WO2012142670A1 - Agent de résonance magnétique nucléaire - Google Patents

Agent de résonance magnétique nucléaire Download PDF

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Publication number
WO2012142670A1
WO2012142670A1 PCT/AU2012/000415 AU2012000415W WO2012142670A1 WO 2012142670 A1 WO2012142670 A1 WO 2012142670A1 AU 2012000415 W AU2012000415 W AU 2012000415W WO 2012142670 A1 WO2012142670 A1 WO 2012142670A1
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WIPO (PCT)
Prior art keywords
agent
nmr
nuclides
polymer chain
chemical reaction
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PCT/AU2012/000415
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English (en)
Inventor
Andrew Keith WHITTAKER
Hui Peng
Kristofer James THURECHT
Idriss Blakey
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The University Of Queensland
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Priority claimed from AU2011901492A external-priority patent/AU2011901492A0/en
Application filed by The University Of Queensland filed Critical The University Of Queensland
Publication of WO2012142670A1 publication Critical patent/WO2012142670A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/05—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves 
    • A61B5/055—Detecting, measuring or recording for diagnosis by means of electric currents or magnetic fields; Measuring using microwaves or radio waves  involving electronic [EMR] or nuclear [NMR] magnetic resonance, e.g. magnetic resonance imaging
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01R—MEASURING ELECTRIC VARIABLES; MEASURING MAGNETIC VARIABLES
    • G01R33/00—Arrangements or instruments for measuring magnetic variables
    • G01R33/20—Arrangements or instruments for measuring magnetic variables involving magnetic resonance
    • G01R33/44—Arrangements or instruments for measuring magnetic variables involving magnetic resonance using nuclear magnetic resonance [NMR]
    • G01R33/48—NMR imaging systems
    • G01R33/54—Signal processing systems, e.g. using pulse sequences ; Generation or control of pulse sequences; Operator console
    • G01R33/56—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution
    • G01R33/5601—Image enhancement or correction, e.g. subtraction or averaging techniques, e.g. improvement of signal-to-noise ratio and resolution involving use of a contrast agent for contrast manipulation, e.g. a paramagnetic, super-paramagnetic, ferromagnetic or hyperpolarised contrast agent

Definitions

  • NUCLEAR MAGNETIC RESONANCE AGENT Field of the Invention relates in general to nuclear magnetic resonance (NMR) agents.
  • the invention relates to NMR agents for use in medical applications such as magnetic resonance imaging (MRI).
  • MRI magnetic resonance imaging
  • NMR is an effect whereby magnetic nuclei in a magnetic field absorb and then re-emit electromagnetic energy.
  • a given nuclei absorbs electromagnetic energy it is described as being on resonance.
  • Different nuclei within a molecule resonate at different frequencies for a given magnetic field strength, which in turn enables information to be obtained about chemical and structural features of the molecule.
  • the ability to derive such molecular information has seen NMR become an invaluable analytical technique used in a diverse array of applications.
  • MRI is a non-invasive technique that provides anatomical information about a subject.
  • contrast agent falls into a class known as a "relaxation" agent.
  • These types of agents function by altering the relaxation times (longitudinal relaxation time Ti, and/or transverse relaxation time T 2 ) of nearby water molecules located in tissue, etc.
  • T 2 transverse relaxation time
  • Such contrast agents can promote a brightening or darkening response in the resulting image.
  • Such agents are typically based on gadolinium complexes or iron oxide particles.
  • relaxation contrast agents are not without their limitations.
  • the contrast in anatomical features provided by the agent can be subtle and difficult to interpret.
  • Gadolinium based contrast agents also present toxicity concerns.
  • Contra agents are also somewhat limited in the information that can be derived from their use in that they only in effect provide information relating to their general location in a subject.
  • the present invention therefore provides a switchable nuclear magnetic resonance (NMR) agent comprising a plurality of covalently coupled NMR nuclides selected from one or more of D, B, F, Br, P and Si, one or more of said nuclides being covalently coupled to a polymer chain, said agent having a first form in which the NMR signal of said nuclides is diminished, wherein the agent is capable of undergoing a chemical reaction that causes the first form of the agent to switch into a second form in which the NMR signal of said nuclides is amplified.
  • NMR switchable nuclear magnetic resonance
  • an effective and versatile NMR agent can be provided using polymer having covalentiy coupled thereto one or more specific NMR nuclides selected from D, B, F, Br, P and Si.
  • specific NMR nuclides selected from D, B, F, Br, P and Si.
  • these specific nuclides are NMR visible in their own right and as such the agents in accordance with the invention may be categorised as "direct” signalling or imaging agents. In other words, this class of agent functions differently from the aforementioned "relaxation" agents.
  • the NMR agents in accordance with the invention are switchable in the sense that they (1) present a first form in which the NMR signal of the specified nuclides is diminished, and (2) by undergoing a chemical reaction switch from the first form into a second form in which the NMR signal of the specified nuclides is amplified.
  • the specified nuclides despite being NMR visible and forming part of the agent, the specified nuclides have a low if not absent NMR signal in the first form of the agent, and when the first form of the agent undergoes a chemical reaction it is transformed or switched into a second form of the agent in which the NMR signal of the specified nuclides is increased or appears.
  • an NMR agent in accordance with the invention can not only provide for a direct NMR signal from the specified nuclides from at least the second form of the agent, but the point in time and location of a chemical reaction can be detected as a result of the agent switching or being transformed from the first form to its second form.
  • the agent can therefore not only be used for conventional imaging, but also to image in real time the location of specific biochemical events in vivo.
  • the agent may also be designed such that the chemical reaction which promotes switching between its first form and second form also promotes release of a pharmaceutically active agent such as a drug associated with the agent.
  • the invention enables sophisticated imaging of drug release therapies. Such an approach advantageously allows for non-invasive and potentially quantitative analysis of drug release, accumulation, distribution at a site and its efficacy in vivo.
  • the NMR agent in accordance with the invention is capable of undergoing a chemical reaction in a biological system, said chemical reaction causing the first form of the agent to switch into a second form in which the NMR signal of said nuclides is amplified.
  • the biological system may be in vivo as in a subject, or it may be ex vivo or even in vitro.
  • the present invention also provides a method of detecting a chemical reaction in a medium, the method comprising introducing to the medium a switchable nuclear magnetic resonance (NMR) agent comprising a plurality of covalently coupled NMR nuclides selected from one or more of D, B, F, Br, P and Si, one or more of said nuclides being covalently coupled to a polymer chain, said agent having a first form in which the NMR signal of said nuclides is diminished, wherein upon undergoing the chemical reaction in the medium the first form of the agent switches into a second form in which the NMR signal of said nuclides is amplified, said amplified NMR signal being used to detect occurrence of the chemical reaction.
  • NMR switchable nuclear magnetic resonance
  • the present invention further provides a method of obtaining an image of a region of interest in a medium, the method comprising introducing to the medium a switchable nuclear magnetic resonance (NMR) agent comprising a plurality of covalently coupled NMR nuclides selected from one or more of D, B, F, Br, P and Si, one or more of said nuclides being covalently coupled to a polymer chain, said agent having a first form in which the NMR signal of said nuclides is diminished, wherein upon undergoing a chemical reaction in the medium the first form of the agent switches into a second form in which the NMR signal of said nuclides is amplified, said amplified NMR signal being used to obtain the image.
  • NMR switchable nuclear magnetic resonance
  • the medium in which the chemical reaction takes place, or image of a region of interest is obtained is a biological system.
  • the present invention also provides a composition comprising a switchable nuclear magnetic resonance (NMR) agent according to the invention and at least one pharmacologically acceptable carrier.
  • NMR switchable nuclear magnetic resonance
  • the present invention further provides a composition for magnetic resonance imaging (MRI) comprising a switchable nuclear magnetic resonance (NMR) agent according to the invention and at least one pharmacologically acceptable carrier.
  • MRI magnetic resonance imaging
  • NMR switchable nuclear magnetic resonance
  • the present invention also provides use of a switchable nuclear magnetic resonance (NMR) agent according to the invention in a medium.
  • NMR switchable nuclear magnetic resonance
  • the present invention further provides use of a switchable nuclear magnetic resonance (NMR) agent according to the invention as a magnetic resonance imaging (MRI) agent.
  • NMR switchable nuclear magnetic resonance
  • MRI magnetic resonance imaging
  • the present invention also provides use of a switchable nuclear magnetic resonance (NMR) agent according to the invention in obtaining an image of a region of interest in a medium.
  • NMR switchable nuclear magnetic resonance
  • the NMR agent further comprises a pharmaceutically active agent.
  • the NMR agent comprises a plurality of covalently coupled F NMR nuclides.
  • the specified NMR nuclides are covalently coupled to a polymer chain.
  • the polymer chain will generally be a synthetic polymer chain.
  • the polymer chain forms part of a microgel or a dendritic polymer.
  • the dendritic polymer may be a dendrimer or a hyperbranched polymer.
  • the NMR agent may comprise a plurality of polymer chains.
  • the NMR agent may comprise a plurality of polymer chains that are associated with each other, for example by way of crosslinking. Such polymer chains may form what is commonly known in the art as a microgel.
  • the NMR agent in accordance with the invention may conveniently be referred to as a polymeric NMR agent in the sense that the agent that provides for the first and second forms has a polymeric structure.
  • the polymeric structure of the agent may comprise other components such as a pharmaceutically active agent, the likes of which may be covalently bound thereto or physically constrained therein (for example as in encapsulation).
  • the NMR agent may also comprise one or more radioactive isotopes suitable for use in nuclear medical procedures such as nuclear medical imaging (e.g., positron emission tomography (PET)).
  • nuclear medical imaging e.g., positron emission tomography (PET)
  • Figure 1 illustrates ,9 F images of solutions of polymer wherein the fluorinated segments are in a hydrophobically-trapped environment (acetal protected glycerol methacrylate) (la) and the resulting image of the same solution following deprotection of the acetal group such that the fluorinated segments are in a hydrophilic environment (lb).
  • acetal protected glycerol methacrylate acetal protected glycerol methacrylate
  • the present invention provides for a switchable NMR agent.
  • switchable is meant that the agent is capable of being transformed from a first form into a second form as described herein.
  • the transition or switching of the first form into the second form is promoted through the first form of the agent undergoing a chemical reaction. Further detail in relation to the nature of such a chemical reaction is discussed below.
  • the NMR agent being “capable” of being transformed from a first form into a second form as described herein is therefore a reference to the agents "switchable” characteristic. Accordingly, the word “capable” is a reference to the agent's latent ability to be transformed from its first form to its second form.
  • the agent has latent ability to undergo a chemical reaction that causes the first form of the agent to switch into a second form in which the NMR signal of said nuclides is amplified.
  • the agent has potential to undergo a chemical reaction that causes the first form of the agent to switch into a second form in which the NMR signal of said nuclides is amplified.
  • the first form of the agent switches into a second form in which the NMR signal of said nuclides is amplified.
  • a chemical reaction will cause the first form of the agent to switch into a second form in which the NMR signal of said nuclides is amplified.
  • the NMR agent comprises a plurality of covalently coupled NMR nuclides selected from one or more of D, B, F, Br, P and Si.
  • covalently coupled is meant that one or more of said nuclides is covalently coupled, either directly or indirectly, to a polymer chain. Where only one of said nuclides is coupled to a polymer chain, it will be appreciated that the NMR agent in that case must comprise one or more additional polymer chains having at least one or more of said nuclides covalently coupled thereto (i.e. because the NMR agent itself must comprise a plurality of said nuclides).
  • the NMR agent may of course comprise a single polymer chain having a plurality of said nuclides covalently coupled thereto.
  • D, B, F, Br, P and Si represent the elements deuterium, boron, fluorine, bromine, phosphorus and silicon, respectively.
  • Both F and P have a 100% natural abundance and can be more technically represented as 1 F and 31 P, respectively.
  • the NMR visible nuclide of Si is 29 Si which has a 4.7% natural abundance.
  • the nuclide D may also be represented as 2 H and has a natural abundance of only 0.02%.
  • B has two NMR visible nuclides with n B being the most suitable for use in accordance with the invention and having a natural abundance of 80.4%.
  • Br also has two NMR visible nuclides, with both 79 Br and 81 Br being suitable for use in accordance with the invention and having a natural abundance of 50.5% and 49.5%, respectively.
  • NMR nuclides suitable for use in accordance with the invention may therefore also be represented as 2 H, 12 B, 19 F, 79 Br, 81 Br, 31 P, 29 Si.
  • NMR nuclides suitable for use in accordance with the invention may therefore also be represented as 2 H, 12 B, 19 F, 79 Br, 81 Br, 31 P, 29 Si.
  • the NMR agent comprises a nuclide that does not have 100% natural abundance
  • that nuclide may nevertheless be present in the agent at a relative % abundance higher than its natural abundance due to the agent being prepared using reagents having an enriched abundance of the nuclide.
  • F, D and Br are monovalent nuclides
  • B, P and Si are multivalent nuclides.
  • the remaining valence sites will of course be appropriately occupied by a suitable substituent.
  • the remaining valence sites may be occupied by one of the same or different nuclides.
  • the NMR agent comprises a plurality of coupled F NMR nuclides.
  • the NMR agent does not comprise an NMR nuclide selected from D, B, Br, P and Si.
  • the NMR agents in accordance with the invention are that (1) they have a first form in which the NMR signal of said nuclides is diminished, and (2) the first form of the agent is capable of undergoing a chemical reaction to afford a second form of the agent in which the NMR signal of said nuclides is amplified.
  • NMR signal of said nuclides being “diminished” and “amplified” is intended to be a relative measureable NMR signal difference between the first and second forms of the agent.
  • the amplified signal is amplified relative to the signal afforded by the first form of the agent and the diminished signal is diminished relative to the NMR signal afforded by the second form of the agent.
  • the diminished NMR signal of the first form of the agent may be diminished to such an extent that it is undetectable.
  • the diminished NMR signal may also present as a low intensity signal. It will be appreciated that what is meant by an undetectable or low intensity signal is that the signal attained within an acceptable time frame is not adequate for practical application. Conversely, it will be appreciated that what is meant by an amplified signal is that the signal attained within an acceptable -time frame is, if not more than, adequate for practical application.
  • the NMR signal of the nuclides is in effect being suppressed.
  • reference to an undetectable NMR signal being “amplified” is meant the suppression effect is removed such that the nuclides become detectable.
  • the nuclide NMR signal is "amplified” in the sense that the otherwise NMR visible nuclides transition from having an undetectable signal (i.e. in the first form of the agent) into having a detectable signal (i.e. in the second form of the agent).
  • the NMR agent in accordance with the invention comprises a plurality of the nuclides.
  • the agent will comprise per polymer chain an amount of nuclides ranging from about 0.3-15 mol% nuclides, for example about 1-10 mol% nuclides, or about 2-6 mol% nuclides.
  • the NMR signal of said nuclides is diminished by intramolecular mobility confinement of said nuclides, and the NMR signal of said nuclides is amplified by intramolecular mobility liberation of said nuclides.
  • the invention provides for a switchable polymeric nuclear magnetic resonance (NMR) agent comprising a plurality of covalently coupled NMR nuclides selected from one or more of D, B, F, Br, P and Si, one or more of said nuclides being covalently coupled to a polymer chain, said agent having a first form in which the NMR signal of said nuclides is diminished by intramolecular mobility confinement of said nuclides, wherein the agent is capable of undergoing a chemical reaction that causes the first form of the agent to switch into a second form in which the NMR signal of said nuclides is amplified by intramolecular mobility liberation of said nuclides.
  • NMR switchable polymeric nuclear magnetic resonance
  • intramolecular mobility is intended to mean the molecular motion a given atom or substituent group of a molecule may experience relative to another atom or substituent group of that same molecule.
  • an atom or a substituent group that forms part of a polymer chain will have a degree of mobility relative to other atoms or substituent groups that form part of the polymer chain.
  • the NMR signal of the nuclides may be diminished by intramolecular mobility "confinement of said nuclides". In other words, the diminished NMR signal of the nuclides is caused by the intramolecular mobility of the nuclides being confined in some way.
  • the NMR signal of the nuclides is amplified by intramolecular mobility "liberation of said nuclides". In that case, confinement of the nuclides is reduced or removed to thereby liberate and promote the intramolecular mobility of the nuclides. Given that intramolecular mobility of the nuclides is to be retained, it will be appreciated that liberation of this mobility does not embrace a situation where the nuclides are cleaved from the polymer chain.
  • intramolecular mobility confinement of the nuclides may therefore be considered to be where the molecular motion of the nuclides relative to the remainder of the polymer chain is suppressed.
  • intramolecular mobility liberation of said nuclides may be considered to be where suppressed molecular motion of the nuclides relative to the polymer chain is reduced or removed.
  • molecular motion of a given nuclide plays an important part in the ability of the nuclides to produce an NMR signal. Without wishing to be limited by theory, restricted intramolecular motion is believed to promote an increase in spin-spin relaxation of a nuclide, the effect of which is to diminish an NMR signal of that nuclide. Conversely, more free intramolecular motion of a nuclide is believed to promote a decrease in spin-spin relaxation of the nuclide which in turn gives rise to an amplified NMR signal of that nuclide.
  • the NMR signal of said nuclides may therefore be diminished by intramolecular mobility confinement of said nuclides which causes an increase in spin-spin relaxation of said nuclides, and the NMR signal of said nuclides is amplified by intramolecular mobility liberation of said nuclides which causes a decrease in spin-spin relaxation of said nuclides.
  • the nuclides provide for a diminished or amplified NMR signal as a result of an increase or decrease in dipole-dipole or quadrupolar interactions of the nuclides.
  • confinement and liberation of the nuclides effects the spin-spin relaxation of said nuclides, with this effect on the spin-spin relaxation being promoted by dipole- dipole or quadrupolar interactions of the nuclides.
  • the present invention therefore provides a switchable nuclear magnetic resonance (NMR) agent comprising a plurality of covalently coupled NMR nuclides selected from one or more of D, B, F, Br, P and Si, one or more of said nuclides being covalently coupled to a polymer chain, said agent having a first form in which the NMR signal of said nuclides is diminished by an increase in dipole-dipole or quadrupolar interactions of said nuclides, wherein the agent is capable of undergoing a chemical reaction that causes the first form of the agent to switch into a second form in which the NMR signal of said nuclides is amplified by a decrease in dipole-dipole or quadrupolar interactions of said nuclides.
  • NMR switchable nuclear magnetic resonance
  • the intensity of an NMR signal is believed to be dictated by the mobility of a given nuclide. This is particularly true for polymer chains according to the present invention in which the molecular motion of a nuclide is limited through being covalently bound to a relatively high molecular weight species (relative to small molecules). As molecular motion of the nuclide slows down or becomes confined, the NMR signal diminishes until a point is reached whereby the nuclide presents as a "solid-like material" where the NMR signal can become undetectable.
  • T 2 an important NMR parameter associated with mobility of a given nuclide and NMR signal intensity is the so-called spin-spin relaxation time T 2 .
  • T 2 in units of time
  • the NMR signal intensity is directly related to the inverse of the T 2 .
  • small molecules presenting nuclides with relatively unconfined mobility exhibit a high T 2 and may be of the order of several seconds in duration.
  • nuclides in a rigid solid have confined mobility and as such typically exhibit relatively short T 2 values in the order of only several micro seconds. Depending upon the degree of molecular motion, T 2 values between these two extremes are possible.
  • the NMR parameter T 2 is strongly influenced by a number of intra- and inter-nuclear interactions. Such interactions can be categorised into three classes, namely dipole-dipole couplings, quadrupolar couplings and electron-nuclear couplings.
  • dipole-dipole and quadrupolar couplings are believed to play an important role in influencing the signal intensity of the nuclides.
  • NMR signal intensity when a source of free electrons comes sufficiently close to interact with a given nuclide. Increased interaction results in diminishing the NMR signal of the nuclide even if its intramolecular mobility is not confined.
  • the source of free electrons may be provided by metallic species or so-called paramagnetic species which possess un-paired electrons.
  • the diminished and amplified NMR signal that operates in accordance with the invention is believed to result predominantly (i.e. greater than 50%, or 60%, or 80%) through dipole- dipole and/or quadrupolar couplings.
  • F, P and Si are believed to be primarily influenced through dipole-dipole couplings
  • D, B and Br are believed to be primarily influenced through quadrupolar couplings.
  • the NMR signal provided for and in accordance with the invention is not diminished or amplified through electron-nuclear interactions.
  • the NMR agent in accordance with the invention does not comprise a source of free electrons such as that which may be found in metallic species or paramagnetic species.
  • the nuclides used in accordance with the invention are covalently coupled to a polymer chain.
  • the nuclides may be covalently coupled directly to the polymer backbone of the polymer chain or they may be indirectly covalently coupled to the polymer chain through one or more atoms or substituent groups.
  • the polymer chain will generally be a synthetic polymer chain.
  • synthetic is meant that the polymer does not have a structure corresponding to a naturally occurring polymer such as, for example, a peptide. Accordingly, a “synthetic" polymer is not intended to embrace structures of naturally occurring polymers derived from biomolecules such as amino acids, carbohydrates and nucleic acids.
  • a polymer chain used in accordance with the invention will generally have a number average molecular weight (Mn) ranging up to about 10,000 kg/mol, for example from about 2-500 kg/mol, or from about 4-200 kg/mol.
  • Mn number average molecular weight
  • Mn values are those determined by size exclusion chromatography coupled with a multi-angle laser light scattering (MALLS) detector and a refractive index detector to provide absolute molecular weights and size distributions.
  • MALLS multi-angle laser light scattering
  • the polymer chains are prepared by condensation polymerisation.
  • the condensation polymerisation may be performed using the appropriate combination of poly- carboxylic acids (and ester derivatives thereof), poly-ols, poly-amines, poly-acyl chlorides, lactones and hydroxy-acids.
  • Condensation polymerisation is a form of step-growth polymerisation where monomers react to form polymer and in doing so release a low molecular weight species such as water or methanol. Such reactions are commonly performed using a catalyst.
  • condensation catalysts include Lewis acids such as antimony trioxide, titanium oxide and dibutyl tin dilaurate.
  • the polymer chains used in accordance with the invention are derived from ethylenically unsaturated monomers.
  • Polymerisation of the ethylenically unsaturated monomers may be conducted using a living or non-living polymerisation technique.
  • Living polymerisation is generally considered in the art to be a form of chain polymerisation in which irreversible chain termination is substantially absent.
  • An important feature of living polymerisation is that polymer chains will continue to grow while monomer and reaction conditions to support polymerisation are provided.
  • Polymer chains prepared by living polymerisation can advantageously exhibit a well defined molecular architecture, a predetermined molecular weight and narrow molecular weight distribution or low polydispersity.
  • Examples of living polymerisation include ionic polymerisation and controlled radical polymerisation (CRP).
  • Examples of CRP include, but are not limited to, iniferter polymerisation, stable free radical mediated polymerisation (SFRP), atom transfer radical polymerisation (ATRP), and reversible addition fragmentation chain transfer (RAFT) polymerisation.
  • SFRP stable free radical mediated polymerisation
  • ATRP atom transfer radical polymerisation
  • RAFT reversible addition fragmentation chain transfer
  • the polymer chains are prepared using a living polymerisation technique.
  • Equipment, conditions, and reagents for performing living polymerisation are well known to those skilled in the art.
  • living polymerisation agent a compound that can participate in and control or mediate the living polymerisation of one or more ethylenically unsaturated monomers so as to form a living polymer chain (i.e. a polymer chain that has been formed according to a living polymerisation technique).
  • Living polymerisation agents include, but are not limited to, those which promote a living polymerisation technique selected from ionic polymerisation and CRP.
  • the polymer chain is prepared by ionic polymerisation.
  • Living ionic polymerisation is a form of addition polymerisation whereby the kinetic-chain carriers are ions or ion pairs.
  • the polymerisation proceeds via anionic or cationic kinetic- chain carriers.
  • the propagating species will either carry a negative or " positive charge, and as such there will also be an associated counter cation or counter anion, respectively.
  • the living polymerisation agent might be represented as I ' M + , where I represents an organo-anion (e.g.
  • the living polymerisation agent might be represented as I + M " , where I represents an organo-cation (e.g. an optionally substituted alkyl cation) and M represents an associated counteranion.
  • Suitable agents for conducting anionic and cationic living polymerisation include, but are not limited to, aprotonic acids (e.g. aluminium trichloride, boron trifluoride), protonic (Bronstead) acids, stable carbenium-ion salts, organometallic compounds (e.g. N-butyl lithium, cumyl potassium) and Ziegler-Natta catalysts (e.g. triethyl aluminium and titanium tetrachloride).
  • the polymer chain is prepared by CRP.
  • the polymer chain is prepared by iniferter polymerisation.
  • Iniferter polymerisation is a well known form of CRP, and is generally understood to proceed by a mechanism illustrated below in Scheme 1.
  • Scheme 1 General mechanism of controlled radical polymerisation with iniferters.
  • the iniferter agent AB dissociates chemically, thermally or photochemically to produce a reactive radical species A and generally a relatively stable radical species B (for symmetrical iniferters the radical species B will be the same as the radical species A) (step a).
  • the radical species A can initiate polymerisation of monomer M (in step b) and may be deactivated by coupling with radical species B (in step c). Transfer to the iniferter (in step d) and/or transfer to dormant polymer (in step e) followed by termination (in step f) characterise iniferter chemistry.
  • Suitable iniferter agents are well known to those skilled in the art, and include, but are not limited to, dithiocarbonate, disulphide, and thiuram disulphide compounds.
  • the polymer chains are prepared by SFRP.
  • SFRP agent CD dissociates to produce an active radical species C and a stable radical species D.
  • the active radical species C reacts with monomer M, which resulting propagating chain may recombine with the stable radical species D.
  • SFRP agents do not provide for a transfer step.
  • Suitable agents for conducting SFRP are well known to those skilled in the art, and include, but are not limited to, moieties capable of generating phenoxy and nitroxy radicals. Where the agent generates a nitroxy radical, the polymerisation technique is more commonly known as nitroxide mediated polymerisation (NMP).
  • SFRP agents capable of generating phenoxy radicals include those comprising a phenoxy group substituted in the 2 and 6 positions by bulky groups such as tert-alkyl (e.g. t-butyl), phenyl or dimethylbenzyl, and optionally substituted at the 4 position by an alkyl, alkyloxy, aryl, or aryloxy group or by a heteroatom containing group (e.g. S, N or O) such dimethylamino or diphenylamino group.
  • a heteroatom containing group e.g. S, N or O
  • Thiophenoxy analogues of such phenoxy containing agents are also contemplated.
  • SFRP agents capable of generating nitroxy radicals include those comprising the substituent R'R 2 N-0-, where R 1 and R 2 are tertiary alkyl groups, or where R 1 and R 2 together with the N atom form a cyclic structure, preferably having tertiary branching at the positions a to the N atom.
  • nitroxy substituents include 2,2,5,5- tetraalkylpyrrolidinoxyl, as well as those in which the 5-membered hetrocycle ring is fused to an alicyclic or aromatic ring, hindered aliphatic dialkylaminoxyl and iminoxyl substituents.
  • a common nitroxy substituent employed in SFRP is 2,2,6,6-tetramethyl-l- piperidinyloxy.
  • the polymer chain is prepared by ATRP.
  • ATRP generally employs a transition metal catalyst to reversibly deactivate a propagating radical by transfer of a transferable atom or group such as a halogen atom to the propagating polymer chain, thereby reducing the oxidation state of the metal catalyst as illustrated below in Scheme 3.
  • a transferable group or atom (X , e.g. halide, hydroxyl, Ci-C 6 - alkoxy, cyano, cyanato, thiocyanato or azido) is transferred from the organic compound (E) to a transition metal catalyst (M t , e.g. copper, iron, gold, silver, mercury, palladium, platinum, cobalt, manganese, ruthenium, molybdenum, niobium, or zinc) having oxidation number (n), upon which a radical species is formed that initiates polymerisation with monomer (M).
  • M t transition metal catalyst
  • the polymer chain is prepared by RAFT polymerisation.
  • RAFT polymerisation is well known in the art and is believed to operate through the mechanism outlined below in Scheme 4.
  • RAFT polymerisation is believed to proceed through initial reaction sequence (a) that involves reaction of a RAFT agent (1) with a propagating radical.
  • This radical can then promote polymerisation of monomer (M), thereby reinitiating polymerisation.
  • the propagating polymer chain can then react with the dormant polymer species (3) to promote the reaction sequence (b) that is similar to reaction sequence (a).
  • a labile intermediate radical (4) is formed and subsequently fragments to form again a dormant polymer species together with a radical which is capable of further chain growth.
  • RAFT agents suitable for use in accordance with the invention comprise a thiocarbonylthio group (which is a divalent moiety represented by: -C(S)S-).
  • RAFT agents are described in Moad G.; Rizzardo, E; Thang S, H. Polymer 2008, 49, 1079-1 131 (the entire contents of which are incorporated herein by reference) and include xanthate, dithioester, dithiocarbonate, dithiocarbamate and trithiocarbonate compounds.
  • a RAFT agent suitable for use in accordance with the invention may be represented by general formula (I) or (II):
  • R and R* will typically be an optionally substituted organic group that function as a free radical leaving group under the polymerisation conditions employed and yet, as a free radical leaving group, retain the ability to reinitiate polymerisation.
  • R* is a x-valent group, with x being an integer > 1. Accordingly, R* may be mono-valent, di-valent, tri-valent or of higher valency. For example, R* may be an optionally substituted polymer chain, with the remainder of the RAFT agent depicted in formula (I) presented as multiple groups pendant from the polymer chain. Generally, x will be an integer ranging from 1 to about 20, for example from about 2 to about 10, or from 1 to about 5-.
  • Z* is a y-valent group, with y being an integer > 2. Accordingly, Z* may be di-valent, tri-valent or of higher valency. Generally, y will be an integer ranging from 2 to about 20, for example from about 2 to about 10, or from 2 to about 5.
  • R in RAFT agents used in accordance with the invention include optionally substituted, and in the case of R* in RAFT agents used in accordance with the invention include a x-valent form of optionally substituted, alkyl, alkenyl, alkynyl, aryl, acyl, carbocyclyl, heterocyclyl, heteroaryl, alkylthio, alkenylthio, alkynylthio, arylthio, acylthio, carbocyclylthio, heterocyclylthio, heteroarylthio, alkylalkenyl, alkylalkynyl, alkylaryl, alkylacyl, alkylcarbocyclyl, alkylheterocyclyl, alkylheteroaryl, alkyloxyalkyl, alkenyloxyalkyl, alkynyloxyalkyl, aryloxyalkyl, alkylacyloxy, alkylcarbocyclyloxy
  • R in RAFT agents used in accordance with the invention also include optionally substituted, and in the case of R* in RAFT agents used in accordance with the invention also include an x-valent form of optionally substituted, alkyl; saturated, unsaturated or aromatic carbocyclic or heterocyclic ring; alkylthio; dialkylamino; an organometallic species; and a polymer chain.
  • R in RAFT agents used in accordance with the invention include optionally substituted, and in the case of R* in RAFT agents used in accordance with the invention include an x-valent form of optionally substituted, Ci-C ⁇ alkyl, C 2 -Cig alkenyl, C 2 -Ci 3 ⁇ 4 alkynyl, C 6 -Ci8 aryl, Ci-C 18 acyl, C3-C18 carbocyclyl, C 2 -Cig heterocyclyl, C 3 -Cig heteroaryl, Ci-Cig alkylthio, C 2 -Cig alkenylthio, C 2 -Cig alkynylthio, C 6 -Ci arylthio, Ci-Cjg acylthio, C 3 -Cig carbocyclylthio, C 2 -Cig heterocyclylthio, C 3 -Cig heteroarylthio, C 3 -Ci
  • R in RAFT agents used in accordance with the invention include, and in the case of R* in RAFT agents used in accordance with the invention include an x-valent form of, an optionally substituted polymer chain
  • the polymers chain may be formed by any suitable polymerisation process such as radical, ionic, coordination, step-growth or condensation polymerisation.
  • the polymer chains may comprise homopolymer, block polymer, multiblock polymer, gradient copolymer, or random or statistical copolymer chains and may have various architectures such as linear, star, branched, graft, or brush.
  • Z in RAFT agents used in accordance with the invention include optionally substituted, and in the case of Z* in RAFT agents used in accordance with the invention include a y-valent form of optionally substituted: F, CI, Br, I, alkyl, aryl, acyl, amino, carbocyclyl, heterocyclyl, heteroaryl, alkyloxy, aryloxy, acyloxy, acylamino, carbocyclyloxy, heterocyclyloxy, heteroaryloxy, alkylthio, arylthio, acylthio, carbocyclylthio, heterocyclylthio, heteroarylthio, alkylaryl, alkylacyl, alkylcarbocyclyl, alkylheterocyclyl, alkylheteroaryl, alkyloxyalkyl, aryloxyalkyl, alkylacyloxy, alkylcarbocyclyloxy, alkylheterocyclyloxy,
  • Z in RAFT agents used in accordance with the invention include optionally substituted, and in the case of Z* in RAFT agents used in accordance with the invention include a y-valent form of optionally substituted: F, CI, Ci-Cjg alkyl, C 6 -Cig aryl, Q-Cig acyl, amino, C 3 -C[g carbocyclyl, C 2 -C lg heterocyclyl, C 3 -Cig heteroaryl, Cj-C 18 alkyloxy, Ce-Qg aryloxy, Cj-Cjg acyloxy, C3-C18 carbocyclyloxy, C 2 - Cig heterocyclyloxy, C 3 -C !
  • R k is selected from optionally substituted Ci-Qs alkyl, optionally substituted C 6 -Ci8 aryl, optionally substituted C 2 -Ci8 heterocyclyl, and optionally substituted C 7 -C 24 alkylaryl, cyano (i.e. -CN), and -S-R, where R is as defined in respect of formula (II).
  • the RAFT agent used in accordance with the invention is a trithiocarbonate RAFT agent and Z or Z* is an optionally substituted alkylthio group.
  • each alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, and polymer chain moiety may be optionally substituted.
  • a given Z, Z*, R or R* contains two or more of such moieties (e.g. alkylaryl), each of such moieties may be optionally substituted with one, two, three or more optional substituents as herein defined.
  • groups from which Z, Z*, R and R* may be selected, where a given Z, Z*, R or R* contains two or more subgroups (e.g.
  • a Z, Z*, R or R* with two subgroups defined as [group A][group B] is intended to also be a reference to a Z, Z*, R or R* with two subgroups defined as [group B][group A] (e.g. arylalkyl).
  • the Z, Z*, R or R* may be branched and/or optionally substituted.
  • an optional substituent includes where a -CH 2 - group in the alkyl chain is replaced by a group selected from -0-, -S-, -NR a - , -C(O)- (i.e. carbonyl), -C(0)0- (i.e. ester), and -C(0)NR a - (i.e. amide), where R* may be selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, arylalkyl, and acyl.
  • references herein to a x-valent, y-valent, multi-valent or di-valent "form of." is intended to mean that the specified group is a x-valent, y-valent, multi-valent or di-valent radical, respectively.
  • the specified group is intended to be a divalent radical.
  • a divalent alkyl group is in effect an alkylene group (e.g. - C3 ⁇ 4-).
  • the divalent form of the group alkylaryl may, for example, be represented by -(C 6 H4)-CH 2 -
  • a divalent alkylarylalkyl group may, for example, be represented by -CH2-(C 6 H4)-CH 2 -
  • a divalent alkyloxy group may, for example, be represented by -CH 2 -0-
  • a divalent alkyloxyalkyl group may, for example, be represented by -CH2-0-CH 2 -.
  • x-valent, y-valent, multi-valent, di-valent groups comprise two or more subgroups, for example [group A] [group B] [group C] (e.g. alkylarylalkyl), if viable one or more of such subgroups may be optionally substituted.
  • group A [group A] [group B] [group C] (e.g. alkylarylalkyl)
  • group C e.g. alkylarylalkyl
  • a polymer chain used in accordance with the invention is derived from one or more ethylenically unsaturated monomers.
  • a polymer chain so formed may be a homopolymer or copolymer.
  • Factors that determine copolymerisability of ethylenically unsaturated monomers are well documented in the art. For example, see: Greenlee, R. Z., in Polymer Handbook 3 rd edition (Brandup, J, and Immergut. E. H. Eds) Wiley: New York, 1989, p 11/53.
  • ethylenically unsaturated monomers that may be used to prepare a polymer chain in accordance with the invention include those of formula (III):
  • U and W are independently selected from -C0 2 H, -COR 1 , -CSR 1 , -
  • V is selected from hydrogen, R 1 , -C0 2 H, -C0 2 R', -COR 1 , -CSR 1 , -CSOR 1 , - COSR 1 , -CONH 2 , -CONHR 1 , -CONR !
  • R 1 is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted alkylaryl, optionally substituted alkylheteroaryl, and an optionally substituted polymer chain.
  • the or each R 1 may also be independently selected from optionally substituted C1-C22 alkyl, optionally substituted C 2 -C 22 alkenyl, optionally substituted C 2 -C 22 alkynyl, optionally substituted C ⁇ -Cig aryl, optionally substituted C 3 -Ci 8 heteroaryl, optionally substituted C3-C18 carbocyclyl, optionally substituted C 2 -Ci 8 heterocyclyl, optionally substituted C7-C24 arylalkyl, optionally substituted C4-C18 heteroarylalkyl, optionally substituted C 7 -C 24 alkylaryl, optionally substituted C 4 -Cig alkylheteroaryl, and an optionally substituted polymer chain.
  • R 1 may be independently selected from optionally substituted Ci-C 6 alkyl.
  • R 1 examples include those selected from alkyleneoxidyl (epoxy), hydroxy, alkoxy, acyl, acyloxy, formyl, alkylcarbonyl, carboxy, sulfonic acid,- alkoxy- or aryloxy-carbonyl, isocyanato, cyano, silyl, halo, amino, including salts and derivatives thereof.
  • polymer chains include those selected from polyalkylene oxide, polyarylene ether and polyalkylene ether.
  • Examples of monomers of formula (III) include maleic anhydride, N-alkylmaleimide, N- arylmaleimide, dialkyl fumarate and cyclopolymerisable monomers, acrylate and methacrylate esters, acrylic and methacrylic acid, styrene, acrylamide, methacrylamide, and methacrylonitrile, mixtures of these monomers, and mixtures of these monomers with other monomers.
  • monomers of formula (III) include: methyl methacrylate, ethyl methacrylate, propyl methacrylate (all isomers), butyl methacrylate (all isomers), 2- ethylhexyl methacrylate, isobornyl methacrylate, methacrylic acid, benzyl methacrylate, phenyl methacrylate, methacrylonitrile, alpha-methylstyrene, methyl acrylate, ethyl acrylate, propyl acrylate (all isomers), butyl acrylate (all isomers), 2-ethylhexyl acrylate, isobornyl acrylate, acrylic acid, benzyl acrylate, phenyl acrylate, acrylonitrile, styrene, functional methacrylates, acrylates and styrenes selected from glycidyl methacrylate, 2- hydroxyethyl methacrylate,
  • polar or hydrophilic components are more likely to be wetted or solvated by an aqueous medium such as water (attractive interaction), whereas apolar or hydrophobic components are less likely to be wetted or solvated by an aqueous medium such as water (repulsive interaction).
  • a polymer chain or section or region thereof as having hydrophilic or hydrophobic character.
  • the polymer chain or section or region thereof will generally be derived from one or more monomers having respective hydrophilic or hydrophobic character.
  • hydrophobic ethylenically unsaturated monomers include, but are not limited to, styrene, alpha-methyl styrene, butyl acrylate, butyl methacrylate, amyl methacrylate, hexyl methacrylate, lauryl methacrylate, stearyl methacrylate, ethyl hexyl methacrylate, crotyl methacrylate, cinnamyl methacrylate, oleyl methacrylate, ricinoleyl methacrylate, vinyl butyrate, vinyl tert-butyrate, vinyl stearate and vinyl laurate.
  • hydrophilic ethylenically unsaturated monomers include, but are not limited to, acrylic acid, methacrylic acid, hydroxyethyl methacrylate, hydroxypropyl methacrylate, acrylamide and methacrylamide, hydroxyethyl acrylate, N- methylacrylamide, ⁇ , ⁇ -dimethylacrylamide or dimethylaminoethyl methacrylate, or copolymers thereof.
  • a source of initiating radicals can be provided by any suitable means of generating free radicals, such as the thermally induced homolytic scission of suitable compound(s) (thermal initiators such as peroxides, peroxyesters, or azo compounds), the spontaneous generation from monomers (e.g. styrene), redox initiating systems, photochemical initiating systems or high energy radiation such as electron beam, X- or gamma-radiation.
  • Thermal initiators are generally chosen to have an appropriate half life at the temperature of polymerisation. These initiators can include one or more of the following compounds:
  • Photochemical initiator systems are generally chosen to have an appropriate quantum yield for radical production under the conditions of the polymerisation. Examples include benzoin derivatives, benzophenone, acyl phosphine oxides, and photo-redox systems.
  • Redox initiator systems are generally chosen to have an appropriate rate of radical production under the conditions of the polymerisation; these initiating systems can include, but are not limited to, combinations of the following oxidants and reductants: oxidants: potassium, peroxydisulfate, hydrogen peroxide, t-butyl hydroperoxide. reductants: iron (II), titanium (III), potassium thiosulfite, potassium bisulfite.
  • oxidants potassium, peroxydisulfate, hydrogen peroxide, t-butyl hydroperoxide.
  • reductants iron (II), titanium (III), potassium thiosulfite, potassium bisulfite.
  • Other suitable initiating systems are described in commonly available texts. See, for example, Moad and Solomon "The Chemistry
  • Initiators that are more readily solvated in hydrophilic media include, but are not limited to, 4,4-azobis(cyanovaleric acid), 2,2'-azobis ⁇ 2-methyl-N-[l,l-bis(hydroxymethyl)-2- hydroxyethyl]propionamide ⁇ , 2,2'-azobis[2-methyl-N-(2-hydroxyethyl)propionamide], 2,2'-azobis(N,N'-dimethyleneisobutyramidine), 2,2'-azobis(N,N'- dimethyleneisobutyramidine) dihydrochloride, 2,2'-azobis(2-amidinopropane)
  • Initiators that are more readily solvated in hydrophobic media include azo compounds exemplified by the well known material 2,2'-azobisisobutyronitrile.
  • Other suitable initiator compounds include the acyl peroxide class such as acetyl and benzoyl peroxide as well as alkyl peroxides such as cumyl and t-butyl peroxides. Hydroperoxides such as t-butyl and cumyl hydroperoxides are also widely used.
  • crosslinking of polymer chains may be achieved in numerous ways.
  • crosslinking may be achieved using multi- ethylenically unsaturated monomers.
  • crosslinking is typically derived through a free radical reaction mechanism.
  • crosslinking may be achieved using ethylenically unsaturated monomers which also contain a reactive functional group that is not susceptible to taking part in free radical polymerisation reactions (i.e. "functionalised” unsaturated monomers).
  • ethylenically unsaturated monomers which also contain a reactive functional group that is not susceptible to taking part in free radical polymerisation reactions (i.e. "functionalised” unsaturated monomers).
  • such monomers may be incorporated into the polymer backbone through polymerisation of the unsaturated group, and the resulting pendant functional group provides means through which crosslinking may occur.
  • monomers that provide complementary pairs of reactive functional groups i.e. groups that will react with each other
  • the pairs of reactive functional groups can react through non-radical reaction mechanisms to provide crosslinks.
  • a variation on using complementary pairs of reactive functional groups is where the monomers are provided with non-complementary reactive functional groups.
  • the functional groups will not react with each other but instead provide sites which can subsequently be reacted with a crosslinking agent to form the crosslinks.
  • crosslinking agents will be used in an amount to react with substantially all of the non-complementary reactive functional groups. Formation of the crosslinks under these circumstances will generally occur after polymerisation of the monomers.
  • crosslinking ethylenically unsaturated monomers and “functionalised unsaturated monomers” mentioned above can conveniently and collectively also be referred to herein as “crosslinking ethylenically unsaturated monomers” or “crosslinking monomers”.
  • crosslinking ethylenically unsaturated monomers or “crosslinking monomers” it is meant an ethylenically unsaturated monomer through which a crosslink is or will be derived.
  • Suitable multi-ethylenically unsaturated monomers that may be used to promote crosslinking include ethylene glycol di(meth)acrylate, triethylene glycol di(meth)acrylate, tetraethylene glycol di(meth)acrylate, 1,3-butylene glycol di(meth)acrylate, trimethylolpropane tri(meth)acrylate, 1 ,4-butanediol di(meth)acrylate, neopentyl glycol di(meth)acrylate, 1,6-hexanediol di(meth)acrylate, pentaerythritol di(meth)acrylate, pentaerythritol tri(meth)acrylate, pentaerythritol tetra(meth)acrylate, glycerol di(meth)acrylate, glycerol allyloxy di(meth)acrylate, 1,1,1- tris(hydroxymethyl)ethane di(meth)acryl
  • Suitable ethylenically unsaturated monomers which contain a reactive functional group that is not susceptible to taking part in free radical polymerisation reactions include acetoacetoxyethyl methacrylate, glycidyl methacrylate, N- methylolacrylamide, (isobutoxymethyl)acrylamide, hydroxyethyl acrylate, f-butyl- carbodiimidoethyl methacrylate, acrylic acid, ⁇ -methacryloxypropyltriisopropoxysilane, 2- isocyanoethyl methacrylate and diacetone acrylamide.
  • Examples of suitable pairs of monomers mentioned directly above that provide complementary reactive functional groups include N-methylolacrylamide and itself, (isobutoxymethyl)acrylamide and itself, ⁇ -methacryloxypropyltriisopropoxysilane and itself, 2-isocyanoethyl methacrylate and hydroxyethyl acrylate, and f-butyl- carbodiimidoethyl methacrylate and acrylic acid.
  • Suitable crosslinking agents that can react with the reactive functional groups of one or more of the functionalised unsaturated monomers mentioned above include hexamethylene diamine, melamine, trimethylolpropane tris(2-methyl-l-aziridine propionate) and adipic bishydrazide.
  • pairs of crosslinking agents and functionalised unsaturated monomers that provide complementary reactive groups include hexamethylene diamine and acetoacetoxyethyl methacrylate, hexamethylene diamine and glycidyl methacrylate, melamine and hydroxyethyl acrylate, trimethylolpropane tris(2- methyl-l-aziridine propionate) and acrylic acid, adipic bishydrazide and diacetone acrylamide.
  • the NMR agent comprises a plurality of the covalently coupled nuclides.
  • One or more of the nuclides is coupled to a polymer chain.
  • the NMR agent may comprise a plurality of polymer chains having at least one nuclide covalently coupled to each polymer chain.
  • the NMR agent may comprise a polymer chain to which a plurality of nuclides is covalently coupled.
  • a nuclide may be covalently coupled to a monomer from which the polymer chain is derived.
  • a polymer chain may be prepared using a functionalised monomer.
  • a "functionalised monomer” is intended to mean a monomer having at least one functional group that can participate in a polymerisation reaction so as to form the polymer chain and at least one other functional group that does not participate in the polymerisation reaction.
  • a polymer chain prepared using such a functionalised monomer will therefore comprise a monomer residue having covalently bound thereto a reactive functional group.
  • ethylenically unsaturated monomers which contain a reactive functional group that is not susceptible to taking part in free radical polymerisation reactions are described herein.
  • a polymer chain prepared using such a monomer will comprise a reactive functional group that may undergo subsequent chemical reaction so as to covalently couple a nuclide to the polymer chain.
  • methods of forming a polymer chain may require the use of an initiator.
  • free radical polymerisation reactions typically require the use of a free radical initiator or a residue thereof may as a part of the polymerisation reaction become covalently bound to the polymer chain.
  • the initiator may therefore comprise one or more nuclides and through such, a reaction process in effect covalently couple the nuclides to the so formed polymer chain.
  • methods of forming a polymer chain may require the use of a chain transfer agent.
  • a free radical polymerisation reaction may utilise a RAFT agent, and a residue of that agent will become covalently bound to the polymer chain.
  • the chain transfer agent may therefore comprise one or more nuclides and through such a reaction process in effect covalently couple the nuclides to the so formed polymer chain.
  • a “living polymerisation agent” functions as a chain transfer agent
  • reference herein to a “chain transfer agent” is intended to embrace a living polymerisation agent.
  • the one or more nuclides are therefore covalently coupled to a monomer residue that forms part of the polymer chain.
  • the one or more nuclides are covalently coupled to an initiator residue that forms part of the polymer chain.
  • the one or more nuclides are covalently coupled to a chain transfer agent residue that forms part of the polymer chain.
  • the polymer chain is prepared by polymerising one or more monomers having covalently coupled thereto one or more NMR nuclides selected from D, B, F, Br, P and Si.
  • the polymer chain is prepared using an initiator and/or chain transfer agent which as part of the polymerisation reaction one or both become covalently bound to the so formed polymer chain, wherein the initiator and/or chain transfer agent have covalently bound thereto one or more NMR nuclides selected from D, B, F, Br, P and Si.
  • the polymer chain is prepared using one or more functionalised monomers, the resulting polymer chain comprising at least one reactive functional group derived from the one or more functionalised monomers, wherein the at least one functional group of the polymer chain is reacted with a compound comprising one or more nuclide selected from D, B, F, Br, P and Si so as to covalently couple said one or more nuclides to the polymer chain.
  • the NMR agent comprises a plurality of covalently coupled F NMR nuclides.
  • the polymer chain may comprise one or more fluorine substituted groups selected from trifluoromethyl, perfluoroethyl, 2,2,2-trifluoroethyl, perfluoropropyl, perfluoroisopropyl, bis(trifluoromethyl)methyl, tris(trifluoromethyl)methyl, 2,2,3,3,3- pentafluoropropyl, perfluorobutyl, trifluoromethylphenyl, l,3-di(trifluoromethyl) phenyl, trifluoromethylbenzyl, l,3-di(trifluoromethyl)benzyl, tris(trifluoromethyl)-methylphenyl, tris(trifluoromethyl)-methylbenzyl, fluorophenyl, difluorophenyl, pentafluorophenyl and pentafluorobenzyl.
  • fluorophenyl difluorophenyl, pentafluorophenyl and pent
  • the covalently coupled F NMR nuclides are selected from trifluoromethyl, tris(trifluoromethyl) methyl, perfluorisopropyl, tris(trifluoro-methyl) methylbenzyl and pentafluorobenzyl.
  • the polymer chain is prepared using a monomer, initiator and/or chain transfer agent which form a covalently bound residue of the resulting polymer chain, wherein at least one of the monomer, initiator and chain transfer agent comprise a fluorine substituted group selected from trifluoromethyl, perfluoroethyl, 2,2,2-trifluoroethyl, perfluoropropyl, perfluoroisopropyl, bis(trifluoromethyl)methyl, tris(trifluoromethyl)methyl, 2,2,3, 3,3-pentafluoropropyl, perfluorobutyl, trifluoromethylphenyl, l,3-di(trifluoromethyl) phenyl, trifluoromethylbenzyl, 1,3- di(trifluoromethyl)benzyl, tris(trifluoromethyl)-methylphenyl, tris(trifluoromethyl)- methylbenzyl, fluorophenyl, difluoropheny
  • the covalently coupled F NMR nuclides are selected from trifluoromethyl, tris(trifluoromethyl) methyl, perfluorisopropyl, tris(trifluoro-methyl) methylbenzyl and pentafluorobenzyl.
  • monomers comprising one or more nuclides that may be used to prepare the polymer chain include trifluoroethyl acrylate (tFEA), 1H,1H,2H,2H- perfluorodecyl(meth)acrylate, lH,lH,2H,2H-perfluorooctyl(meth)acrylate, heptadecylfluorodecyl(meth)acrylate, pentafluorophenyl(meth)acrylate trifluoroethyl methacrylate (TFEMA), hexafluoroisopropyl acrylate (HFPA) and hexafluoroisopropyl methacrylate (HFPA), perfluoro-t-butyl ether of ethoxyethyl acrylate, perfluoro-t-butyl ether of ethoxyethyl methacrylate, 2,2,3,3-tetrafluoropropyl acrylate
  • the polymer chain provides for the required features of the NMR agent in ⁇ accordance with the invention, there is no particular limitation concerning the structure of the polymer chain.
  • the polymer chain is a linear polymer chain.
  • the NMR agent may comprise a plurality of linear polymer chains.
  • the plurality of linear polymer chains may be associated so as to form a three dimensional structure such as a microgel.
  • Polymer chains that form a microgel structure may be crosslinked to each other so as to retain the integrity of the three dimensional structure.
  • the microgel per se may not be considered in a strict sense to comprise "linear" polymer chains. Nevertheless, it is common within the art to often refer to microgels as an association of crossiinked linear polymer chains due to at least one technique by which they are commonly prepared.
  • Microgels are generally prepared by one or two approaches. The first of these is commonly referred to as a "self-assembly” approach. In that case, linear polymer chains are prepared such that they are capable of forming a micelle structure. Polymer chains capable of forming a micelle structure will generally exhibit amphipathic character. A conventional micelle structure presented in an aqueous liquid medium will typically be made up of assembled polymer chains having a section or region that exhibits hydrophilic character and is solvated by the surrounding aqueous liquid medium, with a hydrophobic section or region of the polymer chain forming the centre or core of the micelle structure. This type of micelle formation is commonly referred to as a "normal phase micelle” or an "oil-in water micelle".
  • Inverse or reverse micelles may also be formed where the liquid medium is hydrophobic in character and the hydrophobic section or region of the assembled polymer chains is solvated by the hydrophobic liquid medium, with the hydrophilic section or region of the polymer chains forming the centre or core of the micelle ' structure.
  • Inverse or reverse micelles are also commonly referred to as "water-in- oil micelles”.
  • Micelle structures typically exist in a form of equilibrium with their surrounding liquid medium in that the polymer chains that form the micelle structures are free to move away from the structure into the liquid medium.
  • the polymer chains may be provided with reactive functional groups that can function as a site to form a crosslink with one or more of the other polymer chains.
  • Such stabilised micelle structures are known as microgels.
  • Microgels may also be prepared by a so called "in situ" approach. In that case, a three dimensional crossiinked network of polymer chains may be prepared in a one step procedure without transition through a micelle structure. In that case, polymer chains are formed and simultaneously crossiinked during formation of the microgel. Microgels may be prepared using polymerisation techniques outlined herein well known to those skilled in the art.
  • the microgel is of a type that can absorb and can be swollen by a hydrophilic liquid.
  • the microgel is of a type that can absorb and can be swollen by an aqueous liquid.
  • the one or more said nuclides are covalently coupled to a polymer chain that forms part of a microgel structure.
  • the polymer chain may also be or form part of a dendritic polymer.
  • Dendritic polymers are a class of synthetic tree-like macromolecules and include dendrimers and hyperbranched polymers.
  • Dendrimers are known in the art to have completely branched star-like topologies, whereas hyperbranched polymers are known in the art to have imperfectly branched or irregular structures. Both dendrimer and hyperbranched polymer molecules are composed of repeating units that typically emanate from a central core structure or molecule.
  • Dendritic polymers may be prepared using polymerisation techniques well known to those skilled in the art, including those outlined herein. Synthetic techniques for hyperbranched polymers can be divided into two general categories. The first category involves techniques of the so called “single-monomer methodology” (SMM) where the polymers are prepared by polymerisation of so called “AB X , AB * or a latent AB X monomer”. The second category includes techniques of the so called “double-monomer methodology” (DMM) whereby the direct polymerisation of at least two types of monomers or a pair of monomers generates the hyperbranched polymer.
  • SMM single-monomer methodology
  • DMM double-monomer methodology
  • the SMM category includes a step-growth polycondensation approach for producing, for example, polyphenylene, polyester, polyamide and polycarbonate hyperbranched polymers, self-condensing vinyl polymerisation (SCVP) for producing, for example, polystyrene, poly(methacrylate) and poly(acrylate) hyperbranched polymers, multibranching ring-opening polymerisation (SCROP) for producing, for example, polyamine, polyether and polyester hyperbranched polymers, and proton-transfer polymerisation (PTP) for producing, for example, polysiloxane and polyester hyperbranched polymers with epoxy or hydroxyl end groups.
  • SCVP self-condensing vinyl polymerisation
  • SCROP multibranching ring-opening polymerisation
  • PTP proton-transfer polymerisation
  • the DDM category includes so called "A 2 + B 3 " methodology for producing, for example, polyamide, polycarbonate and polyurea hyperbranched polymers, and couple-monomer methodology (CMM), which is a combination of SMM and "A 2 + B 3 " methodologies, for producing, for example, poly(sulphone amine), poly(ester amine) and poly(urea urethane) hyperbranched polymers.
  • CMM couple-monomer methodology
  • hyperbranched polymers are well known to those skilled in the art, for example, as described by Mitsutoshi Jikei, Masa-aki Kakimoto, Prog. Polym. Sci. 26 (2001) 1233-1285, the entire contents of which are incorporated herein by cross reference.
  • the one or more of said nuclides are covalently bound to a polymer chain that is or forms part of a dendritic polymer.
  • the dendritic polymer may be a dendrimer or a hyperbranched polymer.
  • branching monomers include multi-ethylenically unsaturated monomers and poly-carboxylic acids (and ester derivatives thereof), poly-ols, poly-amines, and poly-acyl chlorides as described herein.
  • the "polymer chain” may be conveniently referred to as a "microgel” or a “dendritic polymer”.
  • the nuclides may be referred to as being covalently coupled to a "microgel” or a "dendritic polymer”.
  • NMR agent in accordance with the invention is that it can provide for a first and second form in which the NMR signal of the nuclides is diminished and amplified, respectively.
  • the transition of the agent from its first form to its second form may herein be described as the agent "switching" or being “switched” from the first form to the second form.
  • switching of the NMR agent occurs as a result of the first form of the agent undergoing a chemical reaction to provide for the second form of the agent.
  • the first form of the agent may provide for intramolecular mobility confinement of the nuclides, and this form of the agent undergoes a chemical reaction to provide for intramolecular mobility liberation of the nuclides.
  • the chemical reaction may result in the cleavage of a covalent bond associated with the polymer chain.
  • the chemical reaction may result in decomplexation of a complexed moiety associated with the polymer chain. Such decomplexation may be promoted itself through cleavage of a covalent bond associated with the polymer chain.
  • the chemical reaction that causes the first form of the agent to switch to the second form promotes cleavage of a covalent bond associated with (i.e. forms part of) the polymer chain, said cleavage of the covalent bond not resulting in the covalently coupled nuclides being cleaved from the polymer chain.
  • cleavage of the covalent bond not resulting in the covalently coupled nuclides being cleaved from the polymer chain is meant that after cleavage of the covalent bond the nuclides must still be covalently coupled to a polymer chain.
  • the nuclides of the NMR agent in its first form are in a state of intramolecular mobility confinement.
  • the polymer chain presents a structure in which the intramolecular mobility of the nuclides is restricted or confined such that their NMR signal is diminished or absent.
  • the intramolecular mobility confinement of said nuclides occurs as a result of the nuclides being located within a hydrophobic environment.
  • the nuclides of the NMR agent may be located within a section or region of a microgel or dendritic polymer which is substantially hydrophobic in character whereby the hydrophobic character causes intramolecular mobility confinement of the nuclides. This might be achieved by covalently coupling, complexing or encapsulating a hydrophobic moiety or material so as to promote a hydrophobic environment in the section or region comprising the nuclides.
  • Such a structure presents as the first form of the NMR agent.
  • Decomplexation or cleavage of a covalent bond associated with this form of the agent may promote release of the hydrophobic moiety or material from the agent, thereby reducing or removing the intramolecular mobility confinement of the nuclides so as to provide for intramolecular mobility liberation of the nuclides.
  • the chemical reaction causes release from the agent of a hydrophobic moiety which in turn causes the first form of the agent to switch into a second form in which the NMR signal of said nuclides is amplified.
  • the one or more nuclides may be covalently coupled to a polymer chain that forms part of a microgel or dendritic polymer structure, the polymer chain further comprising a hydrophobic moiety covalently coupled thereto such that the NMR signal of said nuclides is diminished.
  • the nuclides will be of a type that preferentially associate with covalently coupled or complexed hydrophobic character and within the structure of the polymer consequently have their intramolecular mobility confined.
  • This structure of the agent represents the first form of the agent.
  • the chemical reaction then promotes decqmplexation or cleavage of the covalently coupled hydrophobic moiety from the polymer chain, which in turn provides intramolecular mobility liberation of the nuclides.
  • the one or more nuclides may be covalently coupled to a polymer chain that forms part of a microgel or dendritic polymer having a crosslinked structure.
  • the crosslinked polymer structure having encapsulated therein hydrophobic material such that the NMR signal of said nuclides is diminished.
  • the nuclides will be of a type that preferentially associate with encapsulated hydrophobic character and within the structure of the polymer consequently have their intramolecular mobility confined.
  • This structure of the agent represents the first form of the agent.
  • the chemical reaction then promotes cleavage of the crosslinks which enables the hydrophobic material to be released from the polymer, and in turn provides intramolecular mobility liberation of the nuclides.
  • a hydrophobic moiety or material is used to promote intramolecular mobility confinement of the nuclides, it may be desirable to have covalently coupled in the proximity of the nuclides a hydrophilic moiety to facilitate intramolecular mobility liberation of the nuclides.
  • the NMR agent may be present within a hydrophilic liquid environment, such as a predominantly aqueous liquid environment.
  • intramolecular mobility of the nuclides may be confined by being associated with covalently coupled hydrophobic moieties or encapsulated hydrophobic material in and around the location of the nuclides. Release of the hydrophobic moieties or hydrophobic material from the agent will then enable aqueous liquid to more readily interact with the nuclides, the process of which may be facilitated by hydrophilic moieties covalently coupled in the proximity of the nuclides.
  • the covalently coupled hydrophobic moiety may be a protected hydrophilic group, whereby deprotection of the hydrophobic moiety affords a covalently coupled hydrophilic group. This might be achieved by, for example, acetal deprotection.
  • the second form of the agent comprises an aqueous swollen polymer structure which promotes intramolecular mobility liberation of the nuclides.
  • the covalently coupled hydrophobic moiety, the complexed hydrophobic moiety or the encapsulated hydrophobic material may be a pharmaceutically active agent.
  • the NMR agent in accordance with the invention not only provides for a switch that promotes improved NMR-visibility of the nuclides contained therein, but the chemical reaction that causes the NMR signal of the nuclides to be amplified also promotes release of a pharmaceutically active agent from the NMR agent.
  • Such versatility of the NMR agent can allow analysis of drug distribution and accumulation of the target site of a subject while facilitating quantification of delivery.
  • the chemical reaction further causes a pharmaceutically active agent to be released from the NMR agent.
  • the polymer chain further comprises a covalently coupled, complexed or encapsulated pharmaceutically active agent.
  • the pharmaceutically active agent may be covalently coupled or complexed to the polymer chain via a monomer, initiator and/or chain transfer agent residue that forms part of the polymer chain.
  • the pharmaceutically active agent may be covalently coupled or complexed to the polymer chain during the process of forming the polymer chain, or subsequently covalently coupled or complexed to the polymer chain after it has been formed.
  • the polymer chain will of course be prepared with one or more suitable functional groups that will enable the pharmaceutically active agent to -be covalently coupled or complexed thereto.
  • Switching of the NMR agent may also . occur through decomplexation of a moiety complexed to the polymer chain.
  • the polymer chain may present an ionic charge such as a cationic charge or an anionic charge.
  • Complexation of the polymer chain with an oppositely charged moiety can result in a densely packed complexed structure which causes intramolecular mobility confinement of the nuclides. Decomplexation of the complexed structure through a chemical reaction can promote intramolecular mobility liberation of the nuclides.
  • the one or more nuclides may be covalently coupled to a cationic polymer chain, the cationic polymer chain forming a neutral complexed structure with an anionic moiety.
  • the complexed structure promotes intramolecular mobility confinement of the nuclides.
  • This structure of the agent represents the first form of the agent. The chemical reaction then promotes decomplexation of the complexed structure, which in turn provides intramolecular mobility liberation of the nuclides.
  • the one or more of said nuclides are covalently coupled to an ionically charged polymer chain.
  • the NMR signal of said nuclides is diminished due to the ionically charged polymer chain being complexed with an oppositely ionically charged moiety. In a further embodiment, the NMR signal of said nuclides is amplified due to decomplexation of the ionically charged polymer chain and the opposite ionically charged moiety.
  • the polymer chain is cationically charged.
  • the NMR agent is in a complexed form
  • the type of chemical reaction that can cause this first form of the agent to switch into the second and decomplexed form of the agent in which the NMR signal of the nuclides is amplified.
  • the chemical reaction may be, for example an ion exchange reaction or as a result of a change in pH.
  • the complexed form of such an agent may also comprise one or more covalent bonds between the ionically charged polymer and the opposite ionically charged moiety. In that case, the cleavage of such covalent bonds may also promote decomplexation.
  • the opposite ionically charged moiety that may form a complex with the ionically charged polymer chain may be a pharmaceutically active agent such as an oligonucleotide.
  • the complexed form of the NMR agent may also provide for drug release therapy as herein described.
  • the chemical reaction that promotes switching of the first form of the agent into its second form may be a pH, redox or enzyme based reaction.
  • Such reactions, or the conditions to promote such reactions may occur in vivo in connection with a variety of biochemical events. For example, abnormal enzyme activity of certain enzymes is often observed in cancer or cancer related diseases, cardiovascular diseases, diseases of the central nervous system, in inflammations and infections. Determination of abnormal enzyme activity and identification of tissue or cell showing abnormal enzyme activity can therefore provide valuable diagnostic information.
  • the NMR agents in accordance with the invention can advantageously be tailor designed such that the chemical reaction which causes the first form of the agent to switch into the second form of the agent is promoted through a biochemical stimulus such as a change in pH, redox environment or by certain enzyme activity.
  • the covalent bond may form part of a redox degradable linkage, for example a disulfide linkage, or an acid hydrolysable linkage, for example an oxime, imine, ester, hydrazone or acetal linkage.
  • the cleaved covalent bond may form part of an enzyme degradable linkage, for example a peptide linkage.
  • the covalent bond may be enzymatically cleaved.
  • Such degradable linkages may be used to covalently couple a pharmaceutically active agent and/or hydrophobic moiety to a polymer chain used in accordance with the invention, or alternatively used in the formation of a crosslink that crosslinks polymer chains used in accordance with the invention.
  • the chemical reaction promotes cleavage of a hydrazone, oxime, imine, ester, disulfide and/or peptide group.
  • pharmaceutically active agents such as maytansine, doxrubicine, and paclitaxel may be covalently coupled to a polymer chain in accordance with the invention through a disulfide group, a hydrazone group and an acetal group, respectively.
  • the present invention therefore also provides a method of detecting a chemical reaction in a medium, the method comprising introducing to the medium a switchable nuclear magnetic residence (NMR) agent comprising a plurality of covalently coupled NMR nuclides selected from one or more or D, B, F, Br, P and Si, one or more of said nuclides being covalently coupled to a polymer chain, said agent having a first form in which the NMR signal of said nuclides is diminished, wherein upon undergoing the chemical reaction in the medium the first form of the agent switches into a second form in which the NMR signal of said nuclides is amplified, said amplified NMR signal being used to detect occurrence of the chemical reaction.
  • NMR switchable nuclear magnetic residence
  • the medium in which the chemical reaction takes place is a biological system.
  • the method of detecting the chemical reaction will of course comprise administering the switchable NMR agent to the subject.
  • the chemical reaction detected is an enzyme reacting with the NMR agent.
  • the NMR agent may be used to detect enzyme activity in the subject.
  • the method of detecting a chemical reaction may be described as a method of detecting enzyme activity in a subject, the method comprising administering to the subject a switchable NMR agent in accordance with the invention.
  • the amplified NMR signal is used to detect occurrence of the chemical reaction. Accordingly, it will be appreciated that the chemical reaction is required to occur within a suitable NMR detector such as a MRI apparatus or an NMR spectrometer.
  • the expression "pharmaceutically active agent” is intended to mean a drug or any other similar chemical or biological material or compound suitable for administration to a subject, that induces a desired biological or pharmacological effect, which may include but is not limited to (1) having a prophylactic effect on the subject and preventing an undesired biological effect such as preventing an infection, (2) alleviating a condition caused by a disease, for example, alleviating pain or inflammation caused as a result of disease, and/or (3) either alleviating, reducing, or completely eliminating the disease from the subject.
  • the effect may be local, such as providing for a local anaesthetic effect, or it may be systemic.
  • This invention is not intended to be limited to the use of specific pharmaceutically active agents. Rather in the context of pharmaceutically active agents it is concerned with the delivery of agents that exist in the state of the art or that may later be established as active agents and that are suitable for delivery by the present invention.
  • Such agents include broad classes of compounds normally delivered to a subject.
  • this includes but is not limited to: antiinfectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; helminthics; antiarthritics; antiasthmatic agents; anticonvulsants; antidepressants; antidiabetic agents; antidiarrheals; antihistamines; antiinflammatory agents; antimigraine preparations; antinauseants
  • antiproliferatives include ;antineoplastics; antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; cardiovascular preparations including potassium and calcium channel blockers, beta-blockers, alpha- blockers, and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators; including general coronary, peripheral and cerebral; central nervous system stimulants; vasoconstrictors; cough and cold preparations including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; and tranquilizers; probiotics.
  • the pharmaceutically active agent used in accordance with the invention is a cellular toxin.
  • cellular toxin herein should be understood to mean any proteinaceous or non- proteinaceous molecule or group of molecules which will either retard cell growth or induce cell death, for example either by directly killing the cell or else delivering a signal which induces apoptosis. That is, the toxin may be either cytostatic or cytocidal. It would be appreciated by the person of skill in the art that the present invention can be designed to deliver one cellular toxin or multiple cellular toxins (i.e. a "cocktail" of toxin). The decision in relation to how best to proceed can be made by the person of skill in the art as a matter of routine procedure. For example, depending on the diagnosis of the subject, certain specific toxins or combinations of toxins are regarded as particularly desirable to use.
  • cytotoxic agents function via the induction of apoptotic processes. However, this is not the only mechanism by which such agents function and it is conceivable that the subject damage or cell death may be induced by some other mechanism.
  • cytotoxic agents include, but are not limited to, Actinomycin D, Adriamycin, Arsenic Trioxide, Asparaginase, Bleomycin, Busulfan, Camptosar, Carboplatinum, Carmustine, Chlorambucil, Cisplatin, Corticosteroids, Colicheamicin, Cyclophosphamide, Daunorubicin, Docetaxel, Doxorubicin, Epirubicin, Etoposide, Fludarabine, Fluorouracil, Gemcitabina, Gemcitabine, Gemzar, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan, Lomustine, Maytansine, Melphalan, Mercaptomurine, Methotrexate, Mitomycin, Mitoxantrone, Oxaliplatin, Paclitaxel, Platinol, Platinex, Procarbizine, Raltitrexeel, Rixin, Steroids, Streptozocin, Taxol,
  • cellular toxin should also be understood to extend to any other molecule which is perhaps not traditionally regarded as a cytotoxic agent but nevertheless falls within the scope of the present definition on the basis that it induces cellular damage, for example DNA damage, such as nucleophosmin or agents which induce cellular damage as part of a synergistic process with another agent.
  • Examples include catalytic antibodies, prodrugs, CHKl/2 inhibitor (such as CBP-501 or AZD7762), histone deacetylase inhibitor (such as vorinostat), tumor necrosis factor related apoptosis inducing ligand or BH3 mimetic (such as ABT737), small molecule inhibitors such as the tyrosine kinase inhibitors imatinib mesylate (Glivec ® ), gefitinib (fressa ® ) and erlotinib (Tarceva ® ), and the monoclonal antibodies (mAb) such as rituximab (Mabthera ® ) and trastuzumab (Herceptin ® ).
  • CHKl/2 inhibitor such as CBP-501 or AZD7762
  • histone deacetylase inhibitor such as vorinostat
  • tumor necrosis factor related apoptosis inducing ligand or BH3 mimetic such as ABT
  • Combination treatments may include, for example, gemcitabine together with a CHKl 2 inhibitor or irinotecam together with a CHKl/2 inhibitor.
  • RNA interference broadly describes a mechanism of gene silencing which is based on degrading or otherwise preventing the translation of mRNA in a sequence specific manner.
  • exogenous double stranded RNA (dsRNA) specific to a gene sought to be knocked down can be introduced into the intracellular environment.
  • siRNAs double stranded small interfering RNAs 21-23 nucleotides in length that contain 2 nucleotide overhangs on the 3' ends.
  • RISC RNAi induced silencing complex
  • RNAi based gene expression knockdown can also function as a mechanism to regulate endogenous gene expression.
  • miRNA microRNA
  • the DNA sequence that codes for an miRNA gene generally includes the miRNA sequence and an approximate reverse complement.
  • the miRNA sequence and its reverse-complement base pair form a double stranded RNA hairpin loop, this forming the primary miRNA structure (pri-miRNA).
  • a nuclear enzyme cleaves the base of the hairpin to form pre-miRNA.
  • the pre-miRNA molecule is then actively transported out of the nucleus into the cytoplasm where the Dicer enzyme cuts 20-25 nucleotides from the base of the hairpin to release the mature miRNA.
  • RNAi based on the use of exogenously administered dsRNA generally results in mRNA degradation while RNAi based on the actions of miRNAs generally results in translational repression by a mechanism which does not involve mRNA degradation.
  • the RNA interference which is contemplated in the context of the present invention should be understood to encompass reference to both of these RNAi gene knockdown mechanisms.
  • the induction of this miRNA based knockdown mechanism could be achieved by administering, in accordance with the method of the invention, exogenous RNA oligonucleotides of the same sequence as an miRNA, pre-miRNA or pri-miRNA molecules.
  • RNA oligonucleotides may lead to either mRNA degradation (analogous to that observed with the introduction of an exogenous siRNA population) or mRNA translateral repression, this being akin to the mechanism by which the endogenous miRNA molecules function.
  • mRNA degradation analogous to that observed with the introduction of an exogenous siRNA population
  • mRNA translateral repression this being akin to the mechanism by which the endogenous miRNA molecules function.
  • the occurrence of either gene knockdown mechanism is acceptable.
  • RNA interference mechanism herein discussed is effected via the use of an RNA oligonucleotide which can induce an RNA interference mechanism.
  • Reference to an "RNA oligonucleotide” should therefore be understood as a reference to an RNA nucleic acid molecule which is double stranded or single stranded and is capable of either effecting the induction of an RNA interference mechanism directed to knocking down the expression of a gene targeted or downregulating or preventing the onset of such a mechanism.
  • the subject oligonucleotide may be capable of directly modulating an RNA interference mechanism or it may require further processing, such as is characteristic of hairpin double stranded RNA which requires excision of the hairpin region, longer double stranded RNA molecules which require cleavage by dicer or precursor molecules such as pre-miRNA which similarly require cleavage.
  • the subject oligonucleotide may be double stranded (as is typical in the context of effecting RNA interference) or single stranded (as may be the case if one is seeking only to produce a RNA oligonucleotide suitable for binding to an endogenously expressed gene).
  • RNA oligonucleotides suitable for use in the context of the present invention include, but are not limited to: (i) long double stranded RNA (dsRNA) - these are generally produced as a result of the hybridisation of a sense RNA strand and an antisense RNA strand which are each separately transcribed by their own vector. Such double stranded molecules are not characterised by a hairpin loop. These molecules are required to be cleaved by an enzyme such as Dicer in order to generate short interfering RNA (siRNA) duplexes. This cleavage event preferably occurs in the cell in which the dsRNA is transcribed.
  • dsRNA long double stranded RNA
  • hairpin double stranded RNA exhibit a stem-loop configuration and are generally the result of the transcription of a construct with inverted repeat sequences which are separated by a nucleotide spacer region, such as an intron.
  • These molecules are generally of longer RNA molecules which require both the hairpin loop to be cleaved off and the resultant linear double stranded molecules to be cleaved by Dicer in order to generate siRNA. This type of molecule has the advantage of being expressible by a single vector.
  • short interfering RNA (iii) short interfering RNA (siRNA) - these can be synthetically generated or, recombinantly expressed by the promoter based expression of a vector comprising tandem sense and antisense strands each characterised by its own promoter and a 4-5 thymidine transcription termination site. This enables the generation of.2 separate transcripts which subsequently anneal.
  • transcripts are generally of the order of 20-25 nucleotides in length. Accordingly, these molecules require no further cleavage to enable their functionality in the RNAi pathway.
  • shRNA short hairpin RNA
  • small hairpin RNA these molecules are also known as "small hairpin RNA" and are similar in length to the siRNA molecules but with the exception that they are expressed from a vector comprising inverted repeat sequences of the 20-25 nucleotide RNA molecule, the inverted repeats being separated by a nucleotide spacer. Subsequently to cleavage of the hairpin (loop) region, there is generated a functional siRNA molecule.
  • micro RNA/small temporal RNA (miRNA/stRNA) - miRNA and stRNA are generally understood to represent naturally occurring endogenously expressed molecules. Accordingly, although the design and administration of a molecule intended to mimic the activity of a miRNA will take the form of a synthetically generated or recombinantly expressed siRNA molecule, the method of the present invention nevertheless extends to the design and expression of oligonucleotides intended to mimic miRNA, pri-miRNA or pre-miRNA molecules by virtue of exhibiting essentially identical RNA sequences and overall structure.
  • Such recombinantly generated molecules may be referred to as either miRNAs or siRNAs.
  • miRNAs which mediate spatial development (sdRNAs), the stress response (srRNAs) or cell cycle (ccRNAs).
  • sdRNAs which mediate spatial development
  • srRNAs stress response
  • ccRNAs cell cycle
  • RNA oligonucleotides designed to hybridise and prevent the functioning of endogenously expressed miRNA or stRNA or exogenously introduced siRNA. It would be appreciated that these molecules are not designed to invoke the RNA interference mechanism but, rather, prevent the upregulation of this pathway by the miRNA and/or siRNA molecules which are present in the intracellular environment. In terms of their effect on the miRNA to which they hybridise, this is reflective of more classical antisense inhibition.
  • RNA oligonucleotide for use in any given situation.
  • the subject oligonucleotide may nevertheless exhibit some degree of mismatch to the extent that hybridisation sufficient to induce an RNA interference response in a sequence specific manner is enabled.
  • the oligonucleotide comprises at least 70% sequence complementarity, more preferably at least 90% complementarity and even more preferably, 95%, 96%, 97%, 98% 99% or 100% sequence complementarity.
  • oligonucleotides suitable for use in the present invention it is within the skill of the person of skill in the art to determine the particular structure and length of the subject oligonucleotide, for example whether it takes the form of dsRNA, hairpin dsRNA, siRNA, shRNA, miRNA, pre-miRNA, pri-miRNA etc.
  • stem-loop RNA structures such as hairpin dsRNA and shRNA, are more efficient in terms of achieving gene knockdown than, for example, double stranded DNA which is generated utilising two constructs separately coding the sense and antisense RNA strands.
  • the nature and length of the intervening spacer region can impact on the functionality of a given stem-loop RNA molecule.
  • choice of long dsRNA, which requires cleavage by an enzyme such as Dicer, or short dsRNA (such as siRNA or shRNA) can be relevant if there is a risk that in the context of the particular cellular environment an interferon response could be generated, this being a more significant risk where long dsRNA is used than where short dsRNA molecules are utilised.
  • whether a single stranded or double stranded nucleic acid molecule is required to be used will also depend on the functional outcome which is sought.
  • RNA oligonucleotide suitable for specifically hybridising to the subject miRNA.
  • a double stranded siRNA molecule is required. This may be designed as a long dsRNA molecule which undergoes further cleavage or an siRNA.
  • the polymer chain may also comprise one or more ligands to target delivery of the agent within a subject.
  • a "ligand” in this context is meant a molecule that binds two or interacts with a target molecule or cell within the subject.
  • the ligand can be a small molecule, hormone, growth factor, steroid, protein, antibody, antibody fragment, peptide or polypeptide, or mimetic thereof.
  • the ligand may be a molecule that combined to a receptor expressed on the surface of a target cell or conversely, to a molecule expressed on the surface of a target cell.
  • the specific chemical composition of the ligand will be primarily selected based on the. diseased state or condition to be diagnosed or treated.
  • Targets to which ligands can be selected to bind with include a wide variety of molecules including for example, cell signalling ⁇ molecules, antibodies and antibody fragments, proteins and cell surface receptors.
  • the polymer chain therefore further comprises a targeting ligand covalently coupled thereto.
  • the polymer chain further comprises a targeting ligand covalently coupled thereto that targets tissue expressing an enzyme that promotes the chemical reaction.
  • the NMR agent according to the invention may also be suitably adapted for use in imaging techniques not reliant upon NMR.
  • the NMR agent may therefore be adapted for use in applications such as ultrasound, X-ray, Computed Tomography (CT), Single Photon Emission Computed Tomography (SPECT), and PET.
  • CT Computed Tomography
  • SPECT Single Photon Emission Computed Tomography
  • PET PET
  • the NMR agent comprises a radioactive isotope suitable for use in nuclear medical procedures such as nuclear imaging (e.g. PET).
  • suitable radioactive isotopes include yym Tc, °'Ga, u, ey Zr and ' .
  • the polymer chain further comprises covalently coupled thereto a radioactive isotope.
  • the radioactive isotope may be provided in the form of a complex, with the complex being covalently coupled to the polymer chain. In that case, it will be appreciated that the radioactive isotope per se is not directly or indirectly covalently coupled to the polymer chain.
  • the polymer further comprises covalently coupled thereto a complexed moiety, wherein the complex moiety comprises a radioactive isotope.
  • NMR provides the underlying principle in the function of MRI. Accordingly, the NMR agents according to the present invention are particularly useful in MRI applications.
  • the present invention therefore further provides a method of obtaining an image or region of interest in a medium, the method comprising introducing to the medium a switchable nuclear magnetic residence (NMR) agent comprising a plurality of covalently coupled NMR nuclides selected from one or more of D, B, F, Br, P and Si, one or more of said nuclides being covalently coupled to a polymer chain, said agent having a first form in which the NMR signal of said nuclides is diminished, wherein upon undergoing a chemical reaction in the medium the first form of the agents switches into a second form in which the NMR signal of said nuclides is amplified, said amplified NMR signal being used to obtain the image.
  • the method involves obtaining an image of a region of interest in a biological system.
  • the method involves obtaining an image of a region of interest in a subject.
  • Such an image will generally be acquired using MRI.
  • NMR agent in accordance with the invention is used in medical applications, it will usually be provided in the form of a composition comprising at least one pharmacologically acceptable carrier:
  • the present invention therefore provides a composition for magnetic residence imaging (MRI) comprising a switchable nuclear magnetic residence (NMR) agent according to the invention and at least one pharmacologically acceptable carrier.
  • MRI magnetic residence imaging
  • NMR switchable nuclear magnetic residence
  • the present invention further provides use of an NMR agent in accordance with the invention in the manufacture of a composition for obtaining a diagnostic image.
  • the agent/composition will generally be administered to a subject.
  • the NMR agent or composition comprising the agent is to be administered to a subject, they should of course be suitable for administration to the subject.
  • subject is meant either an animal or human subject.
  • animal is meant primates, livestock animals (including cows, horses, sheep, pigs and goats), companion animals (including dogs, cats, rabbits and guinea pigs), and captive wild animals (including those commonly found in a zoo environment).
  • Laboratory animals such as rabbits, mice, rats, guinea pigs and hamsters are also contemplated as they may provide a convenient test system.
  • the subject is a human subject.
  • administration of the agent or composition to a subject is meant that the agent or composition is presented such that it can be or is transferred to the subject.
  • mode of administration There is no particular limitation on the mode of administration, but this will generally be by way of oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intrathecal, and intraspinal), inhalation (including nebulisation), rectal and vaginal modes.
  • compositions in accordance with the invention comprise a pharmacologically acceptable carrier.
  • pharmaceutically acceptable is meant that the carrier, or other constituent of the composition (e.g. stabiliser) is suitable for administration to a subject in their own right. In other words, administration of such material, to a subject will not result in unacceptable toxicity, including allergenic responses and disease states.
  • compositions of the invention may comprise of one or more different liquids.
  • Suitable pharmacologically acceptable liquid carriers are described in Martin, Remington's Pharmaceutical Sciences, 18 th Ed., Mack Publishing Co., Easton, PA, (1990), and include, but are not limited to, liquids that may be sterilised such as water and oils, including those of petroleum, animal, vegetable, mineral or synthetic origin, such as peanut oil, soya bean oil, mineral oil, sesame oil, and the like.
  • suitable liquids include methylene glycol, propylene glycol, polyethylene glycol, polypropylene glycol, ethanol, isopropyl alcohol, benzyl alcohol.
  • Water or soluble saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions.
  • compositions of the invention may comprise one or more pharmacologically acceptable additives known to those in the art.
  • one or more additives such as wetting agents, de-foaming agents, surfactants, buffers, electrolytes, preservatives, colourings, flavourings and sweeteners.
  • the agent or composition comprising the agent may comprise a pharmaceutical adjuvant which may improve the efficacy or potency of the pharmaceutically active agent.
  • carrier and any other additive will in part depend upon the intended application of the NMR agent/composition. Those skilled in the art will be able to select a suitable liquid carrier and additive (if present) for the intended application.
  • the NMR agent described herein may be administered in, as appropriate, a treatment, inhibitory, or diagnostic effective amount.
  • a treatment, inhibitory, or diagnostic effective amount is intended to include an amount which, when administered according to the desired dosing regimen, achieves a desired therapeutic or diagnostic effect, including one or more of: alleviating the symptoms of, preventing or delaying the onset of, inhibiting or slowing the progression of, diagnosing, or halting or reversing altogether the onset or progression of a particular condition being treated and/or assessed.
  • Suitable dosage amounts and dosing regimens to achieve this can be determined by an attending physician and may depend on the particular condition being treated or diagnosed, the severity of the condition as well the general age, health and weight of the subject.
  • Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods.
  • Suitable dosages of the NMR agent per se may lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage.
  • the dosage may be in the range of 1 ⁇ g to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage.
  • the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage.
  • the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage.
  • the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.
  • the NMR agent/compositions in accordance with the invention may be administered in a single dose or a series of doses.
  • compositions in accordance with the invention are suitable for parenteral administration, they will generally be in the form of an aqueous or non-aqueous isotonic sterile injection solution that may contain one or more of an anti-oxidant, buffer, bactericide or solute which renders the composition isotonic with the blood of the intended subject.
  • Such compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials. ⁇
  • the polymer chain will generally need to be maintained in a suspended or dispersed state within the liquid carrier.
  • the polymer chain may have as part of its structure sections or regions that facilitate maintaining the polymer chain within a dispersed state throughout the liquid medium.
  • the polymer chain may comprise stabilising polymeric moieties such as polyethylene glycol (PEG) segment.
  • the NMR agent is provided in a liquid carrier with the polymer chain being in a dispersed state within the carrier, wherein polymer is maintained in that dispersed state without use of a stabiliser.
  • the polymer chain is self- stabilising.
  • the polymer chain may also be maintained in a dispersed state within a liquid carrier using a stabiliser.
  • Suitable pharmaceutically acceptable stabilisers include, but are not limited to, various polymers, low molecular weight oligomers, natural products, and surfactant stabilisers including nonionic, anionic, cationic, ionic, and zwitterionic surfactants.
  • stabilisers include hydroxypropyl methylcellulose (now known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium lauryl sulfate, dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available Tweens® such as e.g., Tween 20® and Tween 80® (ICI Speciality Chemicals)); polyethylene glycols (e.g
  • cationic stabilisers include, but are not limited to, polysaccharides, cellulosics, alginates, phospholipids, and nonpolymeric compounds, such as zwitterionic stabilisers, poly-n- methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene, polymethylmethacrylate trimethylammoniumbromide bromide (PMMTMABr)3 hexyldesyltrimethylammonium bromide (HDMAB), and polyvinylpyrrolidone-2- dimethylaminoethyl methacrylate dimethyl sulfate.
  • zwitterionic stabilisers poly-n- methylpyridinium, anthryul pyridinium chloride, cationic phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene,
  • cationic stabilisers include, but are not limited to, cationic lipids, sulfonium, phosphonium, and quartemary ammonium compounds, such as stearyltrimethylammonium chloride, benzyl-di(2- chloroethyl)ethylammonium bromide, coconut trimethyl ammonium chloride or bromide, coconut methyl dihydroxyethyl ammonium chloride or bromide, decyl triethyl ammonium chloride, decyl dimethyl hydroxyethyl ammonium chloride or bromide, C 12- 15dimethyl hydroxyethyl ammonium chloride or bromide, coconut dimethyl hydroxyethyl ammonium chloride or bromide, myristyl trimethyl ammonium methyl sulfate, lauryl dimethyl benzyl ammonium chloride or bromide, lauryl dimethyl (ethenoxy)4 ammonium chloride or bromide
  • Such exemplary cationic stabilisers and other useful cationic stabilisers are described in J. Cross and E. Singer, Cationic Surfactants: Analytical and Biological Evaluation (Marcel Dekker, 1994); P. and D. Rubingh (Editor), Cationic Surfactants: Physical Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic Surfactants: Organic Chemistry, (Marcel Dekker, 1990).
  • a further list of stabilisers include benzalkonium chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a halonium compound, a cationic organometallic compound, a quarternary phosphorous compound, a pyridinium compound, an anilinium compound, an ammonium compound, a hydroxylammonium compound, a primary ammonium compound, a secondary ammonium compound, a tertiary ammonium compound, and quarternary ammonium compounds.
  • quarternary ammonium compounds include, but are not limited to, behenalkonium chloride, benzethonium chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium chloride, cetalkonium chloride, cetrimonium bromide, cetrimonium chloride, cethylamine hydrofluoride, chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride (Quaternium-5), dodecyl dimethyl ethylbenzyl ammonium chloride (Quaternium- 14), Quatemium-22, Quaternium- 26, Quaterniumrl S hectorite, dimethylaminoethylchloride hydrochloride, cysteine hydrochloride, diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE (3)oleyl ether phosphate, tallow alkonium chloride, dimethyl dioctade
  • the NMR agents in accordance with the invention are particularly suitable for use in biological systems.
  • biological system is meant a subject, an individual cell, a collection of cells such as a cell culture, an organ, a tissue, and a multi-seal organism such as subjects.
  • the NMR agent may be used or applied in vivo, ex vivo or in vitro. Where the NMR agent is used or applied ex vivo or in vitro, its use or application will be with biological material.
  • the agent may be used to obtain an image of a region of interest in a biological material, or the agent may be used to detect a chemical reaction in a biological material.
  • biological material is meant a substance derived or obtained from a living organism.
  • Illustrated examples of biological materials include, but are not limited to, cells, tissues, blood, blood components, proteins (including recombinant proteins, transgenic proteins and proteinaceous materials), peptides, and enzymes.
  • the nuclides of the agent will generally provide for in the second form of the agent in which their NMR signal is amplified a T 2 the value of at least 5ms, for example at least 10 ms or at least 20 ms, or at least 30 ms, or at least 40 ms, or at least 70 ms, or at least 100 ms.
  • Detection of the NMR signal provided by the NMR agent in accordance with the invention may be obtained using NMR detectors well known to those skilled in the art, for example an NMR spectrometer or MRI apparatus.
  • NMR agents in accordance with the invention are particularly versatile and are not limited by the potential toxic nature of conventional gadolinium and iron oxide particle based agents.
  • the agents also exhibit an ability to (1) absolutely quantify the number of molecules in a volume element, (2) deliver and confirm that delivery through observation of an amplified NMR signal, and (3) to follow successive processes such as the passage through a membrane and then binding to a particular target molecule.
  • alkyl used either alone or in compound words denotes straight chain, branched or cyclic alkyl, preferably Ci -2 o alkyl, e.g. Cj.io or Ci -6.
  • straight chain and branched alkyl include methyl, ethyl, H-propyl, isopropyl, M-butyl, sec- butyl, r-butyl, H-pentyl, 1,2-dimethylpropyl, 1,1-dimethyl-propyl, hexyl, 4-methylpentyl, 1- methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3- dimethylbutyl, 1 ,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, 1 ,1,2- trimethylpropyl, heptyl, 5-methylhex
  • cyclic alkyl examples include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. Where an alkyl group is referred to generally as "propyl", butyl” etc, it will be understood that this can refer to any of straight, branched and cyclic isomers where appropriate. An alkyl group may be optionally substituted by one or more optional substituents as herein defined.
  • alkenyl denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or polyunsaturated alkyl or cycloalkyl groups as previously defined, preferably C 2 . 2 o alkenyl (e.g. C 2 .io or C 2-6 ).
  • alkenyl examples include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3- decenyl, 1,3-butadienyl, 1,4-pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4- hexadienyl, 1,3-cyclohexadienyl, 1,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5- cyclohept
  • alkynyl denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon triple bond including ethylenically mono-, di- or polyunsaturated alkyl or cycloalkyl groups as previously defined. Unless the number of carbon atoms is specified the term preferably refers to C 2-2 o alkynyl (e.g. C 2- io or C 2 . 6 ). Examples include ethynyl, 1-propynyl, 2-propynyl, and butynyl isomers, and pentynyl isomers. An alkynyl group may be optionally substituted by one or more optional substituents as herein defined.
  • halogen denotes fluorine, chlorine, bromine or iodine (fluoro, chloro, bromo or iodo).
  • aryl denotes any of single, polynuclear, conjugated and fused residues of aromatic hydrocarbon ring systems(e.g. C$. 2 4 or C6-is).
  • aryl include phenyl, biphenyl, terphenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fiuorenyl, pyrenyl, idenyl, azulenyl, chrysenyl.
  • aryl include phenyl and naphthyl.
  • An aryl group may or may not be optionally substituted by one or more optional substituents as herein defined.
  • arylene is intended to denote the divalent form of aryl.
  • carbocyclyl includes any of non-aromatic monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C 3- 2o (e.g. C3.]o or C 3- 8).
  • the rings may be saturated, e.g. cycloalkyl, or may possess one or more double bonds (cycloalkenyl) and/or one or more triple bonds (cycloalkynyl).
  • Particularly preferred carbocyclyl moieties are 5- 6-membered or 9-10 membered ring systems.
  • Suitable examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, cyclooctenyl, cyclopentadienyl, cyclohexadienyl, cyclooctatetraenyl, indanyl, decalinyl and indenyl.
  • a carbocyclyl group may be optionally substituted by one or more optional substituents as herein defined.
  • the term "carbocyclylene" is intended to denote the divalent form of carbocyclyl.
  • heteroatom refers to any atom other than a carbon atom which may be a member of a cyclic organic group.
  • heteroatoms include nitrogen, oxygen, sulfur, phosphorous, boron, silicon, selenium and tellurium, more particularly nitrogen, oxygen and sulfur.
  • heterocyclyl when used alone or in compound words includes any of monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C 3 . 2 o (e.g. C 3- io or C 3- 8) wherein one or more carbon atoms are replaced by a heteroatom so as to provide a non-aromatic residue.
  • Suitable heteroatoms include O, N, S, P and Se, particularly O, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms.
  • the heterocyclyl group may be saturated or partially unsaturated, i.e. possess one or more double bonds. Particularly preferred heterocyclyl are 5-6 and 9-10 membered heterocyclyl.
  • heterocyclyl groups may include azridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 2H-pyrrolyl, pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, mo ⁇ holinyl, indolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, thiomorpholinyl, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl, tetrahydrothiophenyl, pyrazolinyl, dioxalanyl, thiazolidinyl, isoxazolidinyl, dihydropyranyl, oxazinyl, thiazinyl, thiomorpholinyl, oxathianyl, di
  • heteroaryl includes any of monocyclic, polycyclic, fused or conjugated hydrocarbon residues, wherein one or more carbon atoms are replaced by a heteroatom so as to provide an aromatic residue.
  • Preferred heteroaryl have 3-20 ring atoms, e.g. 3-10.
  • Particularly preferred heteroaryl are 5-6 and 9-10 membered bicyclic ring systems.
  • Suitable heteroatoms include, O, N, S, P and Se, particularly O, N and S. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms.
  • Suitable examples of 'heteroaryl groups may.
  • a heteroaryl group may be optionally substituted by one or more optional substituents as herein defined.
  • Preferred acyl includes C(0)-R e , wherein R e is hydrogen or an alkyl, alkenyl, alkynyl,. aryl, heteroaryl, carbocyclyl,, or heterocyclyl residue.
  • R e is hydrogen or an alkyl, alkenyl, alkynyl,. aryl, heteroaryl, carbocyclyl,, or heterocyclyl residue.
  • Examples of acyl include formyl, straight chain or branched alkanoyl (e.g.
  • Ci- 2 o such as acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2- dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoy
  • phenylacetyl phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyi and phenylhexanoyl
  • naphthylalkanoyl e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]
  • aralkenoyl such as phenylalkenoyl (e.g.
  • phenylpropenoyl e.g., phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g.
  • aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl
  • arylthiocarbamoyl such as phenylthiocarbamoyl
  • arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl
  • arylsulfonyl such as phenylsulfonyl and napthylsulfonyl
  • heterocycliccarbonyl heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl
  • R e residue may be optionally substituted as described herein.
  • sulfoxide either alone or in a compound word, refers to a group -S(0)R f wherein R f is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, and aralkyl. Examples of preferred R f include Cuoalkyl, phenyl and benzyl.
  • sulfonyl refers to a group S(0) 2 -R f , wherein R is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl and aralkyl. Examples of preferred R f include C ⁇ oalkyl, phenyl and benzyl.
  • sulfonamide either alone or in a compound word, refers to a group S(0)NR f R f wherein each R f is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, carbocyclyl, and aralkyl.
  • R examples include C ⁇ . 20 alkyl, phenyl and benzyl.
  • at least one R f is hydrogen.
  • both R f are hydrogen.
  • the term, "amino" is used here in its broadest sense as understood in the art and includes groups of the formula NR a R b wherein R a and R b may be any independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, arylalkyl, and acyl.
  • R a and R b together with the nitrogen to which they are attached, may also form a monocyclic, or polycyclic ring system e.g.
  • amino examples include NH 2 , NHalkyl (e.g. Ci. 2 oalkyl), NHaryl (e.g. NHphenyl), NHaralkyl (e.g. NHbenzyl), NHacyl (e.g. NHC(O)C,. 20 alkyl, NHC(O)phenyl), Nalkylalkyl (wherein each alkyl, for example Ci. 20 , may be the same or different) and 5 or 6 membered rings, optionally containing one or more same or different heteroatoms (e.g. O, N and S).
  • NHalkyl e.g. Ci. 2 oalkyl
  • NHaryl e.g. NHphenyl
  • NHaralkyl e.g. NHbenzyl
  • NHacyl e.g. NHC(O)C,. 20 alkyl, NHC(O)phenyl
  • Nalkylalkyl wherein each alkyl, for example
  • amido is used here in its broadest sense as understood in the art and includes groups having the formula C(0)NR a R b , wherein R a and R b are as defined as above.
  • amido include C(0)NH 2 , C(0)NHalkyl (e.g. d. ⁇ alkyl), C(0)NHaryl (e.g. C(O)NHphenyl), C(0)NHaralkyl (e.g. C(O)NHbenzyl), C(0)NHacyl (e.g. C(O)NHC(O)C,. 20 alkyl, C(0)NHC(0)phenyl), C(0)Nalkylalkyl (wherein each alkyl, for example Ci. 2 o, may be the same or different) and 5 or 6 membered rings, optionally containing one or more same or different heteroatoms (e.g. O, N and S).
  • C(0)NHalkyl e.g. d. ⁇ alkyl
  • C(0)NHaryl e.g. C(O)NH
  • carboxy ester is used here in its broadest sense as understood in the art and includes groups having the formula C0 2 R 8 , wherein R 8 may be selected from groups including alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, aralkyl, and acyl.
  • R 8 may be selected from groups including alkyl, alkenyl, alkynyl, aryl, carbocyclyl, heteroaryl, heterocyclyl, aralkyl, and acyl.
  • Examples of carboxy ester include C0 2 Ci -2 oalkyl, CC ⁇ aryl (e.g.. C0 2 phenyl), C0 2 aralkyl (e.g. C0 2 benzyl).
  • aryloxy refers to an "aryl” group attached through an oxygen bridge.
  • aryloxy substituents include phenoxy, biphenyloxy, naphthyloxy and the like.
  • acyloxy refers to an "acyl” group wherein the "acyl” group is in turn attached through an oxygen atom.
  • acyloxy examples include hexylcarbonyloxy (heptanoyloxy), cyclopentylcarbonyloxy, benzoyloxy, 4-chlorobenzoyloxy, decylcarbonyloxy (undecanoyloxy), propylcarbonyloxy (butanoyloxy), octylcarbonyloxy (nonanoyloxy), biphenylcarbonyloxy (eg 4-phenylbenzoyloxy), naphthylcarbonyloxy (eg 1-naphthoyloxy) and the like.
  • alkyloxycarbonyl refers to a "alkyloxy” group attached through a carbonyl group.
  • alkyloxycarbonyl groups include butylformate, sec- butylformate, hexylformate, octylformate, decylformate, cyclopentylformate and the like.
  • arylalkyl refers to groups formed from straight or branched chain alkanes substituted with an aromatic ring. Examples of arylalkyl include phenylmethyl (benzyl), phenylethyl and pheny .propyl.
  • alkylaryl refers to groups formed from aryl groups substituted with a straight chain or branched alkane. Examples of alkylaryl include methylphenyl and isopropylphenyl.
  • a group may or may not be substituted or fused (so as to form a condensed polycyclic group) with one, two, three or more of organic and inorganic groups, including those selected from: alkyl, alkenyl, alkynyl, carbocyclyl, aryl, heterocyclyl, heteroaryl, acyl, aralkyl, alkaryl, alkheterocyclyl, alkheteroaryl, alkcarbocyclyl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, halocarbocyclyl, haloheterocyclyl, haloheteroaryl, haloacyl, haloaryalkyl, hydroxy, hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycarbocyclyl, hydroxyaryl, hydroxyaryl, hydroxy
  • Optional substitution may also be taken to refer to where a -CH 2 - group in a chain or ring is replaced by a group selected from -0-, -S-, -NR a -, -C(O)- (i.e. carbonyl), -C(0)0- (i.e. ester), and -C(0)NR a - (i.e. amide), where R a is as defined herein.
  • Preferred optional substituents include alkyl, (e.g. Ci-6 alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (e.g. methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl etc) alkoxy (e.g.
  • alkyl e.g. Ci-6 alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl
  • hydroxyalkyl e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl
  • C 1-6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy
  • halo trifluoromethyl, trichloromethyl, tribromomethyi, hydroxy, phenyl (which itself may be further substituted e.g., by Ci. 6 alkyl, halo, hydroxy, hydroxyC
  • benzyl wherein benzyl itself may be further substituted e.g., by C 1-6 alkyl, halo, hydroxy, Ci.
  • Ci-6 alkyl such as methylamino, ethylamino, propylamino etc), dialkylamino (e.g. Ci. 6 alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (e.g. NHC(0)CH 3 ), phenylamino (wherein phenyl itself may be further substituted e.g., by Ci ⁇ alkyl, halo, hydroxy, hydroxyCi -6 alkyl, d-6 alkoxy, alkyl, cyano, nitro OC(0)d-6 alkyl, and amino), nitro, formyl, -C(0)-alkyl (e.g.
  • Ci ⁇ alkyl such as acetyl
  • 0-C(0)-alkyl e.g. C ⁇ . ealkyl, such as acetyloxy
  • benzoyl wherein the phenyl group itself may be further substituted e.g., by Ci ⁇ alkyl, halo, hydroxy hydroxyCi. 6 alkyl, Ci. 6 alkoxy, haloCi-6 alkyl, cyano, nitro OC(0)Ci ⁇ alkyl, and amino
  • CONHalkyl e.g. Ci -6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl amide
  • CONHdialkyl e.g. C 1-6 alkyl
  • aminoalkyl e.g., HN Cj.6 alkyl-, d-ealkylHN-C ⁇ alkyl- and (Ci. 6 alkyl) 2 N-Ci-6 alkyl-
  • thioalkyl e.g., HS Ci-6 alkyl-
  • carboxyalkyl e.g., H0 2 CCi- alkyl-
  • carboxyesteralkyl e.g., Ci.
  • amidoalkyl e.g., H 2 N(0)CC ⁇ alkyl-, H(C,. 6 alkyl)N(0)CC, ⁇ alkyl-
  • sulfonamidoalkyl e.g., 2 HR (0)SCi-6 alkyl, H(Ci ⁇ alkyl)N(0)SCi -6 alkyl-
  • triarylmethyl triarylamino, oxadiazole, and carbazole.
  • Example 1 Production of acetal-protected hyperbranched 19 F imaging agent (PI): hyperbranched solketal methacrylate-co-trifluoroethyl methacrylate.
  • the solution was then purged with argon for 20 minutes to remove oxygen.
  • the round bottom flask was heated to 65°C, and the reaction was allowed to proceed for 24 hours.
  • the crude reaction mixture was then precipitated into hexane to remove residual monomer and dried in a vacuum oven.
  • 19 F T 2 relaxation time at 7 T 28 ms
  • 19 F T 2 measurements were recorded on a Bruker 300 MHz wide-bore system (7 T) using a 5 mm birdcage resonator. Typically, the polymer was dissolved in water to a concentration of 20 mg/mL. The samples were analysed using a standard spin echo pulse sequence with a repetition time of 3 seconds. The 19 F images were recorded on the same instrument using a spin-echo 3D pulse sequence. Sample phantoms were made up as described for the T 2 measurements. A matrix with dimensions of 128x96x8 was collected with two repetitions giving an overall scan time of 68 minutes. An example of a slice from images collected for the acetal-protected monomer (P2) and the deprotected monomer (P3) are shown in Figure 1 - Example 4
  • the flask was placed in a temperature controlled oil bath at 65 °C for 48 hrs.
  • the flask was then recharged with PEGMA (3.35 g, 1.41 M), AIBN (6.7 mg, 8.16 x 10 '3 M), and dioxane (5 mL) and polymerised for another 48 hrs at 65 °C.
  • the reaction was halted by quenching in ice and then exposure to air.
  • the polymerisation mixture was then precipitated into petroleum spirit (BP 40-60) at 0 °C and stirred for 10 min.
  • the supernatant was then decanted off the viscous polymer film. This film was then dried for 1 h under high vacuum at 25 °C.
  • the title compound was synthesised via a three-step procedure as follows.
  • solketal methacrylate P6b
  • the HBP PEGMA-co-TFEA-co-SMA P6a
  • the polymer was then pH balanced to neutral using 50 wt% NaOH solution and then dialysed against water for 3 days, after which it was lyophilised and used without further characterisation.
  • a switchable nuclear magnetic resonance (NMR) agent comprising a plurality of covalently coupled NMR nuclides selected from one or more of D, B, F, Br, P and Si, one or more of said nuclides being covalently coupled to a polymer chain, said agent having a first form in which the NMR signal of said nuclides is diminished, wherein the agent is capable of undergoing a chemical reaction that causes the first form of the agent to switch into a second form in which the NMR signal of said nuclides is amplified.
  • NMR nuclear magnetic resonance
  • NMR switchable nuclear magnetic resonance
  • the polymer chain comprises one or more F substituted groups selected from trifluoromethyl, perfluoroethyl, 2,2,2-trifluoroethyl, perfluoropropyl, perfluoroisopropyl, bis(trifluoromethyl)methyl, tris(trifluoromethyl)methyl, 2,2,3,3,3- pentafluoropropyl, perfluorobutyl, trifluoromethylphenyl, l,3-di(trifluoromethyl) phenyl, trifluoromethylbenzyl, l,3-di(trifluoromethyl)benzyl, tris(trifluoromethyl)-methylphenyl, tris(trifluoromethyl)-methylbenzyl, fluorophenyl, difluorophenyl, pentafluorophenyl and pentafluorobenzyl.
  • F substituted groups selected from trifluoromethyl, perfluoroethyl, 2,2,2-trifluoroe
  • the switchable nuclear magnetic resonance (NMR) agent according to any one of claims 1 to 4, wherein the polymer chain further comprises a targeting ligand covalently coupled thereto.
  • the ligand is selected from a hormone, growth factor, steroid, protein, antibody, antibody fragment, peptide, polypeptide, or mimetic thereof.
  • a method of detecting a chemical reaction in a medium comprising introducing to the medium a switchable nuclear magnetic resonance (NMR) agent comprising a plurality of covalently coupled NMR nuclides selected from one or more of D, B, F, Br, P and Si, one or more of said nuclides being covalently coupled to a polymer chain, said agent having a first form in which the NMR signal of said nuclides is diminished, wherein upon undergoing the chemical reaction in the medium the first form of the agent switches into a second form in which the NMR signal of said nuclides is amplified, said amplified NMR signal being used to detect occurrence of the chemical reaction.
  • NMR switchable nuclear magnetic resonance
  • the chemical reaction that causes the first form of the agent to switch to the second form promotes cleavage of a covalent bond that forms part of the polymer chain, said cleavage of the covalent bond not resulting in the covalently coupled nuclide(s) being cleaved from the polymer chain.
  • a method of obtaining an image of a region of interest in a medium comprising introducing to the medium a switchable nuclear magnetic resonance (NMR) agent comprising a plurality of covalently coupled NMR nuclides selected from one or more of D, B, F, Br, P and Si, one or more of said nuclides being covalently coupled to a polymer chain, said agent having a first form in which the NMR signal of said nuclides is diminished, wherein upon undergoing a chemical reaction in the medium the first form of the agent switches into a second form in which the NMR signal of said nuclides is amplified, said amplified NMR signal being used to obtain the image.
  • NMR switchable nuclear magnetic resonance
  • the polymer chain further comprises a targeting ligand covalently coupled thereto that targets in the subject tissue expressing an enzyme that promotes the chemical reaction.
  • composition for magnetic resonance imaging comprising a switchable nuclear magnetic resonance (NMR) agent according to any one of claims 1 to 9.

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Abstract

La présente invention concerne un agent de résonnance magnétique nucléaire (RNM) commutable, comprenant une pluralité de nucléides RMN liés de manière covalente, sélectionnés parmi un ou plusieurs des éléments suivants : D, B, F, Br, P et Si. Un ou plusieurs desdits nucléides sont liés de manière covalente à une chaîne polymère. L'agent présente une première forme dans laquelle le signal RMN desdits nucléides est diminué. Ledit agent est apte à subir une réaction chimique qui entraîne la commutation de la première forme de l'agent en une seconde forme dans laquelle le signal RMN desdits nucléides est amplifié.
PCT/AU2012/000415 2011-04-20 2012-04-20 Agent de résonance magnétique nucléaire WO2012142670A1 (fr)

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CN105555311A (zh) * 2013-07-23 2016-05-04 诺瓦利克有限责任公司 稳定的抗体组合物

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