US20140314664A1 - Hydrophobic Molecule-Induced Branched Polymer Aggregates And Their Use - Google Patents

Hydrophobic Molecule-Induced Branched Polymer Aggregates And Their Use Download PDF

Info

Publication number
US20140314664A1
US20140314664A1 US13/978,713 US201213978713A US2014314664A1 US 20140314664 A1 US20140314664 A1 US 20140314664A1 US 201213978713 A US201213978713 A US 201213978713A US 2014314664 A1 US2014314664 A1 US 2014314664A1
Authority
US
United States
Prior art keywords
branched
aggregate
paa
polymer
modified
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/978,713
Other languages
English (en)
Inventor
Dujie Qin
Ray Yin
Jing Pan
Yubei Zhang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ANP Technologies Inc
Original Assignee
ANP Technologies Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by ANP Technologies Inc filed Critical ANP Technologies Inc
Priority to US13/978,713 priority Critical patent/US20140314664A1/en
Assigned to ANP TECHNOLOGIES, INC. reassignment ANP TECHNOLOGIES, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: QIN, DUJIE, ZHANG, Yubei, PAN, JING, YIN, RAY
Publication of US20140314664A1 publication Critical patent/US20140314664A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/243—Platinum; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A61K47/48384—
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/56—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/68—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 non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • 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
    • A61K47/51—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 non-active ingredient being a modifying agent
    • A61K47/68—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 non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—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 non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • 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
    • A61K47/6921—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
    • A61K47/6929—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle
    • A61K47/6931—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer
    • A61K47/6935—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 the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores the form being a nanoparticle, e.g. an immuno-nanoparticle the material constituting the nanoparticle being a polymer the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/06—Macromolecular compounds, carriers being organic macromolecular compounds, i.e. organic oligomeric, polymeric, dendrimeric molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to a surface modified branched polymer (MBP), which can either be a surface modified symmetrically branched polymer (SBP) or a surface modified asymmetrically branched polymer (ABP), which on exposure to a water insoluble or poorly water soluble molecule, such as, a drug, forms a composite nanoparticle or nanoaggregate, wherein the drug is dispersed or deposited primarily at the surface of the structures where hydrophobic portions or sites are located.
  • SBP surface modified symmetrically branched polymer
  • ABSP surface modified asymmetrically branched polymer
  • the particles or aggregates of interest are stable, for example, can be desiccated and rehydrated.
  • the nanoparticles or nanoaggregates can range from about 50 nm to about 500 nm in diameter depending, in part, on the drug to polymer ratio, the drug, the polymer, the solvent(s) used, amount of the homopolymer and amount of the drug. Hydrophobic, electrostatic, metal-ligand interactions, hydrogen bonding and other molecular interactions may be involved in the spontaneous interactions between the water insoluble or poorly water soluble molecule and the homopolymer to form aggregates.
  • the particles or aggregates of interest have a controlled release profile and thus find utility, for example, as a carrier for the controlled release of pharmacologically active agents, drugs and the like in a host, for providing a supplement, nutrient or requirement; for treating any of a variety of disorders; and the like.
  • dendritic polymers including Starburst dendrimers (or Dense Star polymers) and Combburst dendrigrafts (or hyper comb branched polymers), recently was developed and studied for various industrial applications.
  • Those polymers often possess: (a) a well defined core molecule, (b) at least two concentric dendritic layers (generations) with symmetrical (equal length) branches and branch junctures, and (c) exterior surface groups, such as, polyamidoamine (PAMAM)-based branched polymers and dendrimers described in U.S. Pat. Nos.
  • PAMAM polyamidoamine
  • PEI polyethyleneimine
  • PPI polypropyleneimine
  • Combburst dendrigrafts are constructed with a core molecule and concentric layers with symmetrical branches through a stepwise synthetic method.
  • Combburst dendrigrafts or polymers are generated with monodisperse linear polymeric building blocks (U.S. Pat. Nos. 5,773,527; 5,631,329 and 5,919,442).
  • the branch pattern is different from that of dendrimers.
  • Combburst dendrigrafts form branch junctures along the polymeric backbones (chain branches), while Starburst dendrimers often branch at the termini (terminal branches).
  • M w /M n the molecular weight distributions (M w /M n ) of those polymers (core and branches) often are narrow.
  • M w /M n ratios often less than about 1.
  • SBP's such as dendrimers
  • dendrimers are predominantly produced by repetitive protecting and deprotecting procedures through either a divergent or a convergent synthetic approach. Since dendrimers utilize small molecules as building blocks for the cores and the branches, the molecular weight distribution of the dendrimers often is defined. In the case of lower generations, a single molecular weight dendrimer often is obtained.
  • SBP's include symmetrical star shaped or comb shaped polymers, such as, symmetrical star shaped or comb shaped polyethyleneoxide (PEO), polyethyleneglycol (PEG), PEI, PPI, polyoxazoline (PDX), polymethyloxazoline (PMOX), polyethyloxazoline (PEOX), polystyrene, polymethylmethacrylate, polydimethylsiloxane or a combination thereof.
  • PEO polyethyleneoxide
  • PEG polyethyleneglycol
  • PEI PEI
  • PPI polyoxazoline
  • PMOX polymethyloxazoline
  • PEOX polyethyloxazoline
  • polystyrene polymethylmethacrylate
  • polydimethylsiloxane or a combination thereof symmetrical star shaped or comb shaped polymers
  • ABSP asymmetrically branched polymers
  • reg-ABP asymmetrically branched dendrimers or regular ABP
  • a random ABP (ran-ABP) possesses: a) no core, b) functional groups both at the exterior and in the interior, c) random/variable branch lengths and patterns (i.e., termini and chain branches), and d) unevenly distributed interior void spaces.
  • ran-ABP such as, made of PEI
  • Ran-ABP such as those made of PDX, i.e., poly(2-methyloxazoline) and poly(2-ethyloxazoline)
  • Litt J. Macromol. Sci. Chem. A9(5), 703-727 (1975)
  • Warakomski J. Polym. Sci. Polym. Chem. 28, 3551 (1990)
  • the synthesis of ran-ABP's often can involve a one-pot divergent or a one-pot convergent method.
  • a homopolymer can relate to a polymer or to a polymer backbone composed of the same repeat unit, that is, the homopolymer is generated from the same monomer (e.g., polyethyleneimine dendrimers, polyamidoamine dendrimers or polyoxazoline dendrimers).
  • the monomer can be a simple compound or a complex or an assemblage of compounds where the assemblage or complex is the repeat unit in the homopolymer.
  • the complex can be depicted as ABC.
  • a polymer composed of (ABC)-(ABC)-(ABC) . . . is a homopolymer for the purposes of the instant disclosure.
  • the homopolymer may be linear or branched.
  • that molecule is a homopolymer for the purposes of the instant disclosure because that branched polymer is composed of a single monomer, ethyleneimine or aziridine.
  • one or more of the monomer or complex monomer components can be modified, substituted, derivatized and so on, for example, modified to carry a functional group.
  • Such molecules are homopolymers for the purposes of the instant disclosure as the backbone is composed of a single simple or complex monomer.
  • the need for hydrophilicity for a molecule to survive in circulation or in tissue spaces can constrain the use of pharmacologically active hydrophobic drug candidates or drugs.
  • development of effective formulations for poorly water soluble pharmaceutically active agents (PAA) is important in drug development and use.
  • Current solutions include improving drug solubility or reducing drug particle size by, for example, chemical modification or physical formulation.
  • Chemical modification methods often involve converting the drug, e.g., by using a salt form, hydrating or attaching various water soluble functional groups, such as, amino/imino, hydroxyl, or carboxyl containing groups; water soluble polymers, such as, PEG or PEO, and the like to the original drug molecule to enhance water solubility.
  • water soluble functional groups such as, amino/imino, hydroxyl, or carboxyl containing groups
  • water soluble polymers such as, PEG or PEO, and the like
  • Physical formulation can include using a cosolvent and/or a surfactant to dissolve a poorly soluble drug; involving a lipid or a liposome-based nanoemulsion or microemulsion; melting drug and polymer without any solvents at elevated temperatures; using a complexing agent (e.g., an inorganic salt, coordination metals (e.g., hexamine cobalt (III) chloride), chelates (e.g., EDTA, EGTA etc.), metal-olefins or metallocenes (e.g., Ferrocene), inclusion compounds (e.g., cyclodextrins, choleic acid etc.) or molecular complexes); as well as solid dispersion in a carrier, such as, e.g., acids, such as, citric acid, tartaric acid, succinic acid, HCl etc.), sugars (e.g., dextrose, sorbitol, sucrose, maltose, gal
  • micronization which can use a milling technique, such as, use of a jet mill or a rotor stator colloid mill to reduce particle size; increase dissolution rate with increased surface area; nanosuspension, which is a submicron colloidal dispersion of pure particles of drugs, which can be stabilized by surfactants; homogenization, which often involves conventional homogenizers, sonicators and high shear fluid processors; wet milling, where the active drug is fragmented in the presence of surfactant by milling or by spraying drug dissolved in a volatile organic solvent into a heated aqueous solution; using supercritical fluids; polymorph changes; using eutectic mixtures; using self microemulsifying drug delivery systems etc.
  • intravenous drug delivery allows rapid and direct equilibration of the drug in the circulation, that can enable effective local concentration.
  • a stable and controlled drug release formulation not only can avoid excessively high serum levels just after dosing but also can allow gradual release of the drug in the intravascular compartment.
  • Microparticles larger than 7 ⁇ m are generally cleared from the circulation by the “blood filtering organs,” such as, the spleen, lungs and liver. Therefore, smaller nanoparticles, e.g., 50-500 nm, often possess longer blood circulation times.
  • PAA pharmaceutically active agents
  • drugs include, but are not limited to, chlormethine, chlorambucil, busulfan, thiotepa, cyclophosphamide, estramustine, ifosfamide, meclilorethamine, melphalan, uramustine, lonuistine, streptozotocin, dacarbazine, procarbazine, temozolamide, cisplatin, carboplatin, oxaliplatin, satraplatin, (SP-4-3)-(cis)-aminedichloro-[2-methylpyridine]-platinum (II), methotrexate, permetrexed, raltitrexed, trimetrexate, camptothecin, camptothecin derivatives (such as, irinotecan, topotecan etc.), cladribine, chlorodeoxyadenosine, clofarabine, fludarabine, mercap
  • molecules above are modified to be more soluble in water.
  • such molecules can be modified or altered to remove such modifications resulting in a pharmaceutically active or biologically active molecule which is less hydrophilic and more hydrophobic, that is, poorly water soluble or water insoluble.
  • PAA's that are water insoluble or poorly water soluble, or those which are sensitive to acid environments generally cannot be conventionally administered (e.g., by intravenous injection or oral administration).
  • parenteral administration of such pharmaceuticals can be achieved by emulsification of oil-solubilized drug with an aqueous liquid (such as normal saline), often in the presence of surfactants or emulsifiers to produce an emulsion for administration.
  • paclitaxel is a water insoluble drug.
  • Paclitaxel is sold as Taxol® by Bristol-Myers Squibb.
  • Paclitaxel is derived from the Pacific Yew tree, Taxus brevifolia (Wan et al., J. Am. Chem. Soc. 93:2325 (1971).
  • Taxanes, including paclitaxel and docetaxel are used to treat various cancers, including, breast, ovarian and lung cancers, as well as colon, and head and neck cancers, etc.
  • Taxol® and generics thereof are formulated using a 1:1 solution of ethanol:Cremaphor® (polyethyoxylated castor oil) to solubilize the drug.
  • ethanol:Cremaphor® polyethyoxylated castor oil
  • Cremaphor® has been linked to severe hypersensitivity reactions and consequently requires medication of patients with corticosteroids (e.g., dexamethasone) and antihistamines.
  • conjugated paclitaxel for example, Abraxane®, which is produced by mixing paclitaxel with human serum albumin, has eliminated the need for corticosteroids and antihistamine injections.
  • Abraxane® generates undesirable side effects, such as, severe cardiovascular events, including chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, hypertension etc, which prevents patients with high cardiovascular risk from using the drug.
  • branched polymers including SBP's and ABP's
  • SBP's and ABP's have been used for drug delivery
  • those attempts are primarily focused on the chemical attachment of the drug to the polymer, or physical encapsulation of such drugs in the interior through unimolecular encapsulation (U.S. Pat. Nos. 5,773,527; 5,631,329; 5,919,442; and 6,716,450).
  • dendrimers and dendrigrafts are believed to physically entrap bioactive molecules using unimolecular encapsulation approaches, as described in U.S. Pat. Nos. 5,338,532; 5,527,524; and 5,714,166 for dense star polymers, and U.S. Pat. No. 5,919,442 for hyper comb branched polymers.
  • unimolecular encapsulation of various drugs using SBP's to form a, “dendrimer box” was reported in Tomalia et al., Angew. Chem. Int. Ed. Engl., 1990, 29, 138, and in “Dendrimers and Other Dendritic Polymers”, edited by Frechet & Tomalia, John Wiley & Sons, Ltd., 2001, 387-424.
  • Branched core shell polymers with a hydrophobic core and a hydrophilic shell may be used to entrap a poorly water soluble drug through molecular encapsulation.
  • Randomly branched and hyperbranched core shell structures with a hydrophilic core and a hydrophobic shell have also been used to carry a drug through unimolecular encapsulation and pre-formed nanomicelles (U.S. Pat. No. 6,716,450 and Liu et al., Biomaterials 2010, 10, 1334-1341). However, those unimolecular and pre-formed micelle structures are generated in the absence of a drug.
  • Block copolymers such as miktoarm polymers (i.e., Y shape/AB 2 type star polymers) and linear (A)-dendritic (B) block copolymers, were observed to form sterocomplexes with paclitaxel (Nederberg et al., Biomacromolecules 2009, 10, 1460-1468 and Luo et al., Bioconjugate Chem. 2010, 21, 1216).
  • Those block copolymers closely resemble traditional lipid or AB-type linear block copolymers, which are well known surfactants used for the generation of micelles.
  • the present disclosure is directed to use of modified branched polymers (MBP) to increase the solubility of water insoluble or poorly water soluble pharmaceutically active agents (PAA), such as, drugs.
  • MBP modified branched polymers
  • PAA pharmaceutically active agents
  • MBP's can include both symmetrically and asymmetrically branched polymers.
  • the symmetrically branched polymer has regular symmetrical branches within the polymer.
  • the asymmetrically branched polymer has either random or regular, asymmetrical branches.
  • the random ABP can also have a mixture of terminal and chain branching patterns.
  • both ABP's and SBP's can be modified further with at least one molecule or group capable of forming additional branches at a given time so that new material properties can be achieved, wherein additional functional groups may be further attached.
  • All of the modified polymers can be defined as modified symmetrically or asymmetrically branched polymers.
  • the unmodified and modified branched polymers either can be produced by a divergent or a convergent method, and either a stepwise or a one-step synthetic process can be used.
  • the SBP includes, but is not limited to, polyamidoamine dendrimers; polyethyleneimine dendrimers; polypropyleneimine dendrimers; polyether dendrimers; polyester dendrimers; comb branched/star branched polymers, such as, polyamidoamine, polyethyleneoxide (PEO), polyethyleneglycol (PEG), polymethyloxazoline, polyethyloxazoline, polymethylmethacrylate (PMA), polystyrene, polybutadiene, polyisoprene and polydimethylsiloxane; comb branched dendrigrafts, such as, polyethyloxazoline, polymethyloxazoline, polyethyleneimine, polyamidoamine; and so on.
  • polyamidoamine dendrimers such as, polyethyleneoxide (PEO), polyethyleneglycol (PEG), polymethyloxazoline, polyethyloxazoline, polymethylmethacrylate (PMA), polystyrene
  • the SBP can have an interior void space, while the ABP can have unevenly distributed void spaces.
  • a hybrid branched polymer comprising the aforementioned SBP's, such as, dendrimers or dendrigrafts, and ABP's, such as, regular and randomly branched polymers, as well as star branched and comb branched polymers, or combination thereof, can also be used for the generation of said drug-induced aggregates or nanoparticles of interest.
  • SBP's such as, dendrimers or dendrigrafts
  • ABP's such as, regular and randomly branched polymers, as well as star branched and comb branched polymers, or combination thereof
  • the branched polymers are modified with functional groups, such as, but not limited to, NH 2 , NHR, NR 2 , NR 3 + , COOR, COOH, COO ⁇ , OH, C(O)R, C(O)NH 2 , C(O)NHR or C(O)NR 2 , wherein R can be any aliphatic group, aromatic group or combination thereof; an aliphatic group (e.g., a hydrocarbon chain), which can be branched, can contain one or more double and/or triple bonds and/or may be substituted; an aromatic group, which may contain a plurality of rings, which may be fused or separated, the rings may be of varying size and/or may contain substituents; perfluorocarbon chains; saccharides and/or polysaccharides, which may be of varying ring sizes, the rings may contain a heteroatom, such as a sulfur or a nitrogen atom, may be substituted, may contain more than one species of sacchar
  • the molecular weight of the MBP's can range from about 500 to over 5,000,000; from about 500 to about 1,000,000; from about 1,000 to about 500,000; or from about 2,000 to about 100,000.
  • the surface of the symmetrically and asymmetrically polymers is modified so that the physical properties of the surface groups will be more compatible with a PAA of interest, thus making the PAA more miscible with the surface group region/domain of the MBP's.
  • the modification of branched polymers is with hydrophobic functional groups, such as, aliphatic chains (e.g., hydrocarbon chains comprising 1 to about 22 carbons, whether linear or branched), aromatic structures (e.g. containing one or more aromatic rings, which may be fused) or combinations thereof.
  • hydrophobic functional groups such as, aliphatic chains (e.g., hydrocarbon chains comprising 1 to about 22 carbons, whether linear or branched), aromatic structures (e.g. containing one or more aromatic rings, which may be fused) or combinations thereof.
  • the PAA's of the instant disclosure are not physically entrapped within said branched polymer structures. Instead, the PAA either can be located at or dispersed in the domains/regions containing surface functional groups of each branched polymer.
  • the resulting structures of interest optionally can be preserved, for example, by lyophilization or other form of desiccation, which may further stabilize the structures of interest.
  • nanoparticles with sizes ranging from about 50 to about 500 nm in diameter can be obtained.
  • the branched polymer can comprise targeting moieties/groups including, but not limited to, an antibody or antigen-binding portion thereof, antigen, cognate carbohydrates (e.g., sialic acid), a cell surface receptor ligand, a moiety bound by a cell surface receptor, a moiety that binds a cell surface saccharide, an extracellular matrix ligand, a cytosolic receptor ligand, a growth factor, a cytokine, an incretin, a hormone, a lectin, a lectin ligand, such as, a galactose, a galactose derivative, an N-acetylgalactosamine, a mannose, a mannose derivative and the like, a vitamin, such as, a folate or a biotin, avidin, streptavidin, neutravidin, DNA, RNA etc.
  • targeting moieties/groups including, but not limited to, an antibody or antigen-binding portion thereof, antigen
  • a targeting moiety/group and a functional group are attached to the branched polymer prior to the formation of the composite nanoparticle for targeted drug delivery.
  • a diagnostic agent such as, a contrast reagent
  • a diagnostic agent also can be carried by said structures of interest, for example, for in vivo imaging.
  • the diagnostic agent is one which is poorly soluble or insoluble in water, thereby negating a need for a drug to form a structure of interest.
  • an imaging agent is one comprising a metal or is paramagnetic, e.g., magnetic resonance imaging materials, which can be deposited or entrapped within said branched polymer of said nanocomposite-based particle.
  • the diagnostic material containing nanoparticles can further comprise a targeting moiety/group, which allows such nanoparticle to target specific locations for diagnosis.
  • a structure of interest comprises a second or more PAA's.
  • the second or more PAA's may or may not be poorly soluble or insoluble in water.
  • the nanoparticle can carry plural similar PAA's or can carry PAA's of different function or activity, such as, types of drugs to form a combination or cocktail therapy.
  • drugs may include, but are not limited to, small molecule drugs, inorganic drugs and biological molecule-based drugs, such as peptides, proteins, antibodies or antigen-binding portions thereof, enzymes, vaccines and so on, for the treatment of various diseases or general use, such as, for cosmetics and over the counter products.
  • the nanoparticle-based drug formulations also can be used in drug discovery and development, where various therapeutic formulations can be screened and tested rapidly.
  • FIG. 1 depicts SBP's including a dendrimer, a star shaped polymer, a dendrigraft and a comb shaped polymer. All have a core, whether globular or linear.
  • FIG. 2 depicts a chemical structure of symmetrically branched PPI dendrimers.
  • FIG. 3 depicts chemical modification reactions of symmetrically branched PPI dendrimers.
  • the numbers, 8, 16, 32 and so on indicate the number of reactive groups at the surface of the dendrimer.
  • FIGS. 4A and 4B depict random (A) and regular (B) ABP's with asymmetrical branch junctures and patterns.
  • FIG. 5 depicts a chemical structure of a random asymmetrically branched PEI homopolymer.
  • FIGS. 6A and 6B depict synthetic schemes.
  • FIG. 6A presents chemical modification reactions of random asymmetrically branched PEI homopolymers.
  • FIG. 6B depicts a one-pot synthesis of hydrophobically modified, randomly branched poly(2-ethyloxazoline) with a primary amino group at the focal point of the polymer.
  • the initiator/surface group (I) is the brominated hydrocarbon. The reaction opens the oxazoline ring.
  • FIG. 7 illustrates a drug loaded in or at the surface domain or region of the branched polymer (SBP's and ABP's).
  • R indicates a surface group and a solid circle depicts a drug of interest.
  • FIG. 8 illustrates one type of composite-based nanoparticles containing both drug molecules and branched polymers.
  • FIG. 9 illustrates an insoluble or poorly water soluble drug that is loaded at hydrophobic surface groups of branched polymers (SBP's and ABP's).
  • SBP's and ABP's hydrophobic surface groups of branched polymers
  • FIG. 10 illustrates various drug-containing nanoparticles also carrying at least one targeting group or moiety, such as, an antibody, depicted herein and in other figures as a, “Y.”
  • FIG. 11 illustrates drug-containing nanoparticles carrying both magnetic imaging contrast agents and a targeting moiety or group, such as an antibody.
  • M denotes an imaging material, such as, a magnetic resonance imaging contrast agent.
  • FIG. 12 illustrates drug-containing nanoparticles carrying both radioactive (Rad) agents and a targeting moiety or group, such as, an antibody.
  • Rad radioactive
  • FIG. 13 shows the size comparison of polymer-only and polymer-drug aggregates with the polymer concentration at 25 mg/mL and the drug concentration at 5 mg/mL in saline.
  • the polymer is a hydrophobically-modified, randomly-branched PEOX and the drug is paclitaxel.
  • FIG. 14 shows the size comparison of polymer-only and polymer-drug aggregates with the polymer concentration at 2.5 mg/mL and the drug concentration at 0.5 mg/mL in saline.
  • the polymer is a hydrophobically-modified, randomly-branched PEOX and the drug is paclitaxel.
  • FIG. 15 shows the size comparison of polymer-only and polymer-drug aggregates with the polymer concentration at 250 ⁇ g/mL and the drug concentration at 50 ⁇ g/mL in saline.
  • the polymer is a hydrophobically-modified, randomly-branched PEOX and the drug is paclitaxel.
  • FIG. 16 shows the size comparison of polymer-only and polymer-drug aggregates with the polymer concentration at 25 ⁇ g/mL and the drug concentration at 5 ⁇ g/mL in saline.
  • the polymer is a hydrophobically-modified, randomly-branched PEOX and the drug is paclitaxel.
  • FIG. 17 summarizes data comparing cytotoxicity of a drug and a drug aggregate.
  • MCF-7 human breast cancer cells were exposed to various concentrations of each and survivability was determined.
  • FIG. 18 summarizes data comparing cytotoxicity of a drug and a drug aggregate. H460 human epithelial lung cancer cells were exposed to various concentrations of each and survivability was determined.
  • the drug solubility in this disclosure is defined as, relative to parts of solvent required to solubilize for one part of drug, ⁇ 30 (soluble), 30-100 (poorly soluble) and >100 (insoluble).
  • a drug of interest can be a small molecule, a salt thereof in which the molecule is modified to be water insoluble or poorly water soluble or can be a biological molecule which is modified to be water insoluble or poorly water soluble.
  • Chemical/small molecule drugs can include any substantially poorly soluble or water insoluble pharmacologically active agents contemplated for use in the practice of the present disclosure include PAA's, drugs, imaging agents, diagnostic agents, agents of nutritional value, supplements, vitamins, lifestyle chemicals and the like. Some of those may need to be converted to a less water soluble form, for example, changing the PAA from a salt to a non-salt form or from a charged to a non-charged molecule.
  • PAA's include drugs which are poorly soluble or insoluble in water, which include, growth agents, AIDS adjunct agents, alcohol abuse preparations, such as, agents for treating dependence or withdrawal, Alzheimer's Disease treatments, Amyotrophic Lateral Sclerosis treatments, analgesics, anesthetics, anticonvulsants, antidiabetic agents, antidotes, antifibrosis therapies, antihistamines, anti-infective agents, such as, antibiotics, antivirals, antifungals, amebicides, antihelmintics, antimalarials, leprostatics and so on, antineoplastics, antiparkinsonian agents, antirheumatic agents, appetite stimulants, biological response modifiers, biologicals, blood modifiers, such as, anticoagulants, colony stimulating factors, hemostatics, plasma extenders, thrombin inhibitors and so on, bone metabolism regulators, cardioprotective agents, cardiovascular agents, such as, adrenergic blockers, adrenergic stimulators, ACE inhibitors
  • drugs of interest as well as forms of drugs which may be modified, for example, as salts.
  • any such ionized or hydrophilic forms are modified as known in the art to remove such functional groups, modifications and the like to yield non-modified or other forms of drugs which are poorly soluble or not soluble in water.
  • Examples of pharmaceutically active agents, drugs and the like include those listed herein and, for example, analgesics/antipyretics (e.g., aspirin, acetaminophen, ibuprofen, naproxen sodium, buprenorphine hydrochloride, propoxyphene hydrochloride, propoxyphene napsylate, meperidine hydrochloride, hydromorphone hydrochloride, morphine sulfate, oxycodone hydrochloride, codeine phosphate, dihydrocodeine bitartrate, pentazocine hydrochloride, hydrocodone bitartrate, levorphanol tartrate, diflunisal, trolamine salicylate, nalbuphine hydrochloride, mefenamic acid, butorphanol tartrate, choline salicylate, butalbital, phenyltoloxamine citrate, diphenhydramine citrate, methotrimeprazine, cinnamedrine hydrochloride, me
  • diagnostic agents contemplated for use in the practice of the present disclosure include, but are not limited to, for example, magnetic resonance imaging contrast agents (e.g., various metal ions, such as, gadolinium based compounds for functional MRI, fluorocarbons, lipid soluble paramagnetic compounds and the like), ultrasound contrast agents, radiocontrast agents, such as, conventional radionuclides, such as, iodine, copper, fluorine, gallium, thallium and the like, which may be complexed with a carrier (e.g., iodo-octanes, halocarbons, renografin and the like), as well as other diagnostic agents which cannot readily be delivered without some physical and/or chemical modification to accommodate the substantially water insoluble nature thereof.
  • Metals and radionuclides can be carried or bound to a protein, lipid, nucleic acid, chelator, such as a small molecule, or combinations thereof.
  • agents of nutritional or lifestyle value contemplated for use in the practice of the present disclosure include amino acids, sugars, lipids, proteins, carbohydrates, oils, such as, fish oil, fat-soluble vitamins (e.g., vitamins A, D, E, K and the like), minerals, supplements, fats, emollients, tanning agents, moisturizers and the like, or combinations thereof.
  • fat-soluble vitamins e.g., vitamins A, D, E, K and the like
  • minerals e.g., minerals, supplements, fats, emollients, tanning agents, moisturizers and the like, or combinations thereof.
  • a nanocomposite is a physical mixture of two or more materials or components (e.g., polymer and PAA molecules). In the instant disclosure, such a mixture could contain different nanoscopic phases or domains formed between the PAA and branched homopolymer molecule in either solid or liquid states. Nanocomposite can include a combination of a bulk matrix (e.g., branched homopolymers and PAA's) and nanodimensional phase(s), which may exhibit different properties due to dissimilarities of structure and chemistry (e.g., the domain formed by the PAA and the surface groups of branched polymer, as well as the domains formed by the interior of the branched polymers).
  • a bulk matrix e.g., branched homopolymers and PAA's
  • nanodimensional phase(s) which may exhibit different properties due to dissimilarities of structure and chemistry (e.g., the domain formed by the PAA and the surface groups of branched polymer, as well as the domains formed by the interior of the branche
  • one of the phases may dissolve faster than the other or others, resulting in a gradual breakdown of the composite aggregate resulting in a graded and controlled release of the composite components and optionally, reformation of one or more of the components into a novel form, such as, a new aggregate.
  • the size of the aggregates described in the disclosure ranges from between about 10 to about 500 nm in diameter, or from about 30 nm to about 300 nm in diameter. Aggregates may exhibit size-related properties that differ significantly from those observed for microparticles or bulk materials.
  • SBP's are depicted in FIG. 1 , with symmetric branches, wherein all the homopolymers of interest possess a core and exhibit symmetric branch junctures consisting either of terminal or chain branches throughout the homopolymer.
  • the functional groups are present predominantly at the exterior.
  • the modified SBP's can be obtained, for example, through chemically linking functional groups on, for example, symmetrically branched PAMAM or PPI dendrimers, commercially available from Aldrich, polyether dendrimers, polyester dendrimers, comb branched/star branched polymers, such as, those containing PEO, PEG, PMOX or PEOX, polystyrene, and comb branched dendrigrafts, such as, those containing PEOX, PMOX or PEI.
  • PAMAM or PPI dendrimers commercially available from Aldrich
  • polyether dendrimers such as, those containing PEO, PEG, PMOX or PEOX
  • polystyrene polystyrene
  • comb branched dendrigrafts such as, those containing PEOX, PMOX or PEI.
  • the higher branching densities of SBP's render the polymers molecularly compact with a well defined interior void space, which makes such molecules suitable as a carrier for entities, such as, reporters or PAA's entrapped or encased therein.
  • a water insoluble SBP can become water soluble, while an SBP with a high charge density can be modified to carry very low or no charge on the polymer or at the polymer surface.
  • a water soluble SBP can be modified with hydrophobic surface groups to enhance the ability to solubilize water insoluble or poorly water soluble drugs at the surface thereof.
  • the SBP (for example, either a symmetrically branched PEI dendrimer, a PPI dendrimer, a PAMAM dendrimer or a symmetrically branched PEI dendrigraft) can be modified with different kinds of, for example, primary amine groups through, for example, Michael addition or an addition of acrylic esters onto amine groups of the homopolymer.
  • methyl acrylate can be introduced onto the primary and/or secondary amino groups of PEI, PPI and polylysine (PLL) homopolymers.
  • the ester groups then can be further derivatized, for example, by an amidation reaction.
  • such an amidation reaction with, for example, ethylenediamine can yield the addition of an amino group at the terminus of the newly formed branch.
  • Other modifications to the homopolymer can be made using known chemistries, for example, as provided in, “Poly(amines) and Poly(ammonium salts)” in Handbook of Polymer Synthesis (Part A), Kricheldorf, ed., New York, Marcel Dekker, 1994; and “Dendrimers and Other Dendritic Polymers,” Frechet & Tomalia, eds., John Wiley & Sons, Ltd., 2001.
  • a modified SBP such as, a modified PEI, PPI, PAMAM dendrimer or PEI dendrigraft
  • a modified SBP such as, a modified PEI, PPI, PAMAM dendrimer or PEI dendrigraft
  • the resulting modified SBP also is symmetrically branched.
  • the surface functional groups can carry different charge and/or charge density, and/or hydrophobic groups. The molecular shape and surface functional group locations (i.e., surface functional group back folding) then can be tuned further, based on those characteristic properties.
  • the modified SBP's can be produced using any of a variety of synthetic schemes that, for example, are known to be amenable to reaction with a suitable site on the homopolymer.
  • any of a variety of reagents can be used in a synthetic scheme of choice to yield any of a variety of modifications or additions to the homopolymer backbone.
  • the addition of any of a variety of substituents can be used, for example, at the alkylation stage, using for example, any of a variety of acrylate reagents, such as, an acrylate comprising a hydrocarbon substituent, such as saturated or unsaturated hydrocarbons comprising 1 to about 22 carbons, which my be substituted, aliphatic, aromatic, ringed, saturated at one or more bonds or a combination thereof.
  • acrylate reagents such as, an acrylate comprising a hydrocarbon substituent, such as saturated or unsaturated hydrocarbons comprising 1 to about 22 carbons, which my be substituted, aliphatic, aromatic, ringed, saturated at one or more bonds or a combination thereof.
  • suitable reactants include, methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, pentyl acrylate, hexyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl acrylate, undecyl acrylate, dodecyl acrylate and so on, and mixtures thereof.
  • any of a variety of amines can be used.
  • ethylenediamine, monoethanolamine, tris(hydroxymethyl)aminomethane, alkyl amine, allyl amine, or any amino modified polymer, including those comprising PEG, PEO, perfluoropolymers, polystyrene, polyethylene, polydimethylsiloxane, polyacrylate, polymethylmethacrylate and the like, and mixtures thereof, can be used.
  • Such a synthetic strategy would allow not only symmetric growth of the molecule, where more branches with different chemical compositions can be introduced, but also the addition of multiple functional groups at the exterior of the structure.
  • the precursor homopolymer can be modified, and continuously, using the same or a different synthetic process until the desired SBP's with appropriate molecular weight and functional groups are attained.
  • the hydrophobic and hydrophilic properties, as well as charge densities of such polymers can be tailored to fit specific application needs using appropriate monomers for constructing the homopolymer and suitable modification reactions.
  • the chain end of symmetrically star branched or comb branched homopolymer such as, a poly(2-substituted oxazoline), including, for example, poly(2-methyloxazoline), poly(2-ethyloxazoline), poly(2-propyloxazoline) and poly(2-butyloxazoline, etc.), PEI, PEO/glycol, polyvinylpyrrolidone, polyphosphate, polyvinyl alcohol or polystyrene, can be modified with another small molecule or polymer to generate various functional groups at the homopolymeric chain ends including a primary, secondary or tertiary amine, carboxylate, hydroxyl, aliphatic (e.g., hydrocarbon chain), aromatic, fluoroalkyl, aryl, PEG, PEO, acetate, amide and/or ester groups.
  • a poly(2-substituted oxazoline) including, for example, poly(2-methyloxazoline), poly(2-ethy
  • various initiators also can be utilized so that the same type of functional groups can be introduced at the chain end if a convergent synthetic approach is utilized (Dendritic Molecules, Newkome et al., eds., VCH, Weinheim, 1996; Dendrimers and Other Dendritic Polymers, Frechet & Tomalia, eds., John Wiley & Sons, Ltd., 2001; and J. Macromol. Sci. Chem. A9(5), pp. 703-727 (1975)).
  • ABP's are depicted in FIGS. 4A and 4B with asymmetric branches, wherein some of the polymers of interest possess no core and exhibit asymmetrical branch junctures consisting of both chain and terminal branches throughout the entire homopolymer.
  • the functional groups often are present both at the exterior and in the interior. However, when a larger functional group (e.g., a large hydrophobic or hydrophilic group) is used, the functional groups often can be attached preferentially and perhaps necessarily at the exterior of the ABP, for example, possibly due to steric effects. Therefore, such surface MBP's can be utilized for solubilization of or aggregate formation with an insoluble or poorly soluble drug.
  • the modified ABP's can be obtained, for example, through chemically linking functional groups on regular ABP's, such as, polylysine (e.g., branched PLL), on random ABP's, such as, PEI's (commercially available from Aldrich, Polysciences, or BASF under the trade name, LuposalTM) or polyoxazolines, which can be prepared according to the procedure of Litt (J. Macromol. Sci. Chem. A9(5), pp. 703-727 (1975)).
  • regular ABP's such as, polylysine (e.g., branched PLL)
  • random ABP's such as, PEI's (commercially available from Aldrich, Polysciences, or BASF under the trade name, LuposalTM) or polyoxazolines, which can be prepared according to the procedure of Litt (J. Macromol. Sci. Chem. A9(5), pp. 703-727 (1975)).
  • Other ABP's can include, but are not
  • PEI asymmetrically branched PEI
  • PEI's with various molecular weights are available commercially from different sources, such as, Aldrich, Polysciences and BASF (under the trade name LuposalTM)
  • the random asymmetrically branched PEI's are produced primarily through cationic ring opening polymerization of ring strained cyclic imine monomers, such as aziridines (ethyleneimine) and azetidines (propyleneimine), with Lewis or Bronsted acids as initiators. (Dermer et al., “Ethylenediamine and Other Aziridines”, Academic Press, New York, (1969); and Pell, J. Chem. Soc. 71 (1959)).
  • Randomly branched poly(2-substituted oxazoline) polymers can be prepared using the procedure of Litt (J. Macromol. Sci. Chem. A9 (5), pp. 703-727 (1975)).
  • the synthetic processes for making ABP's often generate various branch junctures within the macromolecule.
  • a mixture of terminal and chain branch junctures is distributed throughout the molecular structure.
  • the branching densities of the random ABP's can be lower, and the molecular structure can be more open when compared with dendrimers and dendrigrafts.
  • the branch pattern is random, the average ratio of primary, secondary and tertiary amine groups can be relatively consistent with a ratio of about 1:2:1, as described by Dick et al., J. Macromol. Sci. Chem., A4 (6), 1301-1314 (1970) and Lukovkin, Eur. Polym. J. 9, 559 (1973).
  • the presence of the branch junctures can make the random ABP's, such as, asymmetrically branched PEI's, form macromolecules with a possible spherical, ovoid or similar configuration.
  • the random ABP's within the globular structure, there are various sizes of pockets formed from the imperfect branch junctures at the interior of the macromolecule.
  • the pockets of random ABP's are spread unevenly throughout the entire molecule.
  • random ABP's possess both exterior and unevenly distributed interior functional groups that can be further reacted with a variety of molecules, thus forming new macromolecular architectures, a modified random ABP of interest.
  • the functional groups of the regular ABP are also distributed both at the exterior and in the interior, which is very similar to the random ABP.
  • One such homopolymer is PLL, which can be made as described in U.S. Pat. Nos. 4,289,872; 4,360,646; and 4,410,688.
  • Such homopolymers also can be modified in a manner similar as that for random ABPs, as taught herein, and as known in the art.
  • the ABP (for example, either a random asymmetrically branched PEI or a regular asymmetrically branched PLL) is modified with different kinds of primary amine groups through, for example, Michael addition or an addition of acrylic esters onto amines of the polymer.
  • Michael addition for example, through a Michael addition reaction, methyl acrylate, or other acrylates as provided herein, can be introduced onto the primary and/or secondary amino groups of, for example, PEI and PLL homopolymers.
  • the ester groups then can be further derivatized, for example, by an amidation reaction.
  • such an amidation reaction with, for example, ethylenediamine, can yield the addition of an amino group at the terminus of the newly formed branch.
  • a modified ABP such as, a modified PEI or PLL homopolymer
  • the resulting modified ABP is also asymmetrically branched.
  • the surface functional groups can carry different charge and charge density.
  • the molecular shape and functional group locations i.e., functional group back folding then can be further tuned, based on those characteristic properties.
  • the modified ABP's can be produced using any of a variety of synthetic schemes that, for example, are known to be amenable to reaction with a suitable site on the homopolymer.
  • any of a variety of reagents can be used in a synthetic scheme of choice to yield any of a variety of modifications or additions to the polymer backbone.
  • an acrylate which can comprise a saturated or unsaturated hydrocarbon, such as one comprising one carbon to about 22 carbons, which may be aliphatic, branched, saturated, aromatic, ringed or combination thereof.
  • Suitable reactants include methyl acrylate, ethyl acrylate, propyl acrylate, butyl acrylate, pentyl acrylate, hexyl acrylate, heptyl acrylate, octyl acrylate, nonyl acrylate, decyl acrylate, undecyl acrylate, dodecyl acrylate and the like, and mixtures thereof.
  • any of a variety of amines can be used in the methods provided herein and known in the art.
  • ethylenediamine, monoethanolamine, tris(hydroxymethyl)aminomethane, alkyl amine, allyl amine or any amino modified polymers including polyethylene glycol (PEG), perfluoropolymers, polystyrene, polyethylene, polydimethylsilixane, polyacrylate, polymethylmethacrylate and the like, and mixtures thereof, can be used.
  • PEG polyethylene glycol
  • perfluoropolymers polystyrene
  • polyethylene polydimethylsilixane
  • polyacrylate polymethylmethacrylate and the like, and mixtures thereof
  • hydrophobic groups including aliphatic (e.g., hydrocarbons from C 1 to about C 22 ) groups, aromatic groups, polyethylene polymers, polystyrene polymers, perfluoropolymers, polydimethylsiloxanes, polyacrylates, polymethylmethacrylates, as well as, hydrophilic groups, including a OH group, hydrophilic polymers, such as, PEOX, PEG, PEO etc.
  • a modified ABP can be achieved by using, for example, epoxy reactions, amidation reactions, Michael addition reactions, including using a —SH or an —NH 2 group reacted with maleimide, aldehyde/ketone-amine/hydrazide coupling reactions, iodo/iodoacetyl-SH coupling reactions, hydroxylamine-aldehyde/ketone coupling reactions etc.
  • Such synthetic strategies allow not only asymmetric growth of the molecule, where more pockets are introduced, but also the addition of multiple functional groups at both the interior and the exterior of the structure.
  • the homopolymer can be modified further using the same or a different synthetic process until the desired ABP's with appropriate molecular weight and functional groups are attained.
  • the hydrophobic and hydrophilic properties, as well as charge density of such homopolymers can be tailored to fit specific application needs using appropriate monomers for constructing the homopolymer and suitable modification reactions.
  • a focal point (merged from various reactive chain ends during a convergent synthesis) of a random ABP can be terminated or reacted with another small molecule to generate various functional groups at the homopolymeric chain ends, including primary, secondary or tertiary amines, carboxylate, hydroxyl, alkyl, fluoroalkyl, aryl, PEG, acetate, amide and/or ester groups.
  • various initiators also can be utilized so that the same type of functional group can be introduced at the surface groups where a polymerization begins during a convergent synthesis (J. Macromol. Sci. Chem. A9 (5), pp. 703-727 (1975)).
  • An alkyl surface modified, randomly branched poly(2-ethyloxazoline) with a primary amine group at the focal point of the branched polymer can be prepared using the Litt and Warakomski procedures, supra.
  • CH 3 (CH 2 ) 17 —Br can be utilized as an initiator for 2-ethyloxazoline polymerization through a cationic ring opening process to generate a randomly branched polymer, followed by quenching with N-tert-butyloxycarbonylpiperazine (N-Boc-piperazine) or ethylenediamine (EDA).
  • hydrophobically modified branched poly(2-ethyloxazoline) polymer to be functionalized with a primary amine group at the focal point ( FIG. 6B ).
  • N-tert-butyloxycarbonylpiperazine (N-Boc-piperazine) terminated hydrophobically modified branched poly(2-ethyloxazoline) polymer also can be deprotected to generate a primary amino group at the focal point. If not terminated, the focal point of the polymer can be hydrolyzed to, for example, a hydroxyl group on dissolving in water (e.g., containing 1N Na 2 CO 3 ).
  • the primary amine group While the introduction of a primary amine group to a hydrophobically modified branched poly(2-oxazoline) homopolymer enhances drug solubility and produces PAA induced aggregates, the primary amine group also allows the attachment of various targeting groups, such as, an antibody, antigen binding portion thereof, an antigen, or a member of a binding pair to the hydrophobically modified branched poly(2-oxazoline) polymer ( FIG. 10 ). Such aggregates or nanoparticles containing such targeting groups and modifications thereto can provide a targeting ability on the aggregate with PAA and enables PAA to be released preferentially or solely at the desired treatment location.
  • various targeting groups such as, an antibody, antigen binding portion thereof, an antigen, or a member of a binding pair
  • the MBP's such as, a hydrophobically modified homopolymers, including both SBP's and ABP's
  • a hydrophobically modified homopolymers can be used to generate a surface-modified branched polymer for solubilizing water insoluble or poorly water soluble PAA's, or for forming PAA induced nanoparticles with water insoluble or poorly water soluble PAA's, such as, paclitaxel, camptothecin, doxorubin, dolargin, loperamide, tubocurarine, ibuprofen, diazepam, naproxen, carbamazepine, griseofulvin, nifedipine, phytosterol, omeprazol, domperidone, zidovudine, amphotericin B and the like, as well as drugs described herein, and known to be or are modified to be poorly soluble in water or insoluble in water.
  • the hydrophilic or amphiphilic core can be poly(2-oxazoline), poly(2-substituted oxazolines), including poly(2-methyloxazoline, poly(2-ethyloxazoline), poly(2-propyloxazoline) and poly(2-butyloxazoline) etc., PEG, PEO, polyphosphonate and the like.
  • the hydrophobic shell can comprise aliphatic hydrocarbons (such as, from C 1 to about C 22 ), aromatic hydrocarbons, polyethylene polymers, polystyrene polymers, perfluoropolymers, polydimethylsiloxanes, polyacrylates, polymethylmethacrylates and the like.
  • asymmetrically branched PLL, PEI or PEOX homopolymers also can be modified with hydrophobic surface groups listed above to enhance the solubility of water insoluble or poorly water soluble PAA's.
  • the branching density e.g., from low generation, such as, star and comb homopolymers, to high generation of dendrimers and dendrigrafts
  • the amount of hydrophobic surface group coverage e.g., from 0% to 100% coverage
  • the increase in branching density and the amount of hydrophobic group coverage will make the homopolymer more compatible with hydrophobic PAA's.
  • the ABP's and SBP's with from about 1 to about 30% or more surface hydrophobic component by weight are effective at solubilizing or dispersing poorly water soluble or water insoluble PAA's, such as, paclitaxel.
  • the branched homopolymers utilized for example, a PDX, a PEOX, a PMOX, PEO/PEG, polyacrylamides, polyphosphates, polyvinylpyrrolidones and polyvinyl alcohols are soluble in both water and in various organic solvents, thereby facilitating forming various PAA containing nanoparticles or aggregates.
  • the good water solubility along with good hydrophobic drug miscibility in an aqueous solution, with or without other organic solvents, makes such homopolymers useful for enhancing the solubility of poorly water soluble PAA's.
  • the homopolymers of interest simplify manufacturing processes and decrease production cost by reducing formulation steps, processing time, as well as the need to use complex and expensive equipment currently used in the pharmaceutical industry. If additional branching densities are needed, the SBP's or ABP's first can be modified with additional groups as described herein, and then, for example, attached with additional hydrophobic functional groups for enhancing PAA solubility.
  • a distinct physical aggregate is formed of size distinct from aggregates formed only of polymer ( FIGS. 13-15 ).
  • the size and distribution of the polymer PAA aggregates become much more similar to that of polymer only aggregates suggesting PAA is released from the induced aggregates or nanoparticles.
  • the broad size distribution of polymer only aggregates is similar to that observed for other structures composed of lipid, whether or not associated with a PAA.
  • the PAA induced aggregates of interest are of a particular size of narrower distribution, that is, unique aggregates of certain size are produced.
  • the aggregates of interest release PAA as evidenced by a reduction of aggregate size and/or a broader distribution of aggregate size.
  • the broader distribution may result from a mixture of homopolymer only aggregates and polymer PAA aggregates of varying size due to PAA release, until the only aggregates observed are those which have the characteristics of those which are homopolymer only.
  • the PAA is released gradually after introduced into a host, such as, in the circulatory system. That mechanism is important for various drug delivery applications including, intravenous (IV), oral, transdermal, ocular, intramuscular and the like modes of administration, and where a delayed release or sustained release profile may be desirable.
  • the PAA induced aggregates also can be linked with a targeting moiety or group including, but not limited to, an antibody (or antigen-binding portion thereof), antigen, cognate carbohydrates (e.g., sialic acid), a cell surface receptor ligand, a moiety that binds a cell surface receptor, a moiety that binds a cell surface saccharide, an extracellular matrix ligand, a cytosolic receptor ligand, a growth factor, a cytokine, an incretin, a hormone, a lectin, a lectin target, such as, a galactose, a galactose derivative, an N-acetylgalactosamine, a mannose, a mannose derivative and the like, a vitamin, such as, a folate, a biotin and the like, an avidin, a streptavidin, a neutravidin, a DNA, an RNA etc. to form a conjugate so that the targeting group(s
  • a diagnostic agent such as, an imaging agent, a radionuclide or any of a variety of contrasting agents also can be carried by said aggregates of interest.
  • a combination of chemotherapy, radiotherapy and/or targeted therapy with real time diagnostic/monitoring capabilities can be achieved ( FIGS. 11 and 12 ).
  • the diagnostic agent is poorly soluble or water insoluble, thereby negating the need, for example, of a PAA of interest to induce aggregation.
  • a diagnostic agent can be a metal containing material or a paramagnetic material, e.g., magnetic resonance imaging materials, which can be deposited on the surface or entrapped within a nanocomposite of interest so that the nanoparticle can be used as both a diagnostic and a therapeutic agent.
  • the imaging material containing nanoparticles further can comprise a targeting moiety/group, which allows such nanoparticle to target specific locations that need therapeutic treatment, for example, a tumor site.
  • a molecule with the ability to bind another molecule such as a biological polymer, such as a polypeptide, or a polysaccharide, an enzyme, a receptor and the like, which can bind a vitamin, a lectin, a metal and so on, can be used in a composite of interest.
  • a biological polymer such as a polypeptide, or a polysaccharide, an enzyme, a receptor and the like, which can bind a vitamin, a lectin, a metal and so on
  • Metals and metal ions that can be carried by a polymer of interest may include, but are not limited to, transition metals, such as Sc, Y, Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Tc, Re, Fe, Ru, Os, Co, Rh, Ir, Ni, Pd, Pt, Cu, Ag, Au, Zn, Cd Hg, Ga, In or Tl, alkali metals, alkaline earth metals, Lanthanide series elements, such as Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu, Actinide series elements, such as Th, Pa, U, Np, Pu, Am, Cm, Bk, Cf, Es, Fm, Md, No and Lr, and the like.
  • transition metals such as Sc, Y, Ti, Zr, Hf, V, Nb, Ta, Cr, Mo, W, Mn, Tc, Re,
  • Such can be carried by, for example, one or more chelating groups, including, but not limited to, ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaacetic acid (DTPA), diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A), 1-oxa-4,7,10-triazacyclododecane-triacetic acid (DOXA), 1,4,7-triazacyclononanetriacetic acid (NOTA), 1,4,8,11-tetraazacyclotetradecanetetraacetic acid (TETA), DOTA-N(2-aminoethyl)amide and DOTA-N-(2-aminophenethyl)amide.
  • EDTA ethylenediaminetetraacetic acid
  • DTPA diethylene
  • a conjugate of interest comprises a reporter molecule that can be detected by an external device, such as, a gamma camera.
  • a conjugate can be configured to comprise, for example, a radioisotope that will emit detectable radiation.
  • the conjugate is placed into a format suitable for consumption or placement in a body, employing reagents suitable therefor as known in the art.
  • the conjugate composition is administered as known in the art, such as orally, rectally, intravenously and so on.
  • the nanoparticle can carry different types of PAA's so that a combination or cocktail therapy can be achieved.
  • PAA's may include, but are not limited to, various small molecule drugs, inorganic drugs and biological molecule based drugs, such as, a peptide, a protein, an antibody, an enzyme, a vaccine and the like.
  • the second or more PAA's need not be poorly soluble or water insoluble as the second or more PAA's can be situated within voids in the aggregate and need not be located at the surface.
  • any of the PAA's noted herein or known in the art can comprise the second or more PAA's.
  • PAA and modified homopolymer can be suspended individually in suitable buffers and/or solvents, such as, a buffer, acetone, ethanol and the like, at suitable concentrations, such as those which are established for in vivo use, generally in milligram or nanogram quantities. Then, the two solutions are mixed at a suitable temperature, such as, room temperature or at another temperature known to be acceptable for maintaining integrity of the PAA and homopolymer, for a suitable period of time, such as, one hour, two hours and so on. Other incubation times can vary from minutes to hours as the aggregates of interest are stable once formed.
  • the aggregates can be concentrated or collected practicing methods known in the art, for example, by filtration, centrifugation, evaporation, lyophilization, dialysis and the like. The aggregates can be desiccated for extended shelf life.
  • paclitaxel was dissolved in ethanol in various amounts of up to 40 mg/mL.
  • a hydrocarbon (CH 3 (CH 2 ) 17 ) modified randomly branched PEOX was prepared as taught herein and dissolved at varying concentrations of up 100 mg/mL in saline.
  • the two solutions then were mixed in various volumes to result in final homopolymer to paclitaxel molar ratios in the mixtures ranging from 3:1 to 10:1.
  • the mixtures subsequently were frozen at ⁇ 80° C. for 3 hours then lyophilized for 20 to 48 hours depending on volume to yield a dry powder.
  • the size of the aggregates or nanoparticles can range from about 120 nm (e.g., at 3 mg paclitaxel per mL) to about 165 nm (e.g., at 5 mg paclitaxel per mL) in diameter depending on the concentration of drug and concentration of homopolymer.
  • PAA and homopolymer can be dissolved in a common solvent, which generally is not necessarily hydrophilic but is miscible with water, and then added to an aqueous solution.
  • paclitaxel and PEOX can be dissolved in acetone and then dropwise added to water under agitation, such as, while stirred or sonicated, followed by dialysis with a 1000 MW cutoff membrane. The final product then can be lyophilized.
  • a conjugate of interest can be incorporated into pharmaceutical compositions suitable for administration, for example, for diagnostic imaging, for lifestyle management or to attain a therapeutic milestone.
  • Such compositions typically comprise an aggregate of interest and a pharmaceutically acceptable carrier, excipient or diluent, which is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like, that is, those ingredients of a pharmaceutically acceptable composition aside from the PAA's that are included therein for particular purposes, such as, bulking, preservation, delayed release, binding and so on, as known in the art, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agents are incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds also can be incorporated into the composition.
  • a pharmaceutical composition of the disclosure for use as disclosed herein is formulated to be compatible with the intended route of administration.
  • routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), transmucosal and rectal administration.
  • Solutions or suspensions used for parenteral, intradermal or subcutaneous application can include a sterile diluent, such as, water for injection, saline, oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents, such as, benzyl alcohol or methyl parabens; antioxidants, such as, ascorbic acid or sodium bisulfate; chelating agents, such as, EDTA; buffers, such as, acetates, citrates or phosphates; and agents for the adjustment of tonicity, such as, sodium chloride or dextrose. pH can be adjusted with acids or bases, such as HCl or NaOH.
  • parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic as an article of manufacture.
  • an in vivo diagnostic agent will be administered orally, rectally, intravenously, intraperitoneally and so on.
  • compositions suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • suitable carriers include physiological saline, bacteriostatic water or phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • the composition generally is sterile and is fluid to the extent that easy syringability exists.
  • the composition must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as, bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like) and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal and the like.
  • Isotonic agents for example, sugars, polyalcohols, such as, mannitol, sorbitol or sodium chloride can be included in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, aluminum monostearate or gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount of an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the active compound in a sterile vehicle that contains a basic dispersion medium and the required other ingredients, for example, from those enumerated above, and as known in the art.
  • the preparation can be prepared by, for example, lyophilization, vacuum drying or freeze drying, that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • the preparation of interest can be stored and reconstituted with a suitable liquid for use.
  • Oral compositions generally include an inert diluent, flavorant, odorant or an edible carrier.
  • the composition can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules.
  • Oral compositions also can be prepared using a fluid carrier to yield a syrup or liquid formulation, or for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed.
  • Pharmaceutically compatible binding agents and/or adjuvant materials can be included as part of the composition.
  • Tablets, pills, capsules, troches and the like can contain a binder, such as, microcrystalline cellulose, gum tragacanth or gelatin; an excipient, such as, starch or lactose, a disintegrating agent, such as, alginic acid, Primogel or corn starch; a lubricant, such as, magnesium stearate or Sterotes; a glidant, such as, colloidal silicon dioxide; a sweetening agent, such as, sucrose or saccharin; or a flavoring agent, such as, peppermint, methyl salicylate or orange flavoring.
  • a binder such as, microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as, starch or lactose, a disintegrating agent, such as, alginic acid, Primogel or corn starch
  • a lubricant such as, magnesium stearate
  • the compound is delivered in the form of, for example, a wet or dry aerosol spray from a pressurized container or dispenser that contains a suitable propellant, e.g., a gas, such as, carbon dioxide or a nebulizer, or a mist.
  • a suitable propellant e.g., a gas, such as, carbon dioxide or a nebulizer, or a mist.
  • Systemic administration also can be by transmucosal or transdermal means.
  • penetrants appropriate to the barrier to be permeated are used in the formulation.
  • penetrants generally are known in the art and include, for example, for transmucosal administration, detergents, bile salts and fusidic acid derivatives.
  • Transmucosal administration can be accomplished through the use of nasal sprays or suppositories.
  • the active compounds are formulated into ointments, salves, gels or creams as generally known in the art.
  • a suitable carrier includes dimethylsulfoxide.
  • the compound also can be prepared in the form of suppositories (e.g., with conventional suppository bases, such as, cocoa butter and other glycerides) or retention enemas for rectal delivery.
  • suppositories e.g., with conventional suppository bases, such as, cocoa butter and other glycerides
  • retention enemas for rectal delivery.
  • the active compound is prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid.
  • the instant aggregates can be used in topical forms, such as, creams, ointments, lotions, unguents, other cosmetics and the like.
  • PAA's and other bioactive or inert compounds can be carried, and include emollients, bleaching agents, antiperspirants, pharmaceuticals, moisturizers, scents, colorants, pigments, dyes, antioxidants, oils, fatty acids, lipids, inorganic salts, organic molecules, opacifiers, vitamins, pharmaceuticals, keratolytic agents, UV blocking agents, tanning accelerators, depigmenting agents, deodorants, perfumes, insect repellants and the like.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for a subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce a desired therapeutic endpoint.
  • the dosages for example, preferred route of administration and amounts are obtainable based on empirical data obtained from preclinical and clinical studies, practicing methods known in the art.
  • the dosage and delivery form can be dictated by and can be dependent on the characteristics of the PAA, the polymer, the particular therapeutic effect to be achieved, the characteristics and condition of the recipient and so on.
  • the treatment can be sustained until a desired endpoint is attained.
  • An exemplary dosing regimen is disclosed in WO 94/04188.
  • the progress of the therapy can be monitored by conventional techniques and assays, as well as patient input.
  • compositions can be included in a container, pack or dispenser together with instructions for administration.
  • Another method of administration comprises the addition of a compound of interest into or with a food or drink, as a food supplement or additive, or as a dosage form taken on a prophylactic basis, similar to a vitamin.
  • the aggregate of interest can be encapsulated into forms that will survive passage through the gastric environment. Such forms are commonly known, for example, enteric coated formulations.
  • the aggregate of interest can be modified to enhance half life, such as, chemical modification or combination with agents known to result in delayed, sustained or controlled release, as known in the art.
  • Symmetrically branched PPI dendrimers were purchased from Sigma-Aldrich. Symmetrically branched PEI dendrimers and dendrigrafts were prepared according to procedures provided in U.S. Pat. Nos. 4,631,337, 5,773,527, 5,631,329 and 5,919,442. All of the antibodies were purchased from Sigma-Aldrich, Biodesign or Fitzgerald. Different generation PAMAM dendrimers were purchased from Dendritech, Inc.
  • SB-PPI-4 symmetrically branched PPI
  • MA methyl acrylate
  • EDA ethylenediamine
  • Random asymmetrically branched PEI's were purchased from Aldrich and Polysciences. Regular ABP's were prepared according to procedures provided in U.S. Pat. No. 4,289,872. All of the antibodies were purchased from Sigma-Aldrich, Biodesign or Fitzgerald.
  • Random asymmetrically branched PEI (ran-AB-PEI, MW 2,000, 25,000 and 75,000), MA, EDA and methanol were utilized.
  • the modification of a randomly branched PEI with 10% hydrocarbon chains is used as an example.
  • MBP's such as, PAMAM, PEI and PPI dendrimers and dendrigrafts, and asymmetric PLL with various percentages and lengths (e.g., C 4 , C 12 , C 18 and C 22 ) of hydrocarbon chains were prepared in a similar manner.
  • the crude product then was precipitated from an ethyl ether solution and further purified by dialysis to give about 2.4 g of mixed hydroxyl and amino functionalized random ABP (m-ran-AB-PEI-NH 2 /OH-2.0, with an average of 20% NH 2 and 80% OH surface groups and the molecular weight was about 18,000).
  • CH 3 —(CH 2 ) 11 -PEOX-ABP100 (ABP100 is an arbitrary name to denote the ratio of monomer to initiator in the initial reaction) is provided as a general procedure for the preparation of core shell structures.
  • a mixture of CH 3 (CH 2 ) 11 —Br (2.52 g) in 500 ml of toluene was azeotroped to remove water with a distillation head under N 2 for about 15 min.
  • 2-Ethyloxazoline (100 g) was added dropwise through an addition funnel and the mixture was allowed to reflux between 24 and 48 hours.
  • 12.12 g of EDA were added to the reactive polymer solution (A) to introduce the amine function group.
  • the molar ratio of polyoxazoline chain end to EDA was 1 to 20.
  • N-tert-butyloxycarbonylpiperazine (N-Boc-piperazine) or water (e.g., with 1N Na 2 CO 3 ) can be added to terminate the reaction.
  • Morpholine or PEI also can be added to the reactive polymer solution (A) to terminate the reaction.
  • the crude product was redissolved in methanol and then precipitated from a large excess of diethyl ether.
  • the bottom layer was redissolved in methanol and dried by rotary evaporation and vacuum to give an asymmetrically random branched PEOX polymer or PEOX-PEI copolymer as a white solid (101 g).
  • asymmetrically randomly branched polymers such as, C 6 -PEOX ABP20, 50, 100, 200, 300, 500, C 18 -PEOX ABP20, 50, 200, 300, 500, C 22 -PEOX ABP20, 50, 100, 200, 300, 500, and polystyrene-PEOX etc., as well as, non-modified and modified poly(2-substituted oxazoline), such as, poly(2-methyloxazoline), were prepared in a similar manner. All the products were analyzed by SEC and NMR.
  • mixed surface (OH/NH 2 mix) modified symmetrically branched PPI-IgG conjugates (mix-m-SB-PPI-64-NH 2 /OH-2-IgG conjugates) is provided as a general procedure for the preparation of polymer antibody and polymer streptavidin conjugates.
  • conjugates such as, m-SB-PPI-4-NH 2 -1-IgG, m-SB-PPI-8-NH 2 -1-IgG, m-SB-PPI-16-NH 2 -1-IgG, m-SB-PPI-32-NH 2 -1-IgG, m-SB-PPI-4-NH 2 -2-IgG, m-SB-PPI-8-NH 2 -2-IgG, m-SB-PPI-16-NH 2 -2-IgG, m-SB-PPI-32-NH 2 -2-IgG, m-SB-PPI-4-NH 2 -3-IgG, m-SB-PPI-8-NH 2 -3-IgG, m-SB-PPI-16-NH 2 -3-IgG, m-SB-PPI-32-NH 2 -3-IgG, mix-m-SB-PPI-4-NH 2 /OH-1
  • the LC-SPDP-mix-m-SB-PPI-64-NH 2 /OH-2 was purified by gel filtration chromatography and equilibrated with buffer A (0.1 M phosphate, 0.1 M NaCl and 5 mM EDTA, pH 6.8). The product was concentrated further to yield 465 ⁇ L of solution with a concentration of approximately 0.77 nmol.
  • the LC-SPDP mix-m-SB-PPI-64-NH 2 /OH-2 (50 nmol in 65 ⁇ l of buffer A) was mixed with 100 ⁇ L of dithiothreitol (DTT) (50 mM in buffer A) and was incubated at room temperature for 15 minutes. Excess DTT and byproducts were removed by gel filtration with buffer A. The product was concentrated in a 10 K Centricon Concentrator to yield 390 ⁇ L of the thiolated mix-m-SB-PPI-64-NH 2 /OH-2 that was used for conjugation with activated antibody.
  • DTT dithiothreitol
  • conjugates such as PEI-IgG, m-ran-AB-PEI-NH 2 -1-IgG, m-ran-AB-PEI-NH 2 -2-IgG, m-ran-AB-PEI-NH 2 -3-IgG, m-ran-AB-PEI-NH 2 -4-IgG, as well as m-ran-AB-PEI-NH 2 /OH-1 (OH/NH 2 mix)-IgG, m-ran-AB-PEI-NH 2 /OH-2 (OH/NH 2 mix)-IgG, m-ran-AB-PEI-NH 2 /OH-3 (OH/NH 2 mix)-IgG, regular polylysine polymer, alkyl modified random branched poly(2-ethyloxazoline) with primary amine chain ends were all synthesized in a similar manner.
  • the LC-SPDP m-ran-AB-PEI-NH 2 /OH-2 (50 nmol in 65 ml of buffer A) was mixed with 100 ⁇ L of dithiothreitol (DTT) (50 mM in buffer A) and was allowed to incubate at room temperature for 15 minutes. Excess DTT and byproducts were removed by gel filtration with buffer A. The product was concentrated in a 10 K Centricon Concentrator to yield 390 ⁇ L of the thiolated m-ran-AB-PEI-NH 2 /OH-2 that was used for conjugation with activated antibody.
  • DTT dithiothreitol
  • Paclitaxel was dissolved in ethanol to a concentration of up to 40 mg/mL.
  • a C 18 hydrocarbon modified randomly branched PEOX was prepared as taught herein.
  • the polymer was separately dissolved to a concentration of up to 100 mg/mL in saline. The two solutions were then mixed at various volumes to result in final polymer to paclitaxel molar ratios in the mixtures ranging from 3:1 to 10:1. The mixtures were subsequently frozen at ⁇ 80° C. for 3 hours then lyophilized for 20 to 48 hours depending on volume.
  • the size of the aggregates as measured by light scattering ranged from about 120 nm to about 165 nm in diameter.
  • both paclitaxel and the PEOX polymer can be dissolved in a common solvent, such as, acetone and then dropwise added to water while being stirred or sonicated, followed by dialysis with a 1000 MW cutoff membrane. The final product then can be generated by lyophilization and the size of the aggregates was measured by light scattering.
  • a common solvent such as, acetone
  • PAA induced aggregates or nanoparticles using various hydrophobically surface modified branched polymers such as, C 4 , C 6 , C 12 or C 22 hydrocarbon modified randomly branched PEOX, PEI and PPI polymers; C 4 , C 6 , C 12 , C 18 and C 22 hydrocarbon modified PAMAM, PEI and PPI dendrimers and dendrigrafts; and C 4 , C 6 , C 12 , C 18 and C 22 hydrocarbon modified branched PLL/polymers can be prepared in a similar manner.
  • various hydrophobically surface modified branched polymers such as, C 4 , C 6 , C 12 or C 22 hydrocarbon modified randomly branched PEOX, PEI and PPI polymers; C 4 , C 6 , C 12 , C 18 and C 22 hydrocarbon modified PAMAM, PEI and PPI dendrimers and dendrigrafts; and C 4 , C 6 , C 12 , C 18 and C 22 hydrocarbon modified branched PLL/
  • C 18 -PEOx-100-NH 2 (500 mg) is dissolved in 5 mL of ethanol to yield a 100 mg/mL solution.
  • a 20 mg/mL solution of Paclitaxel is also prepared by dissolving 100 mg in 5 mL of ethanol. The two solutions are mixed for 20 minutes resulting in a solution containing 10 mg Paclitaxel and 50 mg polymer per mL, providing a solution with a 1:5 drug:polymer ratio. The mixture is placed on a rotary evaporator and the ethanol removed to dryness. The resultant solid is redissolved with stirring in 33 mL of saline solution to a final Paclitaxel concentration of 3 mg/mL.
  • the solution preparation is passed through a 0.8 ⁇ m filter and then a 0.22 ⁇ m filter.
  • the filtrate is frozen in a vial at ⁇ 70° C. for at least 2 hours then lyophilized over a 72 hour period.
  • the vial is stoppered and the ready-to-use white powder is stored at room temperature.
  • the size of various polymers, polymer only aggregates, as well as drug-induced polymer aggregates was measured by a dynamic light scattering method using a Malvern Zetasizer Nano-ZS Zen3600 particle size analyzer.
  • Metabolism in viable cells produces “reducing equivalents,” such as, NADH or NADPH.
  • reducing compounds pass electrons to an intermediate electron transfer reagent that can reduce the tetrazolium product, MTS (Promega), into an aqueous, soluble formazan product, which is colored.
  • MTS tetrazolium product
  • At death cells rapidly lose the ability to reduce tetrazolium products.
  • the production of the colored formazan product therefore, is proportional to the number of viable cells in culture.
  • the CellTiter 96® Aqueous products are MTS assays for determining the number of viable cells in culture.
  • the MTS tetrazolium is similar to MTT tetrazolium, with the advantage that the formazan product of MTS reduction is soluble in cell culture medium and does not require use of a solubilization solution.
  • a single reagent added directly to the assay wells at a recommended ratio of 20 ⁇ l reagent to 100 ⁇ l of culture medium was used. Cells were incubated 1-4 hours at 37° C. and then absorbance was measured at 490 nm.
  • cytotoxicity of various paclitaxel containing aggregates of interest along with commercially available Taxol and Abraxane, a paclitaxel nanoparticle encapsulated with human serum albumin, were tested on different cancer cell lines (from ATCC) including, lung cancer A549, breast cancer MDA-MB-231 and OV 90 ovarian cancer cell lines, as well as on a normal human fibroblast cell line.
  • the drug-induced nanoparticles were at least the same or more potent at killing the cancer cells, particularly at low drug concentrations ranging from 0.5 ⁇ g/mL to 0.5 ng/mL. No toxicity to the normal human fibroblast cell line was observed.
  • the maximum tolerated dose (MTD) of the drug-induced nanoparticles was compared to that of Taxol. Over the course of seven weeks, various doses of Taxol and the paclitaxel-containing nanoparticles of interest were injected into the tail vein of CD-1 mice. The MTD of the paclitaxel nanoparticles was more than 7-fold higher than that of Taxol, with no major side effects to the surviving mice. Also, significant weight loss was observed in mice receiving Taxol as compared to no weight loss for the cohort that received the paclitaxel nanoparticles of interest.
  • a controlled study using lung cancer A548 cell line and breast cancer MDA-MB-231 cell line in a xenograft mouse model revealed that the paclitaxel nanoparticles inhibited tumor growth in vivo significantly better than did Taxol and Abraxane.
  • a rapid reduction of tumors in mice receiving the paclitaxel nanoparticles of interest was observed, as compared to mice receiving Taxol or Abraxane.
  • Camptothecin (2.1 mg) and polymer (10.5 mg) are dissolved in a 4:1 v/v chloroform:ethanol mixture. Following thorough mixing, the solvent is removed to dryness on a rotary evaporator. The resultant solid mixture is redissolved in 2 mL of saline solution, mixed, then filtered through a 0.8 um syringe filter. The filtrate is frozen at ⁇ 70° C. for at least 2 hours in a lyophilization vial, then lyophilized overnight ( ⁇ 16 hours). The vial is stoppered and the ready-to-use white powder is stored at ⁇ 70° C. The material is reconstituted with 2 mL of water immediately prior to use.
  • Irinotecan also known as CPT-11, is a synthetic analog of camptothecin.
  • CPT-11 contains, for example, a bipiperidine carboxylate group and an ethyl group on the A and B rings, to yield a compound with greater cytotoxicity than the parent molecule.
  • Varying concentrations of CPT-11 and the camptothecin branched polymer aggregates described above were prepared.
  • MCF-7 is a human breast cancer cell line and H460 is a human epithelial lung cancer cell line. Those cell lines were exposed to varying concentrations of CPT-11 and concentrations of the camptothecin aggregates based on the amount of drug. Cell survivability was assessed as described above.
  • FIG. 17 summarizes results obtained with the MCF-7 breast cancer cell line. It can be seen that cytotoxicity of the cells to CPT-11 increased with increasing drug concentration. On the other hand, the camptothecin aggregate was more highly cytotoxic at all dosages tested. Polymer not associated with drug was not cytotoxic. Thus, although camptothecin per se does not have the same level of cytotoxicity as does CPT-11, when aggregated with a branched polymer, that aggregate was more cytotoxic than CPT-11.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nanotechnology (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Biomedical Technology (AREA)
  • Inorganic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Radiology & Medical Imaging (AREA)
  • Endocrinology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pathology (AREA)
  • Rheumatology (AREA)
  • Toxicology (AREA)
  • Urology & Nephrology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
US13/978,713 2011-01-09 2012-01-06 Hydrophobic Molecule-Induced Branched Polymer Aggregates And Their Use Abandoned US20140314664A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/978,713 US20140314664A1 (en) 2011-01-09 2012-01-06 Hydrophobic Molecule-Induced Branched Polymer Aggregates And Their Use

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201161431042P 2011-01-09 2011-01-09
US201161500633P 2011-06-24 2011-06-24
US201161502793P 2011-06-29 2011-06-29
US13/978,713 US20140314664A1 (en) 2011-01-09 2012-01-06 Hydrophobic Molecule-Induced Branched Polymer Aggregates And Their Use
PCT/US2012/020524 WO2012094620A2 (en) 2011-01-09 2012-01-06 Hydrophobic molecule-induced branched polymer aggregates and their use

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2012/020524 A-371-Of-International WO2012094620A2 (en) 2011-01-09 2012-01-06 Hydrophobic molecule-induced branched polymer aggregates and their use

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US15/818,742 Division US10688048B2 (en) 2011-01-09 2017-11-21 Hydrophobic molecule-induced branched polymer aggregates and their use

Publications (1)

Publication Number Publication Date
US20140314664A1 true US20140314664A1 (en) 2014-10-23

Family

ID=46457985

Family Applications (3)

Application Number Title Priority Date Filing Date
US13/978,713 Abandoned US20140314664A1 (en) 2011-01-09 2012-01-06 Hydrophobic Molecule-Induced Branched Polymer Aggregates And Their Use
US15/818,742 Active US10688048B2 (en) 2011-01-09 2017-11-21 Hydrophobic molecule-induced branched polymer aggregates and their use
US16/900,978 Active US12042561B2 (en) 2011-01-09 2020-06-14 Hydrophobic molecule-induced branched polymer aggregates and their use

Family Applications After (2)

Application Number Title Priority Date Filing Date
US15/818,742 Active US10688048B2 (en) 2011-01-09 2017-11-21 Hydrophobic molecule-induced branched polymer aggregates and their use
US16/900,978 Active US12042561B2 (en) 2011-01-09 2020-06-14 Hydrophobic molecule-induced branched polymer aggregates and their use

Country Status (6)

Country Link
US (3) US20140314664A1 (zh)
EP (2) EP3925625A1 (zh)
JP (1) JP6092121B2 (zh)
CN (1) CN103429267B (zh)
CA (1) CA2824063C (zh)
WO (1) WO2012094620A2 (zh)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9763892B2 (en) 2015-06-01 2017-09-19 Autotelic Llc Immediate release phospholipid-coated therapeutic agent nanoparticles and related methods
US20180289821A1 (en) * 2011-08-03 2018-10-11 Anp Technologies, Inc. Oxazoline Polymer Compositions and Use Thereof
US10688048B2 (en) 2011-01-09 2020-06-23 Anp Technologies, Inc. Hydrophobic molecule-induced branched polymer aggregates and their use
US10842147B2 (en) * 2014-11-26 2020-11-24 Microban Products Company Surface disinfectant with residual biocidal property
US10925281B2 (en) 2014-11-26 2021-02-23 Microban Products Company Surface disinfectant with residual biocidal property
US11026418B2 (en) 2014-11-26 2021-06-08 Microban Products Company Surface disinfectant with residual biocidal property
US11033023B2 (en) 2014-11-26 2021-06-15 Microban Products Company Surface disinfectant with residual biocidal property
US11503824B2 (en) 2016-05-23 2022-11-22 Microban Products Company Touch screen cleaning and protectant composition
US11801230B2 (en) 2013-02-05 2023-10-31 Anp Technologies, Inc. Nanoparticles containing a taxane and their use
CN117860742A (zh) * 2023-11-16 2024-04-12 上海交通大学医学院 氨来占诺在耐药性肺癌治疗中的新应用

Families Citing this family (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150366818A1 (en) * 2013-02-05 2015-12-24 Anp Technologies, Inc. Nanoparticles containing a Taxane and their Use
DE102017002454A1 (de) 2017-03-14 2018-09-20 Friedrich-Schiller-Universität Jena Organische Polymerpartikel enthaltend Poly(oxazolin)-Stabilisatoren und Verwendung von Poly(oxazolinen) zur Stabilisierung von organischen Polymerpartikeln
CN108175864A (zh) * 2018-01-12 2018-06-19 中山大学 一种多模态成像纳米探针及其合成方法
CN109880346B (zh) * 2019-03-05 2021-02-19 中原工学院 一种有机-无机复合导电凝胶的制备方法
WO2022174171A1 (en) * 2021-02-15 2022-08-18 Anp Technologies, Inc. Pharmaceutical composition containing taxane nanoaggregates and use thereof
WO2023044365A1 (en) * 2021-09-17 2023-03-23 Doublerainbow Biosciences Inc. Use of cyclodextrin to enhance solubility of substrates and increase enzymatic glycosylation reaction efficiency
WO2023177629A1 (en) * 2022-03-14 2023-09-21 Anp Technologies, Inc. Polymer nanoaggregate pharmaceutical composition and use thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020041888A1 (en) * 2000-04-10 2002-04-11 Moshe Flashner-Barak Method and composition for treating cancer by administration of apoptosis-inducing chemotherapeutic agents
US20080200562A1 (en) * 2005-05-02 2008-08-21 Anp Technologies Polymer Conjugate Enhanced Bioassays

Family Cites Families (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4360646A (en) 1979-04-06 1982-11-23 Allied Corporation Preparation of lysine based macromolecular highly branched homogeneous compound
US4289872A (en) 1979-04-06 1981-09-15 Allied Corporation Macromolecular highly branched homogeneous compound based on lysine units
US4435548A (en) 1981-04-27 1984-03-06 The Dow Chemical Company Branched polyamidoamines
US4410688A (en) 1981-04-29 1983-10-18 Allied Corporation Macromolecular highly branched homogeneous compound
US4631337A (en) 1983-01-07 1986-12-23 The Dow Chemical Company Hydrolytically-stable dense star polyamine
US4568737A (en) 1983-01-07 1986-02-04 The Dow Chemical Company Dense star polymers and dendrimers
US4507466A (en) 1983-01-07 1985-03-26 The Dow Chemical Corporation Dense star polymers having core, core branches, terminal groups
US4587329A (en) 1984-08-17 1986-05-06 The Dow Chemical Company Dense star polymers having two dimensional molecular diameter
US6312679B1 (en) * 1986-08-18 2001-11-06 The Dow Chemical Company Dense star polymer conjugates as dyes
US5338532A (en) 1986-08-18 1994-08-16 The Dow Chemical Company Starburst conjugates
US5527524A (en) 1986-08-18 1996-06-18 The Dow Chemical Company Dense star polymer conjugates
US5631329A (en) 1990-08-27 1997-05-20 Dendritech, Inc. Process for producing hyper-comb-branched polymers
US5773527A (en) 1990-08-27 1998-06-30 Dendritech, Inc. Non-crosslinked, polybranched polymers
US5530092A (en) 1992-01-13 1996-06-25 Dsm N.V. Dendritic macromolecule and the preparation thereof
US5610268A (en) 1992-01-13 1997-03-11 Dsm N.V. Dendritic macromolecule and the preparation thereof
AU687755B2 (en) 1992-08-21 1998-03-05 Genentech Inc. Method for treating an LFA-1-mediated disorder
DK0741756T3 (da) 1994-01-28 1999-02-22 Dsm Nv Dendritisk makromolekyle og fremgangsmåde til fremstilling heraf
IL128775A (en) * 1994-03-07 2001-05-20 Dow Chemical Co A preparation containing a dendritic polymer in a complex with at least one unit of biological reaction sub
CA2226299A1 (en) 1995-08-11 1997-02-27 Dendritech, Inc. Hyper comb-branched polymer conjugates
JP2003520210A (ja) * 2000-01-05 2003-07-02 イマレックス セラピューティクス， インコーポレイテッド 低い水溶性を有する薬物の送達のための薬学的処方物
US20040009229A1 (en) 2000-01-05 2004-01-15 Unger Evan Charles Stabilized nanoparticle formulations of camptotheca derivatives
US20020041898A1 (en) 2000-01-05 2002-04-11 Unger Evan C. Novel targeted delivery systems for bioactive agents
US6716450B1 (en) 2000-05-18 2004-04-06 The United States Of America As Represented By The Secretary Of The Army Enhancing protein activity through nanoencapsulation
JP2004523624A (ja) * 2001-02-26 2004-08-05 デューク ユニバーシティ 新規なデンドリティックポリマー、およびその生物医学的使用
US20060051315A1 (en) 2002-02-01 2006-03-09 Scaria Puthupparampil V Polymers for delivering peptides and small molecules in vivo
US7169793B2 (en) * 2002-06-27 2007-01-30 Dr. Reddy's Laboratories Limited Process for preparation of optically pure or optically enriched sulfoxide compounds, including amorphous esomeprazole and salts thereof
DK1567195T3 (da) * 2002-11-26 2011-02-14 Upfront Chromatography As Dendrimerkonjugater til selektiv opløsning af proteinaggregater
BRPI0409663A (pt) * 2003-04-25 2006-04-18 Penn State Res Found método e sistema para o envio sistêmico de compostos bioativos derivados de lipìdeo de detenção de crescimento
SE0302029D0 (sv) * 2003-07-07 2003-07-07 Astrazeneca Ab Novel process
JP5268255B2 (ja) * 2003-11-21 2013-08-21 エイエヌピー テクノロジーズ， インコーポレイテッド 非対称分岐ポリマー抱合体およびマイクロアレイアッセイ
WO2006102484A2 (en) * 2005-03-21 2006-09-28 Anp Technologies, Inc. Symmetrically branched polymer conjugates and microarray assays
EP1877103A4 (en) * 2005-04-20 2010-11-03 Dendritic Nanotechnologies Inc DENDRITIC POLYMERS WITH ENHANCED INNER FUNCTIONALITY AND AMPLIFICATION
WO2006114738A2 (en) * 2005-04-26 2006-11-02 Koninklijke Philips Electronics N.V. Mri contrast agents comprising cest active paramagnetic complex
US20090208580A1 (en) * 2005-09-19 2009-08-20 Regents Of The University Of Michigan Functionalized dendrimer-encapsulated and dendrimer-stabilized nanoparticles
JP5989294B2 (ja) * 2006-01-20 2016-09-07 スターファーマ・プロプライエタリー・リミテッドＳｔａｒｐｈａｒｍａ Ｐｔｙ Ｌｔｄ 修飾高分子
JP2009524430A (ja) * 2006-01-26 2009-07-02 ユニバーシティ オブ マサチューセッツ 治療的使用のためのｒｎａ干渉剤
US8252834B2 (en) * 2008-03-12 2012-08-28 The Regents Of The University Of Michigan Dendrimer conjugates
WO2009123934A2 (en) * 2008-03-29 2009-10-08 Emory University Branched multifunctional nanoparticle conjugates and their use
CN103429267B (zh) 2011-01-09 2016-05-04 Anp科技公司 疏水分子诱导的支化聚合物集合体及其用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020041888A1 (en) * 2000-04-10 2002-04-11 Moshe Flashner-Barak Method and composition for treating cancer by administration of apoptosis-inducing chemotherapeutic agents
US20080200562A1 (en) * 2005-05-02 2008-08-21 Anp Technologies Polymer Conjugate Enhanced Bioassays

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10688048B2 (en) 2011-01-09 2020-06-23 Anp Technologies, Inc. Hydrophobic molecule-induced branched polymer aggregates and their use
US12042561B2 (en) 2011-01-09 2024-07-23 Anp Technologies, Inc. Hydrophobic molecule-induced branched polymer aggregates and their use
US20180289821A1 (en) * 2011-08-03 2018-10-11 Anp Technologies, Inc. Oxazoline Polymer Compositions and Use Thereof
US11801230B2 (en) 2013-02-05 2023-10-31 Anp Technologies, Inc. Nanoparticles containing a taxane and their use
US11033023B2 (en) 2014-11-26 2021-06-15 Microban Products Company Surface disinfectant with residual biocidal property
US11026418B2 (en) 2014-11-26 2021-06-08 Microban Products Company Surface disinfectant with residual biocidal property
US11134678B2 (en) 2014-11-26 2021-10-05 Microban Products Company Surface disinfectant with residual biocidal property
US11134674B2 (en) 2014-11-26 2021-10-05 Microban Products Company Surface disinfectant with residual biocidal property
US10925281B2 (en) 2014-11-26 2021-02-23 Microban Products Company Surface disinfectant with residual biocidal property
US10842147B2 (en) * 2014-11-26 2020-11-24 Microban Products Company Surface disinfectant with residual biocidal property
US9763892B2 (en) 2015-06-01 2017-09-19 Autotelic Llc Immediate release phospholipid-coated therapeutic agent nanoparticles and related methods
US11503824B2 (en) 2016-05-23 2022-11-22 Microban Products Company Touch screen cleaning and protectant composition
CN117860742A (zh) * 2023-11-16 2024-04-12 上海交通大学医学院 氨来占诺在耐药性肺癌治疗中的新应用

Also Published As

Publication number Publication date
CN103429267A (zh) 2013-12-04
CA2824063A1 (en) 2012-07-12
WO2012094620A9 (en) 2013-01-03
CN103429267B (zh) 2016-05-04
JP6092121B2 (ja) 2017-03-08
CA2824063C (en) 2020-02-18
EP2661281B1 (en) 2021-03-10
WO2012094620A2 (en) 2012-07-12
US10688048B2 (en) 2020-06-23
US20210059939A1 (en) 2021-03-04
JP2014501786A (ja) 2014-01-23
US20180235884A1 (en) 2018-08-23
EP3925625A1 (en) 2021-12-22
US12042561B2 (en) 2024-07-23
EP2661281A4 (en) 2015-04-15
WO2012094620A8 (en) 2013-08-08
EP2661281A2 (en) 2013-11-13
WO2012094620A3 (en) 2012-10-26

Similar Documents

Publication Publication Date Title
US12042561B2 (en) Hydrophobic molecule-induced branched polymer aggregates and their use
Agarwal et al. Tumour and dendrimers: a review on drug delivery aspects
NZ525580A (en) Vehicles for intravenous administration of paclitaxel having reduced toxicity
WO2023177629A1 (en) Polymer nanoaggregate pharmaceutical composition and use thereof
JP6772282B2 (ja) 抗癌薬の新規ナノ製剤及びその製造方法
US20240016754A1 (en) Pharmaceutical composition containing taxane nanoaggregates and use thereof
US20240108586A1 (en) Nanoparticles Containing a Taxane and their Use
JP6661700B2 (ja) タキサンを含有するナノ粒子およびその使用
AU2021101355A4 (en) Nanocarriers for treatment of breast cancer
CA2765222C (en) Novel formulations of pharmacological agents, methods for the preparation thereof and methods for the use thereof
Modirrousta et al. Amine-terminated dendrimers: A novel method for diagnose, control and treatment of cancer
Ningthoujam Preclinical, clinical, and patented nanodrug delivery systems
Bauer et al. Gu se
Balaji et al. Nanotechnology and cancer-an overview
Bhadra et al. PEGylated Dendritic Nanoparticulate Carriers of Anti-Cancer Drugs
Gokhale et al. Nanoparticles: Biomaterials for Drug Delivery

Legal Events

Date Code Title Description
AS Assignment

Owner name: ANP TECHNOLOGIES, INC., DELAWARE

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:QIN, DUJIE;YIN, RAY;PAN, JING;AND OTHERS;SIGNING DATES FROM 20130930 TO 20131001;REEL/FRAME:031488/0270

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION