COMPOSITIONS FOR TREATING CANCER AND METHODS FOR MAKING THE SAME

• US 20150174263A1
• Filed: 06/14/2013
• Published: 06/25/2015
• Est. Priority Date: 06/15/2012
• Status: Active Grant

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Sengupta, Shiladitya, Kulkarni, Ashish, Rao, Poornima, Roy, Bhaskar
• Granted Patent: US 9,789,193 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

Described herein are compositions and methods relating to chemotherapeutic agent conjugates and the treatment of cancer.

Claims

1-58. -58. (canceled)

59. A composition comprising a conjugate, the conjugate comprising a chemotherapeutic agent conjugated to cholesterol.

60. The composition of claim 59, wherein the conjugate is an amphiphile.

61. The composition of any of claims 59-60, wherein the agent is conjugated to cholesterol via a linker.

62. The composition of claim 61, wherein the linker is selected from the group consisting of:

C(O), C(O)CH₂CH₂C(O);

C(O)NH(CH₂)₂NHC(O)(CH₂)₂C(O);

—

O—

, —

S—

, —

S—

S—

, —

NR¹—

, —

C(O)—

, —

C(O)O—

, —

C(O)NR¹—

, —

SO—

, —

SO₂—

, —

SO₂NR¹—

, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, alkynylhereroaryl;

wherein one or more methylenes can be interrupted or terminated by O, S, S(O), SO₂, N(R¹)₂, C(O), C(O)O, C(O)NR¹, cleavable linking group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, and wherein R¹ is hydrogen, acyl, aliphatic or substituted aliphatic.

63. The composition of any of claims 59-63, wherein the chemotherapeutic agent selected from the group consisting of:

a PI3K inhibitor;

PI103;

P1828;

LY294002;

wortmannin;

demethoxyviridin;

IC486068;

IC87114;

GDC-0941;

perifosine;

CAL101;

PX-866;

IPI-145;

BAY 80-6946;

BEZ235;

P6503;

TGR1202;

SF1126;

INK1117;

BKM120;

IL147;

XL765;

Palomid 529;

GSK1059615;

ZSTK474;

PWT33597;

TG100-115;

CAL263;

GNE-447;

CUDC-907; and

AEZS-136.

64. The composition of claim 63, having a structure selected from the group consisting of:

Formula I;

65. The composition of any of claims 59-62, wherein the chemotherapeutic agent is selected from the group consisting of:

a taxane;

paclitaxel; and

docetaxel.

66. The composition of claim 65, having the structure of Formula III:

67. The composition of any of claims 59-66, wherein the composition further comprises a lipid in addition to the conjugate.

68. The composition of claim 67, wherein the lipid is a lipid conjugated with polyethylene glycol (PEG).

69. The composition of claim 68, wherein the PEG conjugated lipid is selected from the group consisting of:

PEG conjugated diacylglycerols and dialkylglycerols;

PEG-conjugated phosphatidylethanolamine and phosphatidic acid;

PEG conjugated ceramides;

PEG conjugated dialkylamines;

PEG conjugated 1,2-diacyloxypropan-3-amines;

1,2-distearoyl-sn-glycem-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] (DSPE-PEG2000); and

any combinations thereof.

70. The composition of any of claims 59-69, wherein the composition further comprises a phospholipid.

71. The composition of claim 70, wherein the phospholipid is selected from the group consisting of:

phosphatidyl cholines;

phosphatidyl cholines with acyl groups having 6 to 22 carbon atoms;

phosphatidyl ethanolamines;

phosphatidyl inositols;

phosphatidic acids;

phosphatidyl serines;

sphingomyelin;

phosphatidyl glycerols;

phosphatidylcholine;

phosphatidylglycerol;

lecithin;

β

,γ

-dipalmitoyl-α

-lecithin;

sphingomyelin;

phosphatidylserine;

phosphatidic acid;

N-(2,3-di(9-(Z)-octadecenyloxy))-prop-1-yl-N,N,N-trimethylammonium chloride;

phosphatidylethanolamine;

lysolecithin;

lysophosphatidylethanolamine;

phosphatidylinositol;

cephalin;

cardiolipin;

cerebrosides;

dicetylphosphate;

dioleoylphosphatidylcholine;

dipalmitoylphosphatidylcholine;

dipalmitoylphosphatidylglycerol;

dioleoylphosphatidylglycerol;

palmitoyl-oleoyl-phosphatidylcholine;

di-stearoyl-phosphatidylcholine;

stearoyl-palmitoyl-phosphatidylcholine;

di-palmitoyl-phosphatidylethanolamine;

di-stearoyl-phosphatidylethanolamine;

di-myrstoyl-phosphatidylserine;

di-oleyl-phosphatidylcholine;

dimyristoyl phosphatidyl choline (DMPC);

dioleoylphosphatidylethanolamine (DOPE);

palmitoyloleoylphosphatidylcholine (POPC);

egg phosphatidylcholine (EPC);

distearoylphosphatidylcholine (DSPC);

dioleoylphosphatidylcholine (DOPC);

dipalmitoylphosphatidylcholine (DPPC);

dioleoylphosphatidylglycerol (DOPG);

dipalmitoylphosphatidylglycerol (DPPG);

-phosphatidylethanolamine (POPE);

dioleoyl-phosphatidylethanolamine 4-(N-maleimidomethyl)-cyclohexane-1-carboxylate (DOPE-mal);

L-a-phosphatidylcholine; and

any combinations thereof.

72. The composition of any of claims 59-71, further comprising a targeting agent.

73. The composition of claim 72, wherein the targeting agent is selected from the group consisting of:

peptides;

polypeptides;

proteins;

enzymes;

peptidomimetics;

glycoproteins;

antibodies (monoclonal or polyclonal) and portions and fragments thereof;

lectins;

nucleosides;

nucleotides;

nucleoside and nucleotide analogues;

nucleic acids;

monosaccharides;

disaccharides;

trisaccharides;

oligosaccharides;

polysaccharides;

lipopolysaccharides;

vitamins;

steroids;

hormones;

cofactors;

receptors;

receptor ligands;

iRGD; and

analogs and derivatives thereof.

74. The composition of any of claims 59-73, wherein the composition further comprises an anticancer agent in addition to the conjugate.

75. The composition of claim 74, wherein the anticancer agent is selected from the group consisting of:

a platinum compound, paclitaxel;

carboplatin;

bortezomib;

vorinostat;

rituximab;

temozolomide;

rapamycin;

an alkylating agent;

cyclosphosphamide;

an alkyl sulfonate;

busulfan;

improsulfan;

piposulfan;

an aziridine;

an ethylenimine;

a methylamelamine;

an acetogenin;

a camptothecin;

a cryptophycin;

a nitrogen mustard;

a nitrosurea;

an antibiotic;

a enediyne antibiotic;

a bisphosphonate;

doxorubicin;

a mitomycin;

an anti-metabolite;

a folic acid analogue;

a purine analog;

a pyrimidine analog;

an androgen;

an anti-adrenal;

an epothilone;

a maytansinoid;

a trichothecene;

gemcitabine;

6-thioguanine;

mercaptopurine;

methotrexate;

vinblastine;

etoposide;

ifosfamide;

mitoxantrone;

vincristine;

vinorelbine;

novantrone;

teniposide;

edatrexate;

daunomycin;

aminopterin;

xeloda;

ibandronate;

irinotecan;

a topoisomerase inhibitor;

a retinoid;

capecitabine;

combretastatin;

leucovorin;

lapatinib;

erlotinib; and

a compound having the structure of formula (IV);

76. The composition of any of claims 59-75, wherein the composition comprises the conjugate, a PEG conjugated lipid, and a phospholipid.

77. The composition of claim 76, wherein the PEG conjugated lipid is DSPE-PEG2000 and the phospholipid is phosphatidylcholine.

78. A method of treating cancer, comprising, administering a composition of any of claims 59-77 to a patient in need of treatment for cancer.

79. The method of claim 78, wherein the cancer is selected from the group consisting of:

breast cancer;

ovarian cancer;

glioma;

gastrointestinal cancer;

prostate cancer;

carcinoma, lung carcinoma, hepatocellular carcinoma, testicular cancer;

cervical cancer;

endometrial cancer;

bladder cancer;

head and neck cancer;

lung cancer;

gastro-esophageal cancer, and gynecological cancer.

80. The method of any of claims 78-79, wherein the subject has been determined to have tumor cells with aberrant PI3K.

81. A method of reducing blood glucose levels, comprising administering a composition of any of claims 59-77, to a subject in need of a reduction of blood glucose levels.