Metal bisphosphonate nanoparticles for anti-cancer therapy and imaging and for treating bone disorders

Patent metadata

Field	Value
Publication number	US-2017333347-A1
Application number	US-201715613847-A
Country	US
Kind code	A1
Filing date	Jun 5, 2017
Priority date	Jul 8, 2011
Publication date	Nov 23, 2017
Grant date	—

Abstract

Metal-bisphosphonate nanoparticles are disclosed. Also disclosed are pharmaceutical compositions including the metal-bisphosphonate nanoparticles, methods of preparing the metal-bisphosphonate nanoparticles and materials comprising the nanoparticles, and methods of using the compositions to treat cancer or bone-related disorders (e.g., bone-resorption-related diseases, osteoporosis, Paget's disease, and bone metastases) and as imaging agents.

First claim

1 - 64 . (canceled)

65 . A metal-bisphosphonate nanoparticle comprising a core comprising:
(a) M 1 , wherein M 1 is a multivalent metal ion; and (b) a bisphosphonate, wherein the bisphosphonate comprises a metal complex having the formula M 2 L x , wherein x is an integer of 2 or greater, M 2 is a second metal ion, and wherein each L is a metal ion ligand, further wherein at least two L are phosphonate group-containing metal ion ligands, wherein the phosphonate group of each of said phosphonate group-containing metal ion ligands is available to coordinate to multivalent metal ion M 1 .

66 . The metal-bisphosphonate nanoparticle of claim 65 , wherein the bisphosphonate comprises at least one metal ion ligand L that does not contain a phosphonate group.

67 . The metal-bisphosphonate nanoparticle of claim 66 , wherein the bisphosphonate comprises a metal ion ligand selected from the group consisting of halo, NH 3 , alkylamino, hydroxyl, alkoxyl, diol, and diamine.

68 . The metal-bisphosphonate nanoparticle of claim 66 , wherein the bisphosphonate comprises a metal ion ligand that does not comprise a phosphonate group and wherein said ligand is a metal ion ligand other than NH 3 or diamine.

69 . The metal-bisphosphonate nanoparticle of claim 65 , wherein x is 5 or 6.

70 . The metal-bisphosphonate nanoparticle of claim 65 , wherein two L are NH 3 .

71 . The metal-bisphosphonate nanoparticle of claim 65 , wherein two L are halo.

72 . The metal-bisphosphonate nanoparticle of claim 65 , wherein at least one L is a diamine.

73 . The metal-bisphosphonate nanoparticle of claim 65 , wherein at least two phosphonate group-containing metal ion ligands are each coordinated to M 2 via a coordinative bond between M 2 and an oxygen atom of the phosphonate group-containing ligand.

74 . The metal-bisphosphonate nanoparticle of claim 73 , wherein each of the phosphonate group-containing metal ion ligands is coordinated to M 2 via a coordinative bond between M 2 and an oxygen atom of the phosphonate group-containing ligand, further wherein said oxygen atom of the phosphonate group-containing ligand is covalently bound to a carbon atom of the phosphonate group-containing ligand.

75 . The metal-bisphosphonate nanoparticle of claim 74 , wherein the carbon atom of the phosphonate group-containing ligand is a carbon atom of a carbonyl group.

76 . The metal-bisphosphonate nanoparticle of claim 74 , wherein the carbon atom of the phosphonate group-containing ligand is a carbon atom of a thiocarbonyl group.

77 . The metal-bisphosphonate nanoparticle of claim 65 , wherein the bisphosphonate is prepared by reacting a metal complex comprising two hydroxyl ligands with a reagent selected from the group consisting of diethoxyphosphinyl isocyanate, diethoxyphosphinyl isothiocyanate, a diethyoxyphosphinyl-containing carboxylic anhydride, and a diethoxyphosphinyl-containing acyl chloride.

78 . The metal-bisphosphonate nanoparticle of claim 65 , wherein M 2 is a platinum ion.

79 . The metal-bisphosphonate nanoparticle of claim 65 , wherein M 1 is Zn 2+ .

80 . The metal-bisphosphonate nanoparticle of claim 65 , wherein the nanoparticle further comprises one or more coating agents or layers surrounding at least a portion of an outer surface of the core.

81 . The metal-bisphosphonate nanoparticle of claim 80 , wherein the nanoparticle comprises at least one lipid coating layer or agent.

82 . The metal-bisphosphonate nanoparticle of claim 80 , wherein one or more coating agents or layers comprise a targeting moiety or a passivating moiety.

83 . A pharmaceutical composition comprising a metal-bisphosphonate nanoparticle of claim 65 and a pharmaceutically acceptable carrier.

84 . A method of treating cancer to a subject in need of treatment thereof, wherein the method comprises administering to said subject an effective amount of a metal-bisphosphonate nanoparticle of claim 65 .

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Lin Wenbin
• Liu Demin
• Della Rocca Joseph
• Kramer Stephanie
• Poon Christopher Y

Classifications

• A61K31/675

  having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate · CPC title

• A61K9/5123

  Organic compounds, e.g. fats, sugars · CPC title

• A61K47/6929

  the form being a nanoparticle, e.g. an immuno-nanoparticle · CPC title

• A61K9/5115

  Inorganic compounds · CPC title

• A61K9/0019

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title