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US20030092672A1 - Amphiphilic macrocyclic derivatives and their analogues - Google Patents

Amphiphilic macrocyclic derivatives and their analogues Download PDF

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Publication number
US20030092672A1
US20030092672A1 US10/281,070 US28107002A US2003092672A1 US 20030092672 A1 US20030092672 A1 US 20030092672A1 US 28107002 A US28107002 A US 28107002A US 2003092672 A1 US2003092672 A1 US 2003092672A1
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groups
derivative
macrocycle
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amphiphile
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Raphael Darcy
Lawrence Penkler
Bart Ravoo
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COLLEGE DUBLIN UNIVERSITY
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COLLEGE DUBLIN UNIVERSITY
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Publication of US20030092672A1 publication Critical patent/US20030092672A1/en
Priority to US11/295,724 priority Critical patent/US7786095B2/en
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
    • C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
    • C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Definitions

  • the present invention is directed to the production of soluble macrocyclic derivatives of a type which forms micelles and vesicles for use in encapsulation of molecules.
  • the invention particularly relates to soluble amphiphilic macrocyclic derivatives having lipophilic groups attached to one side of the units making up the macrocycle and hydrophilic groups attached to the other side.
  • Macrocyclic oligosaccharides are typified by cyclodextrins, which are cyclic oligosaccharides composed of D-glucose residues linked together by ⁇ -(1-4) bonds (FIG. 1).
  • the most common examples of cyclodextrins contain six, seven or eight ⁇ -(1-4)-linked D-glucopyranosyl units bonded together into cylinder-shaped molecules and are referred to as ⁇ -, ⁇ -, and ⁇ -cyclodextrins, respectively.
  • all secondary hydroxyl groups are placed on one rim of the cylinder and all primary hydroxyl groups are placed on the other.
  • the cylindrical interior (cavity) of the molecule is lined with hydrogen atoms and glycosidic oxygen atoms which cause it to be hydrophobic.
  • the cylindrical structures can be used as hosts for the inclusion of various compounds within their cavities, usually organic compounds, in the food, pharmaceutical and chemical industries.
  • Cyclodextrins have been used to form inclusion complexes with hydrophobic molecules in which these molecules are encapsulated within the compatible hydrophobic cavity of the cyclodextrin macrocycle. This process of molecular encapsulation confers increased water solubility on the included molecule, as well as other properties such as increased stability and lowered volatility. It also allows control of the availability of the molecule, for example the bioavailability of a drug. See, e.g., Uekama et al, in CRC Critical Reviews in Therapeutic Drug Carrier Systems, Vol. 3, 1-40 (1987).
  • cyclodextrins as hosts for molecules, are limited by the size of the central cavity.
  • Several attempts have been made to alter the cyclodextrin structures to enable them to encapsulate other molecules regardless of size.
  • Cyclodextrins have been modified with lipophilic groups at the 2- and 3- positions (the secondary-hydroxyl side) of the glucose units, together with polar groups such as amino groups at the 6-positions (the primary-hydroxyl side), in order to confer amphiphilic character.
  • Such derivatives are described by Skiba et al. in U.S. Pat. No. 5,718,905 and form monolayers, nanoparticles, and mixed lyotropic (solution) phases with other amphiphiles.
  • a first object of the present invention is to modify macrocyclic derivatives typified by cyclodextrins and other macrocyclic oligosaccharides so that they are enabled by molecular self-assembly to form micelles and vesicles in aqueous solvents of their own accord giving rise to structures which enable retention of entrapped molecules within the micelle or vesicle even after dilution in a solution medium, with advantages for the delivery of therapeutic molecules.
  • a second object of the invention is to modify the surface of the micelles or vesicles of the invention to facilitate specific attachment of the micelle or vesicle to certain cell membrane structures, with advantages for targeting and intracellular delivery of entrapped therapeutic molecules.
  • soluble amphiphilic derivatives having lipophilic groups attached to one side of the units forming the macrocycle and hydrophilic groups attached to the opposite side of the macrocycle characterised in that:
  • two or more hydrophilic groups are attached to one side of each unit forming the macrocycle.
  • one or more lipophilic groups are attached to the opposite side of each unit forming the macrocycle such that the number of hydrophilic groups present is always greater than the number of lipophilic groups.
  • the derivatives themselves preferably are oligosaccharide derivatives and even more preferably are cyclodextrin derivatives.
  • the oligosaccharide derivatives if derived far enough are no longer saccharides but still retain a basic cyclic structure which can be utilised as derivatives according to the invention.
  • These “non-oligosaccharide” molecules can be modified to incorporate the relative numbers of lipophilic and hydrophilic groups, described above, using the same chemical processes as are used to modify the oligosaccharide derivatives and which is described in greater detail below.
  • the lipophilic groups are attached at the 6-positions of cyclodextrin molecules, and the hydrophilic groups are attached to the 2- and 3-positions.
  • the resulting wedge-shaped or cylindrical macrocyclic amphiphiles (FIG. 2) self-assemble in aqueous solutions into micelles or bilayer vesicles.
  • the micelles can encapsulate hydrophobic molecules, while the bilayer vesicles can encapsulate hydrophobic or hydrophilic molecules.
  • the aggregates of macrocyclic derivatives encapsulate other molecules.
  • the aggregates of macrocyclic derivatives encapsulate molecules for human or veterinary therapeutic use.
  • a macrocyclic derivative characterised in that the macrocyclic derivative is a cyclodextrin derivative of the following formula:
  • n 5-11 or higher, and indicates the number of modified glucose units in the macrocycle which may be the same or different, depending on the X- and R-groups.
  • X 1 , X 2 , X 3 independently, provide linking groups; in further embodiments these may independently be a simple covalent bond, or a dendrimeric group; and in further embodiments may be an atom or radical with a valency of at least two, O, S, Se, N, P, CH 2 , CH 2 O, carbonyl, ester, amido, amino, phosphate, sulfonyl, sulfoxide.
  • R 1 independently, provide groups which are predominantly lipophilic; examples of R 1 are: H, a saturated or unsaturated aliphatic or aromatic carbon or silicon radical or a halogenated version of these. Where R 1 is a straight or branched aliphatic chain, the number of carbons may be between 2-18. R 1 may be a cyclic aliphatic system such as hexyl or cholesteryl. Examples of aromatic R 1 are benzyl and pyridyl.
  • R 2 and R 3 independently, provide groups which are predominantly polar and/or capable of hydrogen-bonding.
  • R 2 , R 3 are: H, (CH 2 ) 2-4 OH, CH 2 CH(OH)CH 2 OH, CH 2 CH(OH)CH 2 NH 2 , CH 2 CH 2 NH 2 ; a cation such as a protonated amino group, an anion such as sulfate, sulfonato; any pharmaceutically acceptable ion; a predominantly hydrophilic group.
  • R 2 , R 3 may be dendrimeric, and may include polymeric groups such as poly(ethylenimine) (PEI), polyamides, polyaminoacids such as polylysine; or groups which are employed because of their non-immunogenic as well as polar character, such as poly(ethylene glycol), or sialylGalGlcNAc; or antigenic groups such as antennary oligosaccharides which are intended to stimulate the production of antibodies; or groups such as lactosyl which may be attached for the purpose of promoting adhesion of the amphiphile or of its complex with a guest molecule to specific cells or to specific proteins.
  • polymeric groups such as poly(ethylenimine) (PEI), polyamides, polyaminoacids such as polylysine; or groups which are employed because of their non-immunogenic as well as polar character, such as poly(ethylene glycol), or sialylGalGlcNAc; or antigenic groups such as antennary oli
  • groups known in the art which are specific ligands for cellular receptors such as folic acid, galactose, biotin, lipopolysaccharides, gangliosides, sialo-gangliosides, glycosphingolipids and the like may be attached to the secondary face of the modified cyclodextrins thereby expressing a targeting ligand on the external surface of the micelles or vesicles of the invention.
  • the groups may be clustered in order to promote ‘recognition’ by other molecules which involves multifunctional interactions.
  • these groups are polymeric or dendrimeric they may be grafted onto the amphiphile for example by living polymerisation; or the amphiphile may be a copolymer, for example it may be cross-linked by means of difunctional or polyfunctional reagents such as activated diacids or diepoxides, or copolymerised within the matrix of a polylactic or glycolic acid.
  • the coupling of the vesicles or micelles of the invention to antibodies may be an alternative route for targeting specific cell types.
  • the synthetic procedures for antibody coupling are known in the art and may be applied to modified cyclodextrins of the invention which, on the secondary face provide either free amino groups for biotinylation, or free carboxylic groups for peptide coupling of an antibody via N-glutaryl detergent dialysis, or maleimide for sulfhydryl antibody coupling, or pyridyldithiopropionate for sulfhydryl and maleimide antibody coupling, or similar methods appreciated in the art.
  • the macrocyclic derivatives are in the form bis(cyclodextrin amphiphile) in which two amphiphilic cyclodextrins of the above form share common R 1 groups, so as to provide ‘bola amphiphiles’, characterised by having two polar CD molecules joined by one or more lipophilic groups, thus: (R 2 , R 3 )-macrocycle-(R 1 )-macrocycle-(R 2 , R 3 ), where linker groups X are understood.
  • the bis-amphiphile is simplified to a bola amphiphile in which a common set of lipophilic groups (R 1 ) and a common macrocyclic molecule link two sets of polar headgroups (R 2 , R 3 ), thus: (R 2 , R 3 )(R 1 )-macrocycle-(R 2 , R 3 ), where linker groups are understood.
  • R 1 lipophilic groups
  • R 2 , R 3 common macrocyclic molecule link two sets of polar headgroups
  • the groups X 1 , or the groups X 2 and X 3 , or the groups R 1 , or the groups R 2 and R 3 may be linked to each other intramolecularly, as independent sets, by reaction of their chemical precursor groups through catalysis, or by reaction of their chemical precursor groups with a polyfunctional linking agent.
  • catalysis would be photochemical irradiation.
  • the groups X 1 , or the groups X 2 and X 3 , or the groups R 1 , or the groups R 2 and R 3 may be linked to each other intermolecularly, as independent sets, by reaction of their chemical precursor groups through catalysis, or by reaction of their chemical precursor groups with a polyfunctional linking reagent, to provide an oligomerised amphiphilic cyclodextrin.
  • the macrocyclic derivative is provided wherein the units forming the macrocycle are monosaccharide units forming an oligosaccharide macrocycle with the formula:
  • n 3-11 or higher, and indicates the number of modified monosaccharide units in the macrocycle which may be the same or different, depending on the X- and R-groups, and are linked (1-4).
  • the groups X 1 , X 2 and X 3 , R 1 , R 2 and R 3 have the same meanings as described above.
  • Examples of such macrocyclic derivatives are those in which the modified units making up the macrocycle are, independently, aglycone derivatives of L-glucose, or of D- or L-hexoses such as mannose, galactose, altrose, idose, or rhamnose (R 1 X 1 ⁇ CH 3 ), or arabinose (R 1 X 1 ⁇ H); or where the macrocycle is an oligomer of a disaccharide such as lactose.
  • R 2 , R 3 may be dendrimeric, and may include polymeric groups such as poly(ethylenimine) (PEI), polyamides, polyaminoacids such as polylysine; or groups which are employed because of their non-immunogenic as well as polar character, such as poly(ethylene glycol), or sialylGalGlcNAc; or antigenic groups such as antennary oligosaccharides which are intended to stimulate the production of antibodies; or groups such as lactosyl which may be attached for the purpose of promoting adhesion of the amphiphile or of its complex with a guest molecule to specific cells or to specific proteins.
  • PEI poly(ethylenimine)
  • polyamides polyamides
  • polyaminoacids such as polylysine
  • antigenic groups such as antennary oligos
  • groups known in the art which are specific ligands for cellular receptors such as folic acid, galactose, biotin, lipopolysaccharides, gangliosides, sialo-gangliosides, glycosphingolipids and the like may be attached to the polar face of the modified oligosaccharide or oligosaccharide analogue, thereby expressing a targeting ligand on the external surface of the micelles or vesicles of the invention.
  • the groups may be clustered in order to promote ‘recognition’ by other molecules which involves multifunctional interactions.
  • these groups are polymeric or dendrimeric they may be grafted onto the amphiphile for example by living polymerisation; or the amphiphile may be a copolymer, for example it may be cross-linked by means of difunctional or polyfunctional reagents such as activated diacids or diepoxides, or copolymerised within the matrix of a polylactic or glycolic acid.
  • the coupling of the vesicles or micelles of the invention to antibodies may be an alternative route for targeting specific cell types.
  • the synthetic procedures for antibody coupling are known in the art and may be applied to modified oligosaccharides or analogues of the invention which, on the polar face provide either free amino groups for biotinylation, or free carboxylic groups for peptide coupling of an antibody via N-glutaryl detergent dialysis, or maleimide for sulfhydryl antibody coupling, or pyridyldithiopropionate for sulfhydryl and maleimide antibody coupling, or similar methods appreciated in the art.
  • amphiphiles are of the form bis(amphiphile) in which two macrocyclic molecules of the above form share common R 1 groups, so as to provide ‘bola amphiphiles’, characterised by having two polar macrocycle molecules joined by one or more lipophilic groups, thus: (R 2 , R 3 )-macrocycle-(R 1 )-macrocycle-(R 2 , R 3 ), where linker groups X are understood.
  • the bis-amphiphile is simplified to a bola amphiphile in which a common set of lipophilic groups (R 1 ) and a common macrocyclic molecule link two sets of polar headgroups (R 2 , R 3 ), thus: (R 2 , R 3 )(R 1 )-macrocycle-(R 2 , R 3 ), where linker groups are understood.
  • R 1 lipophilic groups
  • R 2 , R 3 common macrocyclic molecule link two sets of polar headgroups
  • the groups X 1 , or the groups X 2 and X 3 , or the groups R 1 , or the groups R 2 and R 3 may be linked to each other intramolecularly, as independent sets, by reaction of their chemical precursor groups through catalysis, or by reaction of their chemical precursor groups with a polyfunctional linking agent.
  • catalysis is photochemical irradiation.
  • the groups X 1 , or the groups X 2 and X 3 , or the groups R 1 , or the groups R 2 and R 3 may be linked to each other intermolecularly, as independent sets, by reaction of their chemical precursor groups through catalysis, or by reaction of their chemical precursor groups with a polyfunctional linking reagent, to provide an oligomerised amphiphile.
  • macrocyclic derivatives wherein the units making up the macrocycle are of the general formula:
  • n 2-11 or higher, and indicates the number of ring units making up the macrocycle, which may be the same or different;
  • K, L, M are zero (thus providing a unit, as part of the macrocycle, which is an open chain rather than a ring), the remaining are independently one or more of: a simple chemical bond (thus providing a five-membered ring unit as in a furanose sugar); or an atom or radical having a valency of at least 2 and can be in any position not occupied by a moiety involved in linking adjacent units forming the macrocycle,
  • Y which may be the same or different, are groups which link the units making up the macrocycle, such as: oxygen, sulfur, selenium, nitrogen, phosphorus, carbon, or silicon radicals having a valency of 2-4; or OCH 2 as in (1-2)-linked fructofuranooligosaccharides; or OCH 2 CH(OH) as in (1-6)-linked furanooligosaccharides; or OCH(CH 2 OH) as in (1-5)-linked furanooligosaccharides.
  • OCH 2 as in (1-2)-linked fructofuranooligosaccharides
  • OCH 2 CH(OH) as in (1-6)-linked furanooligosaccharides
  • OCH(CH 2 OH) as in (1-5)-linked furanooligosaccharides.
  • X 1 , X′ 1 , X 2 , X′ 2 , X 3 , X′ 3 , X 4 , X′ 4 , X 5 , X 6 are zero or provide linking groups for the R groups; these may be a simple covalent bond, or a dendrimeric group; other examples are: an atom or radical with a valency of at least two, CH 2 , CH 2 O, O, S, Se, N, P, carbonyl, ester, amido, amino, phosphate, sulfonyl, sulfoxide.
  • R 1 , R′ 1 , R 4 , R′ 4 when one or more but not all of R 1 , R′ 1 , R 4 , R′ 4 , independently, is zero the remaining are groups which are predominantly lipophilic; examples are: H, a saturated or unsaturated aliphatic or aromatic carbon or silicon radical or a halogenated version of these.
  • R 1 -R′ 4 is a straight or branched aliphatic chain, n is preferably greater than one, and the number of carbons 2-18.
  • R 1 -R′ 4 may be a cyclic aliphatic system such as hexyl or cholesteryl; examples of aromatic groups are benzyl and pyridyl.
  • R 2 , R 3 , R′ 3 when one or more but not all of R 2 , R′ 2 , R 3 , R′ 3 , independently, is zero the remaining are groups which are predominantly polar and/or capable of hydrogen-bonding.
  • R 2 , R 3 are: H, (CH 2 ) 2-4 OH, CH 2 CH(OH)CH 2 OH, CH 2 CH(OH)CH 2 NH 2 , CH 2 CH 2 NH 2 ; a cation such as a protonated amino group, an anion such as sulfate, sulfonato; any pharmaceutically acceptable ion; a predominantly hydrophilic group.
  • R 2 , R′ 2 , R 3 , R′ 3 may be dendrimeric, and may include polymeric groups such as poly(ethylenimine) (PEI), polyamides, polyaminoacids such as polylysine; or groups which are employed because of their non-immunogenic as well as polar character, such as poly(ethylene glycol), or sialylGalGlcNAc; or antigenic groups such as antennary oligosaccharides which are intended to stimulate the production of antibodies; or groups such as lactosyl which may be attached for the purpose of promoting adhesion of the amphiphile or of its complex with a guest molecule to specific cells or to specific proteins.
  • polymeric groups such as poly(ethylenimine) (PEI), polyamides, polyaminoacids such as polylysine; or groups which are employed because of their non-immunogenic as well as polar character, such as poly(ethylene glycol), or sialylGalGlcNAc;
  • groups known in the art which are specific ligands for cellular receptors such as folic acid, galactose, biotin, lipopolysaccharides, gangliosides, sialo-gangliosides, glycosphingolipids and the like may be attached to the polar face of the modified oligosaccharide or oligosaccharide analogue, thereby expressing a targeting ligand on the external surface of the micelles or vesicles of the invention.
  • the groups may be clustered in order to promote ‘recognition’ by other molecules which involves multifunctional interactions.
  • these groups are polymeric or dendrimeric they may be grafted onto the amphiphile for example by living polymerisation; or the amphiphile may be a copolymer, for example it may be cross-linked by means of difunctional or polyfunctional reagents such as activated diacids or diepoxides, or copolymerised within the matrix of a polylactic or glycolic acid.
  • the coupling of the vesicles or micelles of the invention to antibodies may be an alternative route for targeting specific cell types.
  • the synthetic procedures for antibody coupling are known in the art and may be applied to modified oligosaccharides or oligosaccharide analogues of the invention which, on the polar face provide either free amino groups for biotinylation, or free carboxylic groups for peptide coupling of an antibody via N-glutaryl detergent dialysis, or maleimide for sulfhydryl antibody coupling, or pyridyldithiopropionate for sulfhydryl and maleimide antibody coupling, or similar methods appreciated in the art.
  • R 5 , R 6 are groups which may be polar or lipophilic, preferably H.
  • An example of such an amphiphile is that in which at least two monocyclic units making up the macrocycle are derived from a (1-1)- or (1-2)- or (1-3)- or (1-6)-linked disaccharide, or from the disaccharide sucrose, or where at least one of the units (whether cyclic or open-chain) which make up the macrocycle is derived from fructose or a furanose sugar or sialic acid or from a carbohydrate analogue (defined for this purpose as a molecule which is not a natural carbohydrate nor a derivative thereof but which can usefully function either physically or pharmaceutically as a carbohydrate).
  • the amphiphiles are of the form bis(amphiphile) in which two amphiphilic molecules of the above form share common R 1 , R 1 ′, R 4 , R 4 ′ groups, so as to provide ‘bola amphiphiles’, characterised by having two polar macrocycle molecules joined by one or more lipophilic groups, thus: (R 2 , R 2 ′, R 3 , R 3 ′)-macrocycle-(R 1 , R 2 ′, R 4 , R 4 ′)-macrocycle-(R 2 , R 2 ′, R 3 , R 3 ′), where linker groups X are understood.
  • the bis-amphiphile is simplified to a bola amphiphile in which a common set of lipophilic groups (R 1 , R 1 ′, R 4 , R 4 ′) and a common macrocyclic molecule link two sets of polar headgroups (R 2 , R 2 ′, R 3 , R 3 ′), thus: (R 2 , R 2 ′, R 3 ,_R 3 ′)(R 1 , R 1 ′, R 4 , R 4 ′)-macrocycle-(R 2 , R 2 ′, R 3 , R 3 ′), where linker groups are understood.
  • a single layer of such molecules can assemble to constitute a vesicle.
  • the groups X 1 , X′ 1 , X 4 , X′ 4 , or the groups X 2 , X′ 2 , X 3 , X′ 3 , or the groups R 1 , R′ 1 , R 4 , R′ 4 , or the groups R 2 , R′ 2 , R 3 , R′ 3 may be linked to each other, as independent sets, intramolecularly by reaction of their chemical precursor groups through catalysis (for example through irradiation), or by reaction of their chemical precursor groups with a polyfunctional linking agent.
  • the groups X 1 , X′ 1 , X 4 , X′ 4 , or the groups X 2 , X′ 2 , X 3 , X′ 3 , or the groups R 1 , R′ 1 , R 4 , R′ 4 , or the groups R 2 , R′ 2 , R 3 , R′ 3 may be linked to each other, as independent sets, intermolecularly by reaction of their chemical precursor groups through catalysis, or by reaction of their chemical precursor groups with a polyfunctional linking reagent, to provide an oligomerised amphiphile.
  • the amphiphile molecules self-assemble in an aqueous solvent.
  • the resulting micelles or vesicles can be transferred by physical or chemical means from the aqueous solvent into another phase, such as an aqueous phase containing a proportion of an alcohol or other polar solvent for example dimethyl formamide, dimethyl sulfoxide, tetramethylurea, dimethyl carbonate, or a polymer, or into an emulsion, or gel-like matrix, or lyophilised suspension.
  • an alcohol or other polar solvent for example dimethyl formamide, dimethyl sulfoxide, tetramethylurea, dimethyl carbonate, or a polymer
  • the assembly of amphiphile molecules may be composed of more than one of the molecular forms or embodiments described above, to provide the molecular assembly with the complementary properties of the individual amphiphiles, for example the property of cell-adhesion together with prodrug properties, or to modulate the colloidal stability of the assemblies.
  • amphiphile molecules may be mixed with other molecules, preferably other amphiphiles such as ceramides or glycerides, to modulate the properties of their assemblies, for example to control their colloidal stability.
  • other amphiphiles such as ceramides or glycerides
  • amphiphile forms a complex with a therapeutic molecule for its solubilisation or stabilisation, or for its formulation into pharmaceutical compositions useful for the treatment of human or animal diseases.
  • the drugs that complex with the amphiphile are of a lipophilic or polar nature.
  • the drug may bind in the cavity of the macrocycle, in the lipophilic interior of the assembly, or in the aqueous internal compartment(s) of the amphiphile assembly.
  • drugs which may be complexed with the amphiphile or which may be entrapped in the lipophilic interior of the assembly or entrapped in the aqueous internal compartment(s) of the amphiphile assembly include but are not limited to: anti-neoplastic agents (paclitaxel, doxorubicin, cisplatin, etc); anti-inflammatory agents (diclofenac, rofecoxib, celecoxib, etc); antifungals such as amphotericin B; peptides, proteins and their analogues including those to which nonpeptide groups such as carbohydrates, hemes and fatty acids are attached; oligosaccharides and their analogues such as Sialyl Lewis x analogues; oligonucleotides and their analogues; plasmid DNA; and complexes of oligonucleotides or of DNA with gene delivery agents.
  • anti-neoplastic agents paclitaxel, doxorubicin, cis
  • amphiphile is complexed with a molecule or atom used for analysis or diagnosis, for example a peptide antigen or an antibody; or a molecule used as a radiation sensitiser, for example a porphyrin.
  • amphiphile is complexed with a molecule which functions as a prodrug, for example a precursor of nitric oxide.
  • the amphiphile complex may be attached covalently to a polymer; the polymer may be grafted onto the amphiphile molecules of the complex for example by living polymerisation; or the amphiphile may be a copolymer, for example the amphiphile may be cross-linked by means of difunctional or polyfunctional reagents such as activated diacids or diepoxides, or copolymerised within the matrix of a polylactic or polyglycolic acid.
  • difunctional or polyfunctional reagents such as activated diacids or diepoxides, or copolymerised within the matrix of a polylactic or polyglycolic acid.
  • the guest molecule is attached covalently to the amphiphile, that is, it functions as an R-group as specified above, so as to provide a precursor of the active form of the guest molecule, for example to provide a prodrug which may be biodegraded to release an active form of the drug.
  • amphiphile-drug complex is prepared by sonication.
  • the advantage of this is that the complex forms smaller particles, which are easily absorbed.
  • the average particle diameter of the aggregate formed by the amphiphile of the invention is in the range of 50-500 nm.
  • the amphiphile or its complex is present as a pharmaceutical formulation with any pharmaceutically acceptable ingredient such as a diluent, carrier, preservative (including anti-oxidant), binder, excipient, flavouring agent, thickener, lubricant, dispersing, wetting, surface active or isotonic agent which is compatible with the amphiphile or complex or aggregate of same.
  • a pharmaceutically acceptable ingredient such as a diluent, carrier, preservative (including anti-oxidant), binder, excipient, flavouring agent, thickener, lubricant, dispersing, wetting, surface active or isotonic agent which is compatible with the amphiphile or complex or aggregate of same.
  • amphiphile or complex is dispersed in a suitable solvent, buffer, isotonic solution, emulsion, gel or lyophilised suspension.
  • amphiphile or complex is preferably administered parenterally, but may also be administered by alternative routes such as oral, topical, intranasal, intraocular, vaginal, rectal or by inhalation spray in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes percutaneous injections, intravenous, intramuscular, intrasteral, intrathecal, intraperitoneal injection or infusion techniques.
  • the present invention also provides the amphiphile or amphiphile-drug complexes in pharmaceutical formulations exhibiting sustained release of a drug.
  • Such formulations are generally known and include devices made of inert polymers or of biodegradable polyacids or polyesters in which the active ingredient (the present amphiphile or its complex) is either dispersed, covalently linked via labile bonds, or stored as a reservoir between polymer membranes. Sustained release is achieved through diffusion of the active ingredient through the polymer matrix or hydrolysis of any covalent linkages present. Sustained release may also be attained by delivery of the active ingredient via osmotic pumps, in which the amphiphile may also act as an osmotic driving agent providing potential for the influx of water.
  • FIG. 1 formula of a typical macrocyclic oligosaccharide, ⁇ -cyclodextrin,
  • FIG. 2 scheme of modular design of a cylindrical (a), and a wedge-shaped (b) macro-amphiphile based on a macrocyclic core
  • FIG. 3 electron micrograph of HE-SC 16 -CD vesicles
  • FIG. 4 electron micrograph of HE-SC 12 -CD vesicles
  • FIG. 5 elution of carboxyfluorescein (CF) entrapped in HE-SC 12 -CD, HE-SC 16 -CD vesicles,
  • FIG. 6 release of CF from HE-SC 16 -CD vesicles
  • FIG. 7 comparison of transfection abilities of DOTAP and oligoethylenoxy (hydroxyethyl) cyclodextrins (HE)-SC 6 , —SC 6 NH 2 , —SC 16 and —SC 16 NH 2 .
  • the macrocyclic oligosaccharide molecules are amphiphilic, with lipophilic groups on one face of the macrocycle, and polar hydrophilic groups on the other face.
  • the relative effective volumes of the combined lipophilic and polar groups at either side of the molecule determine the shape of the amphiphile (FIG. 2), which in turn determines the geometry of its self-assembly (J. Israelachvili, Intermolecular and Surface Forces, 2nd Edn., Academic Press, 1991, Chapter 17).
  • Example 1 illustrates the introduction of lipophilic groups onto one side (the primary side) of a cyclodextrin molecule.
  • Examples 2 and 3 illustrate the introduction of hydroxyethyl (oligoethylenoxy) groups as polar groups onto the other side (the secondary side) of the molecule.
  • Example 4 illustrates the preparation of a lyotropic phase of amphiphilic cyclodextrin; preparation of a complex of this with a hydrophilic (water-soluble)host molecule, carboxyfluorescein; and confirmation that the lifetime of entrapment is greater than three days.
  • Example 5 illustrates the formation of a complex with a lipophilic guest molecule, an azadipyrromethene.
  • Example 6 illustrates the preparation of a polyamino (polycationic) cyclodextrin amphiphile.
  • Example 7 describes the synthesis of a cyclodextrin bola amphiphile.
  • Example 8 illustrates the use of a cyclodextrin amphiphile in delivery of a guest molecule (plasmid DNA) to the interior of biological cells, as measured by resulting transfection.
  • plasmid DNA guest molecule
  • the reaction mixture was cooled to room temperature and the solvent was removed by rotary evaporation at 100° C.
  • the crude product was isolated as a brown viscous oil, which was taken up in 2 mL of methanol and purified by size-exclusion chromatography through a column of 8 g of lipophilic Sephadex LH 20-100 using methanol as eluent.
  • Product (560 mg, 184 mmol, 89% yield) was isolated as a yellow wax.
  • This product was obtained from 600 mg of heptakis(6-hexadecylthio)- ⁇ -cyclodextrin (213 mmol), 60 mg of K 2 CO 3 and 1.05 g of ethylene carbonate (56 eq.) in 6 mL of tetramethylurea as described for the synthesis of heptakis(2,3-hydroxyethyl, 6-thiododecyl)- ⁇ -cyclodextrin.
  • the crude product was purified by crystallisation from 25 mL of methanol containing 20% acetone and isolated in 71% yield as brown-white powder.
  • the amphiphilic cyclodextrins are dispersed in water by sonication of a thin film (cast by slow rotary evaporation of a solution of the cyclodextrins in chloroform) in a sonication bath.
  • HE-SC 12 is sonicated for 2 hours at room temperature and HE-SC 16 is sonicated for 2 hours at 50° C.
  • Dynamic light scattering indicates the presence of vesicles with an average diameter of 170 nm. Vesicles of cyclodextrins of 50-300 nm diameter are also observed by transmission electron microscopy using uranyl acetate as a negative staining agent (FIG. 1).
  • the particle size can be directed by sonication time, in order to obtain a size suitable for specific molecular inclusion or specific therapeutic use.
  • thermotropic phase transitions which depend on molecular structure, and which can direct important parameters such as vesicle stability and bilayer permeability.
  • Vesicles of heptakis(6-dodecylthio-2-oligoethylenoxy)- ⁇ -cyclodextrin and heptakis(6-dodecylthio-2-oligoethylenoxy)- ⁇ -cyclodextrin were prepared by sonication in a buffered solution of carboxyfluorescein (CF).
  • CF carboxyfluorescein
  • the fluorescence intensity of CF correlates linearly with its concentration, and the incremental change of fluorescence upon addition of Triton X-100 is a direct measure of the percentage of entrapped volume of the vesicles relative to the total volume of the solution.
  • the entrapped volume amounted to 7.7+/ ⁇ 1.9% and 11.4+/ ⁇ 2.7% for two independent preparations of HE-SC 16 ; and to 5.0+/ ⁇ 2.4% and 7.2+/ ⁇ 5.3% for two independent preparations of HE-SC 12 .
  • CF entrapped in the vesicles was separated from free (non-entrapped) CF by gel filtration using Sephadex G25. Independent turbidity measurements indicated that vesicles of HE-SC 12 and of HE-SC 16 elute much faster than free CF. The peak of entrapped CF coincided with the elution of vesicles (FIG. 4). This confirms the existence of an aqueous inner compartment within the vesicles. Furthermore, as anticipated, the amount of entrapped CF in cyclodextrin vesicles correlated with the cyclodextrin concentration.
  • Solutions of azadipyrromethene (fixed concentration) and HE-CD (various concentrations) were prepared as follows: for a solution containing 0.05 mg/ml HE-CD, the HE-CD (20 ⁇ l of a 25 mg/ml soln. in chloroform), HE-CD-F (fluorescently labelled with methylanthranilate) (10 ⁇ l of a 0.5 mg/ml soln. in chloroform) and the azadipyrromethene (100 ⁇ l of a 20 mM soln. in methanol) were combined in a small vial, and the solvents were evaporated in a stream of nitrogen.
  • HEPES buffer (10 mM, 1 ml) was added before sonication (1 h at 60° C.). Fluorescence of the cyclodextrin and absorbance of the dissolved (complexed) azadipyrromethene were measured, and again after one week.
  • Table 1 below Encapsulation of an azadipyrromethene in vesicles of HE-SC 16 amphiphile shows that the lipophilic guest was efficiently dissolved in water by complexation with the vesicle bilayer and/or within the cyclodextrin molecular cavities.
  • MALDI-MS series of m/z from 1774 for deca(ethylenoxy) product to 1950 (MNa + ).
  • the amphiphilic cyclodextrin vesicles were formulated as follows: the CD was dissolved in chloroform; solvent was removed by a stream of nitrogen to leave a film which was hydrated with doubly distilled deionised water.
  • DNA pCMVluc plasmid
  • CD-DNA complexes were added to the cells, at a DNA dose of 1 ⁇ g per well, for 4 hours in the presence of serum free Opti-MEM, after which time serum-containing medium was added and cells were cultured for a further 20 hours. Media were replaced with fresh media and the cells were allowed express for a further 24 hours before the level of luciferase expression was determined using a Promega Luciferase Assay Kit and standardised for protein using the Biorad Dc Protein Assay Kit. The results (FIG. 7) show that the CDs cause a significant increase in transfection compared with uncomplexed DNA, and can approach the commercial vector DOTAP in efficiency.
  • the amphiphilic CDs therefore can deliver a drug, DNA for example, into biological cells.

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US20060110437A1 (en) * 2002-11-14 2006-05-25 Stupp Samuel I Synthesis and self-assembly of abc triblock bola peptide
US20060149036A1 (en) * 2002-11-12 2006-07-06 Stupp Samuel I Composition and method for self-assembly and mineralizatin of peptide amphiphiles
US20070277250A1 (en) * 2005-03-04 2007-11-29 Stupp Samuel I Angiogenic heparin-binding epitopes, peptide amphiphiles, self-assembled compositions and related methods of use
US7371719B2 (en) 2002-02-15 2008-05-13 Northwestern University Self-assembly of peptide-amphiphile nanofibers under physiological conditions
US7390526B2 (en) 2003-02-11 2008-06-24 Northwestern University Methods and materials for nanocrystalline surface coatings and attachment of peptide amphiphile nanofibers thereon
US7452679B2 (en) 2003-12-05 2008-11-18 Northwestern University Branched peptide amphiphiles, related epitope compounds and self assembled structures thereof
US20090042804A1 (en) * 2007-04-17 2009-02-12 Hulvat James F Novel peptide amphiphiles having improved solubility and methods of using same
US7534761B1 (en) 2002-08-21 2009-05-19 North Western University Charged peptide-amphiphile solutions and self-assembled peptide nanofiber networks formed therefrom
US7544661B2 (en) 2003-12-05 2009-06-09 Northwestern University Self-assembling peptide amphiphiles and related methods for growth factor delivery
US20100266557A1 (en) * 2009-04-13 2010-10-21 Northwestern University Novel peptide-based scaffolds for cartilage regeneration and methods for their use
US8207264B2 (en) 2008-07-11 2012-06-26 Tyco Healthcare Group Lp Functionalized inclusion complexes as crosslinkers
US20140200290A1 (en) * 2012-10-12 2014-07-17 Empire Technology Development Llc Paints and coatings containing cyclodextrin additives
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US7838491B2 (en) 2001-11-14 2010-11-23 Northwestern University Self-assembly and mineralization of peptide-amphiphile nanofibers
US20090156505A1 (en) * 2001-11-14 2009-06-18 Northwestern University Self-assembly and mineralization of peptide-amphiphile nanofibers
US7491690B2 (en) 2001-11-14 2009-02-17 Northwestern University Self-assembly and mineralization of peptide-amphiphile nanofibers
US7371719B2 (en) 2002-02-15 2008-05-13 Northwestern University Self-assembly of peptide-amphiphile nanofibers under physiological conditions
US20080177033A1 (en) * 2002-02-15 2008-07-24 Stupp Samuel I Self-Assembly of Peptide-Amphiphile Nanofibers under Physiological Conditions
US7745708B2 (en) 2002-02-15 2010-06-29 Northwestern University Self-assembly of peptide-amphiphile nanofibers under physiological conditions
US8063014B2 (en) 2002-02-15 2011-11-22 Northwestern University Self-assembly of peptide-amphiphile nanofibers under physiological conditions
US20110008890A1 (en) * 2002-02-15 2011-01-13 Northwestern University Self-Assembly of Peptide-Amphiphile Nanofibers Under Physiological Conditions
US7534761B1 (en) 2002-08-21 2009-05-19 North Western University Charged peptide-amphiphile solutions and self-assembled peptide nanofiber networks formed therefrom
US8124583B2 (en) 2002-11-12 2012-02-28 Northwestern University Composition and method for self-assembly and mineralization of peptide-amphiphiles
US20060149036A1 (en) * 2002-11-12 2006-07-06 Stupp Samuel I Composition and method for self-assembly and mineralizatin of peptide amphiphiles
US7554021B2 (en) 2002-11-12 2009-06-30 Northwestern University Composition and method for self-assembly and mineralization of peptide amphiphiles
US20060110437A1 (en) * 2002-11-14 2006-05-25 Stupp Samuel I Synthesis and self-assembly of abc triblock bola peptide
US7683025B2 (en) * 2002-11-14 2010-03-23 Northwestern University Synthesis and self-assembly of ABC triblock bola peptide amphiphiles
US7390526B2 (en) 2003-02-11 2008-06-24 Northwestern University Methods and materials for nanocrystalline surface coatings and attachment of peptide amphiphile nanofibers thereon
US7452679B2 (en) 2003-12-05 2008-11-18 Northwestern University Branched peptide amphiphiles, related epitope compounds and self assembled structures thereof
US8138140B2 (en) 2003-12-05 2012-03-20 Northwestern University Self-assembling peptide amphiphiles and related methods for growth factor delivery
US20090269847A1 (en) * 2003-12-05 2009-10-29 Northwestern University Self-assembling peptide amphiphiles and related methods for growth factor delivery
US8580923B2 (en) 2003-12-05 2013-11-12 Northwestern University Self-assembling peptide amphiphiles and related methods for growth factor delivery
US7544661B2 (en) 2003-12-05 2009-06-09 Northwestern University Self-assembling peptide amphiphiles and related methods for growth factor delivery
US20070277250A1 (en) * 2005-03-04 2007-11-29 Stupp Samuel I Angiogenic heparin-binding epitopes, peptide amphiphiles, self-assembled compositions and related methods of use
US7851445B2 (en) 2005-03-04 2010-12-14 Northwestern University Angiogenic heparin-binding epitopes, peptide amphiphiles, self-assembled compositions and related methods of use
US8076295B2 (en) 2007-04-17 2011-12-13 Nanotope, Inc. Peptide amphiphiles having improved solubility and methods of using same
US20090042804A1 (en) * 2007-04-17 2009-02-12 Hulvat James F Novel peptide amphiphiles having improved solubility and methods of using same
US8207264B2 (en) 2008-07-11 2012-06-26 Tyco Healthcare Group Lp Functionalized inclusion complexes as crosslinkers
US20100266557A1 (en) * 2009-04-13 2010-10-21 Northwestern University Novel peptide-based scaffolds for cartilage regeneration and methods for their use
US8450271B2 (en) 2009-04-13 2013-05-28 Northwestern University Peptide-based scaffolds for cartilage regeneration and methods for their use
US20140200290A1 (en) * 2012-10-12 2014-07-17 Empire Technology Development Llc Paints and coatings containing cyclodextrin additives
US9051479B2 (en) * 2012-10-12 2015-06-09 Empire Technology Development Llc Paints and coatings containing cyclodextrin additives
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