Compositions for treating cancer and methods for making the same

• US 10,300,143 B2
• Filed: 10/02/2017
• Issued: 05/28/2019
• 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
• Primary Examiner(s): Gembeh, Shirley V
• Application Number:
  US15/722,831
• Publication Number:
  US 20180125987A1
• Time in Patent Office: 603 Days
• 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. A composition comprising a conjugate, the conjugate comprising a chemotherapeutic agent conjugated to cholesterol, wherein the chemotherapeutic agent is a PI3K inhibitor.

2. The composition of claim 1, wherein the conjugate is of Formula (I) or Formula (II):

3. The composition of claim 1, wherein the composition further comprises a lipid in addition to the conjugate.

4. The composition of claim 3, wherein the lipid is a lipid conjugated with polyethylene glycol (PEG).

5. The composition of claim 4, 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.

6. The composition of claim 1, wherein the composition further comprises a phospholipid.

7. The composition of claim 6, 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.

8. The composition of claim 1, further comprising a targeting agent.

9. The composition of claim 8, 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 and iRGD (amino acid sequence CRGDKGPDC (SEQ ID NO;

     1)).

10. The composition of claim 1, wherein the composition further comprises an anticancer agent in addition to the conjugate.

11. The composition of claim 10, 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);

12. The composition of claim 1, wherein the composition comprises the conjugate, a PEG conjugated lipid, and a phospholipid.

13. The composition of claim 12, wherein the PEG conjugated lipid is DSPE-PEG2000 and the phospholipid is phosphatidylcholine.

14. A method of treating cancer, comprising, administering a composition of claim 1, to a subject in need of treatment for cancer 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.

15. The method of claim 14, wherein the subject has been determined to have tumor cells with aberrant PI3K.

16. The composition of claim 1, wherein the PI3K inhibitor is selected from the group consisting of PI103;

PI828;

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.