Compositions for treating cancer and methods for making the same

• US 9,789,193 B2
• Filed: 06/14/2013
• Issued: 10/17/2017
• 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:
  US14/406,938
• Publication Number:
  US 20150174263A1
• Time in Patent Office: 1,586 Days
• Field of Search: None
• 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 conjugate is of Formula (III):

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

3. The composition of claim 2, wherein the lipid is a lipid conjugated with polyethylene glycol (PEG).

4. The composition of claim 3, 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.

5. The composition of any of claim 1 or 2-4, wherein the composition further comprises a phospholipid.

6. The composition of claim 5, 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.

7. The composition of any of claim 1 or 2-6, further comprising a targeting agent.

8. The composition of claim 7, 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.

9. The composition of any of claim 1 or 2-8, wherein the composition further comprises an anticancer agent in addition to the conjugate.

10. The composition of claim 9, 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);

11. The composition of any of claim 1 or 2-10, wherein the composition comprises the conjugate, a PEG conjugated lipid, and a phospholipid.

12. The composition of claim 11, wherein the PEG conjugated lipid is DSPE-PEG2000 and the phospholipid is phosphatidylcholine.