus with improved heat transmission
CN104447768A (en) * 2013-09-23 2015-03-25 贵州大学 Cucurbit [7] uril [3] rotaxane as well as preparation method and application thereof
CN105983390A (en) * 2015-01-30 2016-10-05 南京理工大学 Intelligent nano container with pH-stimulated large ring capable of reversibly moving and preparation method thereof
CN105983390B (en) * 2015-01-30 2018-05-01 南京理工大学 Intelligent nano container with pH-stimulated large ring capable of reversibly moving and preparation method thereof
CN114455776A (en) * 2021-12-21 2022-05-10 中煤科工集团杭州研究院有限公司 Stainless steel pickling wastewater treatment method based on biological denitrification
CN114455776B (en) * 2021-12-21 2022-12-06 中煤科工集团杭州研究院有限公司 Stainless steel pickling wastewater treatment method based on biological denitrification

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