EP1934138A2 - Nanotubes amphiphiles et micelles les comprenant pour l'administration d'agents biologiquement actifs - Google Patents

Nanotubes amphiphiles et micelles les comprenant pour l'administration d'agents biologiquement actifs

Info

Publication number
EP1934138A2
EP1934138A2 EP06794776A EP06794776A EP1934138A2 EP 1934138 A2 EP1934138 A2 EP 1934138A2 EP 06794776 A EP06794776 A EP 06794776A EP 06794776 A EP06794776 A EP 06794776A EP 1934138 A2 EP1934138 A2 EP 1934138A2
Authority
EP
European Patent Office
Prior art keywords
micelle
nanotubes
nanotube
surfactant
steps
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP06794776A
Other languages
German (de)
English (en)
Inventor
Dewan Fazlul Hoque Chowdhury
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB0520902.8A external-priority patent/GB0520902D0/en
Application filed by Individual filed Critical Individual
Publication of EP1934138A2 publication Critical patent/EP1934138A2/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y40/00—Manufacture or treatment of nanostructures
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y30/00—Nanotechnology for materials or surface science, e.g. nanocomposites
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B32/00—Carbon; Compounds thereof
    • C01B32/15—Nano-sized carbon materials
    • C01B32/158—Carbon nanotubes
    • C01B32/168—After-treatment
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B32/00—Carbon; Compounds thereof
    • C01B32/15—Nano-sized carbon materials
    • C01B32/158—Carbon nanotubes
    • C01B32/168—After-treatment
    • C01B32/174—Derivatisation; Solubilisation; Dispersion in solvents
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B32/00—Carbon; Compounds thereof
    • C01B32/15—Nano-sized carbon materials
    • C01B32/158—Carbon nanotubes
    • C01B32/168—After-treatment
    • C01B32/178—Opening; Filling
    • C—CHEMISTRY; METALLURGY
    • C01—INORGANIC CHEMISTRY
    • C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
    • C01B2202/00—Structure or properties of carbon nanotubes
    • C01B2202/08—Aligned nanotubes

Definitions

  • Amphiphilic nanotubes and micelles comprising same for use in the delivery of biologically active agents
  • the present invention relates to nanotubes and micelles, and in particular to micelles that are formed from nanotubes and have medical applications.
  • a micelle is an aggregate of surfactant molecules (typically organic molecules that are amphiphilic, meaning that they have a hydrophobic or lipophobic end and a hydrophilic or lipophilic end) dispersed in a liquid colloid.
  • Micelles are often spherical or globular in shape, but can adopt other shapes such as shells, vesicles, clusters, bi-layers, cylinders and ellipsoids.
  • CMC critical micelle concentration
  • Nanotubes can be defined generally as substantially tubular structures with a diameter on the nanoscale, for example less than lOOnm. They are typically made from atomic carbon bonded in a sp 2 structure, although they have been made from other species.
  • the present invention can include single- and multi-walled nanotubes, coated nanotubes, nanotubes that are open-ended and nanotubes that have one or both of their ends closed.
  • the present invention provides a micelle formable from at least one nanotube in a process of self-assembly, the nanotube comprising an amphophilic nanotube made from one or more species selected from the group of carbon, silicon, a noble metal, silicon dioxide and titanium dioxide.
  • the micelle formed is uniform, i.e. has at least one plane of symmetry.
  • the amphophilic nanotube may be made by covering a functionisable part of one or more of the nanotubes with a coating that includes a hydrophilic or hydrophobic surfactant or emulsifying agent, or with a coating that includes a lipophilic or lipophobic surfactant or emulsifying agent, for example.
  • the coating can be applied to an end, to an extending portion which extends away from an end portion towards a distal end of the nanotube, or to a side of the nanotube such as a hemicylindrical portion of the nanotube surface.
  • the other end or side can be left without a coating, or a coating with opposite hydrophobic or hydrophilic properties can be applied.
  • a hydrophobic coating can be applied to one side of each nanotube and the other side of each nanotube can be left uncoated.
  • a hydrophobic coating can be applied to one end of each nanotube and a hydrophilic coating can be applied to the other end of each nanotube.
  • a first coated part of the nanotube may form a core of the micelle and a second part may form a corona of the micelle, or vice versa.
  • Suitable surfactant and emulsifying agents for use in the coatings would include nonionic block copolymers such as polyoxypropylene (POP) or polyoxyethylene (POE), ionic block copolymers, polyoxyethelyne glycol (PEG), lipids such as lecithin, diacyllipids such as phosphatidylethanolamine (PE) and poloxemers such as Pluronic® Fl 27. Alternatively they may be a combination of these and/or other surfactants.
  • POP polyoxypropylene
  • POE polyoxyethylene
  • ionic block copolymers such as polyoxyethelyne glycol (PEG), lipids such as lecithin, diacyllipids such as phosphatidylethanolamine (PE) and poloxemers such as Pluronic® Fl 27.
  • POP polyoxypropylene
  • POE polyoxyethylene
  • ionic block copolymers such as polyoxyethelyne glycol (PEG)
  • the properties of the liquid colloid will determine the orientation of the nanotubes in the micelle. For example, if the liquid colloid is water then the ends of the nanotubes that are hydrophobic will cluster together at a core of the micelle and the ends of the nanotubes that are hydrophilic will form a corona that defines an outer region of the micelle.
  • a micelle can also be formed by relying on steric hindrance where one or more (and preferably all) of the nanotubes are provided with a long chain of molecules such as a polymer, e.g. a block copolymer.
  • the block copolymer restricts the spatial arrangement of the nanotubes to the extent that they will form a micelle if the concentration of the nanotubes is greater than the critical micelle concentration (CMC).
  • CMC critical micelle concentration
  • the ends of the nanotubes that are not provided with the block copolymer are forced by the steric hindrance to cluster together at a core of the micelle and the ends of the nanotubes that are provided with the block copolymer are forced by the steric hindrance to form a corona that defines an outer region of the micelle.
  • a micelle from a variety of different nanotubes.
  • the nanotube is made of one of silicon dioxide, titanium dioxide, carbon, silicon, a noble metal, or a composite of these materials. Preferably it is made from carbon, silicon or a noble metal.
  • the noble metal may be titanium, palladium, gold or silver.
  • the nanotube is made by a manufacturing process rather than produced by a natural process, or supramolecular tubes, or from peptides.
  • the nanotubes may be single walled or multi-walled.
  • a therapeutic composition or agent (such as a form of pharmaceutical preparation, for example) can be located in the micelle, for example at the core of the micelle such - A -
  • the therapeutic agent may be in the corona of the micelle, or between the core of the micelle and the corona. The closer the therapeutic agent is to the outside, the easier it is for it to impart its therapeutic benefit without the kinetics being limited to the 5 controlled degradation of the micelle or a coating of the micelle.
  • the core may remain liquid and a biomarker molecule may be ligated to a magnetic micelle for use in a method of imaging, which may form part of a method of diagnosis.
  • the biomarker may be an antibody marker or a biomarker 10 which interacts with specific cells.
  • the method of diagnosis may be performed on cells in vivo or in vitro.
  • the micelle can be coated with a coating that encapsulates the plurality of nanotubes to form a nanotube-micelle capsule. This can be achieved by processing the micelle
  • the coating_ is applied directly through layer by layer electrostatic deposition in solution without removing the solvent.
  • the nanotube-micele capsules can be suspended in a suitable liquid and
  • a portion, or all, of the nanotube can be magnetic, possessing one or more of diamagnetic, paramagnetic and ferromagnetic properties.
  • the nanotubes can be 25 doped, coated with magnetic materials or grown to have magnetic properties for example. The doping or coating can take place before or after the formation of the micelle. Alternatively attachment of a 'magnetising' element may be undertaken during or after micelle formation.
  • Additional layers of surfactant can be added around the micelle to enhance stability through electrostatic interaction or steric hindrance.
  • the magnetic properties of the micelle can be improved by adding magnetic particles within the additional surfactant layers as a non-bonded dispersion or by binding magnetic particles to the nanotubes or additional surfactant layers.
  • Both nanotube-micelle capsules and non-coated micelles after being introduced into a human or animal body can be made to vibrate in response to a magnetic field. This will have the effect of locally raising the temperature within the body and can be used to destroy tumour cells via tumour ablation therapy. Such vibrations can also be used to disrupt the micelle or coating for the targeted delivery of the therapeutic composition or agent at the core of the micelle. Delivery can also be triggered by other means such as a near-IR radiation.
  • At least one of the nanotube micelles and nanotube micelle capsules may be introduced to the body in various ways including direct injection, ingestion, inhalation or topical administration. They may be directed to a target within the body via the body's natural pathways, for example when the capsule or micelle has been ligated to a marker molecule, or via the magnetic properties of the nanotube or micelle.
  • a beam of radiation such as near-infra red (IR) radiation
  • IR near-infra red
  • the nanotubes will absorb some of this radiation and vibrate, locally raising the temperature.
  • the locally raised temperature may affect the body, for example by denaturing the tumour cell.
  • the increased thermal energy may cause the coating of the capsule to breakdown, either gradually or suddenly, and thereby release the therapeutic agent having delivered it to the desired location
  • This method of treatment is particularly suitable when the nanotubes are made of carbon.
  • an alternating magnetic field of a resonant frequency can be applied to the part of the body. If the nanotubes are magnetic, or the micelles have embedded magnetic particles then the micelles will vibrate in response, generating thermal energy as described above, with similar effects.
  • the invention is intended for use in medical applications, its application is broader and the nanotube micelles may be incorporated in composite polymers or electropolymers to enhance material properties such as conductivity and toughness.
  • the nanotube micelles may also find use in optics, for example as nano-emissive devices in field emission displays, where tfie nanotube micelles can be bound to suitable substrates.
  • the invention also provides methods of manufacturing nanotubes as claimed in claims 14 to 18.
  • the invention also provides methods of treatment using the micelles according the invention, as claimed in claims 19 to 22.
  • FIG. 1 is a schematic drawing of three different amphiphilic nanotubes that can be used to form a micelle according to the present invention
  • Figure 2 is a schematic cross-section drawing of a spherical micelle according to the present invention.
  • Figure 3 is schematic cross-section drawing of a bi-layer micelle according to the present invention.
  • Figure 4 is a schematic cross-section drawing of a spherical micelle with additional surfactant layers.
  • Figure 5 is a schematic cross-section drawing of a spherical micelle with an outer coating.
  • a single- walled carbon nanotube 2 can be coated at one end or side with a hydrophilic surfactant coating 4.
  • the other end or side can be left uncoated (as in the case of the first and second nanotubes) or coated with a hydrophobic surfactant coating 6.
  • the nanotubes 2 may be formed by one of the following methods:
  • Nanotubes with magnetic properties are aligned and anchored to a substrate (such as a metal plate or container, for example) by applying a magnetic field.
  • the nanotubes may be aligned in a monolayer, such that the side of the nanotubes in contact with the container surface is not available for binding with the surfactant.
  • the nanotubes are then treated with surfactant solution at exposed regions with subsequent attachment of surfactant molecules. Upon washing off the excess surfactant solution the tubes can be released from the container surface by removal of the magnetic field used to hold the nanotubes in a specific conformation during the surfactant coating stage.
  • nanotubes which have catalyst ions at one or both ends of the nanotubes.
  • Such nanotubes can be aligned in an electrochemical cell between the anode and cathode, with the end containing the catalyst ions being attracted to the cathode.
  • the nanotubes can be aligned in a layer, which is preferably a monolayer, across a cathode substrate.
  • a protective material e.g. a polymer, can be used to coat the exposed surface.
  • the nanotubes can be released from the substrate.
  • the uncoated surface can then be functionalised via treatment with a weak acid. Subsequently a surfactant molecule can be attached to the functionalised surface.
  • the nanotubes can be treated with a suitable solvent, such as a surfactant solvent, to reduce interfacial tension.
  • a suitable solvent such as a surfactant solvent
  • the nanotube in the solvent is placed in a vacuum chamber so that the solvent is received in the open end of the nanotubes.
  • the nanotubes are then washed to remove excess solvent.
  • a suitable molecule in solution is added to the filled but previously empty nanotubes. The molecule will undergo bonding with surface of the solvent contained in the nanotube in preference to bonding with the surface of the nanotube.
  • the solvent may be a surfactant and the molecule may be obtained from an emulsifier solution.
  • Nanotubes generally have ends that are more susceptible to oxidation than the other parts of the tube, for example in the presence of a weak acid, ozone or oxygen.
  • the closed end can be functionalised by washing the nanotube with a weak acid.
  • a suitable molecule e.g. a surfactant molecule, can then be attached to the functionalised end. If both ends of the nanotube are closed, then the dilute acid wash can be optimised so that only one end is functionalised.
  • each nanotube 8 has a hydrophilic end 8a and a hydrophobic end 8b.
  • the hydrophobic ends 8b of the nanotubes 8 cluster together at the centre of the micelle to form a core 10 while the hydrophilic ends 8 a point away from the centre of the micelle to form a corona 12 that is substantially spherical.
  • the nanotubes can solubilize therapeutic agents through encapsulation of the continuous phase media within the micelle, and preferably within the core.
  • each nanotube 14 has a hydrophilic end 14a and a hydrophobic end 14b.
  • the hydrophobic ends 14b of the nanotubes 14 cluster together to form a pair of elongate cores 16 while the hydrophilic ends 14a point away from the respective cores (in the case of the nanotubes located between the cores this means that the hydrophilic ends may point towards the other core) to form a corona 18 that is substantially cylindrical.
  • one or more additional layers of different types of surfactant molecules 20 may be added as shown in Figure 4.
  • the additional surfactant molecules 20 may enhance the stability of the micelle through electrostatic interaction or via steric hindrance by virtue of the size and long chain length of the surfactant molecules 20.
  • the external surfactant layer(s) can be such that micelle formation occurs upon reaching the threshold concentration of the surfactant coated nanotubes where the continuous phase is oil, thus forming a type of emulsified micellar suspension.
  • Magnetic or metallic particles 22 of various shapes may be imparted by adding magnetic or metallic particles 22 of various shapes in various places, including within the additional surfactant layers, as a non-bonded dispersion amongst the long chains of the surfactant molecules 20, and by addition of metal particles 22 which bind with the individual surfactant-coated nanotubes 2.
  • Figure 5 shows a nanotube-micelle capsule 24 which has been made by further processing a nanotube micelle to encapsulate it within an outer coating 26.
  • the coating 26 is made of a biocompatible material, for example a lipid or a pharmaceutical polymeric material.
  • the material and structure of the outer coating 26 is chosen for its intended purpose and may resist degradation in the body, or may be designed to degrade over time so as to give a controlled release of the nanotube- micelle and optionally the therapeutic agent.
  • the coating 26 completely encapsulates the nanotube micelle, and is substantially rigid so that it constrains the movement of the nanotubes inside.
  • the nanotube-micelle capsule 24 may be made in a variety of ways.
  • the first step of in making the capsule 24 is removal of solvent from the nanotube micelle.
  • the nanotube micelles are substantially rigid and can be coated using various methods to make the rigid nanotube-micelle capsule 24. This may be by spray coating, vapour deposition, or electrostatic layer by layer deposition.
  • the nanotube-micelle capsule 24 can then be re-suspended in aqueous media and ligated to a marker molecule and its therapeutic application may include either direct administration by injection, into tumor sites, or systemic administration by injection, followed by the use of a magnetic field , to ablate tumor cells.
  • nanotubes are spatially restrained within the coating 26 of the nanotube- micelle capsule 24. Because the nanotubes are spatially restrained within the coating 26 of the nanotube- micelle capsule 24, applying a magnetic field or near-IR radiation results in a vibratory excitation of the nanotube micelles and any particles 22 within the nanotube capsule 24. This results in a higher localized temperature than that which might be achieved by using individual nanotubes, thus making it a more efficient mode of tumor ablation therapy.
  • the coating 26 may be broken down by the vibrations or the thermal energy to release the therapeutic agent from the nanotube capsule 24.
  • the size of the micelle is necessarily limited.
  • the size of the nanotube micelle is controlled primarily by the length of the nanotubes.
  • the nanotube length can be reduced prior to or after functionalisation through various methods, e.g. ultra homogenisation or grinding between plates.
  • the method involves oxidising both ends of the nanotubes, adding a surfactant to the nanotubes to bond with the ends, then homongenising or grinding between plates to break the nanotubes into pieces.
  • the resulting nanotubes have surfactant at just one end.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Nanotechnology (AREA)
  • Materials Engineering (AREA)
  • Organic Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Condensed Matter Physics & Semiconductors (AREA)
  • Manufacturing & Machinery (AREA)
  • Composite Materials (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une micelle pouvant être formée à partir d'au moins un nanotube dans un procédé d'auto-assemblage, le nanotube comprenant un nanotube amphiphile (2, 8, 14) fabriqué à partir d'une ou de plusieurs espèces choisies dans le groupe constitué par le carbone, le silicium, un métal noble, le dioxyde de silicium et le dioxyde de titane. Une partie du nanotube (2, 8, 14) est fonctionnalisée et une molécule tensioactive ou un agent émulsifiant est fixé(e) à cette partie fonctionnalisée. Le nanotube (2, 8, 14) peut présenter des propriétés magnétiques. Un agent thérapeutique peut être incorporé dans la micelle. Cette micelle peut être revêtue en vue de la formation d'une capsule (24). Cette capsule (24) peut être introduite dans le corps d'un être humain ou d'un animal en vue d'un traitement de tumeurs ou d'une administration de médicament ciblée lors de l'application d'un champ magnétique ou d'un rayonnement infrarouge proche.
EP06794776A 2005-10-14 2006-10-16 Nanotubes amphiphiles et micelles les comprenant pour l'administration d'agents biologiquement actifs Withdrawn EP1934138A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0520902.8A GB0520902D0 (en) 2005-10-14 2005-10-14 Nanotubes
GB0612701A GB2434363B (en) 2005-10-14 2006-06-27 Amphiphilic nanotubes and micelles comprising them for use in the delivery of biologically active agents
PCT/GB2006/003831 WO2007042833A2 (fr) 2005-10-14 2006-10-16 Nanotubes amphiphiles et micelles les comprenant pour l'administration d'agents biologiquement actifs

Publications (1)

Publication Number Publication Date
EP1934138A2 true EP1934138A2 (fr) 2008-06-25

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EP06794776A Withdrawn EP1934138A2 (fr) 2005-10-14 2006-10-16 Nanotubes amphiphiles et micelles les comprenant pour l'administration d'agents biologiquement actifs

Country Status (2)

Country Link
EP (1) EP1934138A2 (fr)
WO (1) WO2007042833A2 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2952648B1 (fr) * 2009-11-17 2013-05-03 Thales Sa Procede de poration de cellules comprises dans un substrat comportant l'utilisation de nanotubes comme recepteur hyperfrequences
ES2821528T3 (es) 2012-11-14 2021-04-26 Grace W R & Co Composiciones que contienen un material biológicamente activo y un óxido inorgánico no ordenado
WO2014126536A1 (fr) * 2013-02-15 2014-08-21 Agency For Science, Technology And Research Macro et micro-billes liquides photoréactives

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Publication number Priority date Publication date Assignee Title
CA2473529A1 (fr) * 2002-01-15 2003-07-24 Versilant Nanotechnologies, Llc Compositions de nanotubes de carbone en suspension, procedes de fabrication correspondants, et utilisations associees
TW200307563A (en) * 2002-02-14 2003-12-16 Sixty Inc C Use of BUCKYSOME or carbon nanotube for drug delivery
US6890654B2 (en) * 2002-04-18 2005-05-10 Northwestern University Encapsulation of nanotubes via self-assembled nanostructures
AU2003298647A1 (en) * 2002-11-14 2004-06-15 Claussen, Randal, C. Synthesis and self-assembly of abc triblock bola peptide
US7704754B2 (en) * 2004-01-27 2010-04-27 American Environmental Systems, Inc. Method of plasmon-enhanced properties of materials and applications thereof
US7507764B2 (en) * 2003-10-15 2009-03-24 Tego Biosciences Corporation Amphiphilic [5:1]- and [3:3]- hexakisadducts of fullerenes
US20070128440A1 (en) * 2003-12-11 2007-06-07 The Trustees Of The University Of Pennsylvania Cellular probes

Non-Patent Citations (1)

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Title
See references of WO2007042833A2 *

Also Published As

Publication number Publication date
WO2007042833A3 (fr) 2007-07-12
WO2007042833A2 (fr) 2007-04-19

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