Targeted liposomes

a liposome and target technology, applied in the field of drug delivery, can solve the problems of lack of improvement in limited therapeutic dosage, and difficult treatment of primary brain tumors, and achieve the effects of improving the prognosis of brain cancer patients, improving the prognosis, and improving the treatment

Inactive Publication Date: 2014-05-01
GEORGETOWN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Primary brain tumors, and particularly gliomas, are one of the most difficult cancers to treat.
The lack of improvement in the prognosis of patients with brain cancer over the last few years, despite recent advances in drug discovery and development of targeted therapies, is due in large part to the inability of the therapeutics to cross the blood-brain barrier (BBB) (Blakeley, J.
Biochemical and Biophysical Research Communications 406: pp 311-314), however myelosuppression, neutropenia and thrombocytopenia are among its side effects and therapeutic dosages are limited by these.
The extensive tissue distribution that results from the non-tumor specific uptake of the orally administered TMZ is a major cause of these side effects.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Cationic Liposomes Comprising Temozolomide

[0149]Materials:

[0150]DOTAP (1,2-dioleoyl-3-trimethylammonium propane, chloride salt)[0151]Obtained from Avanti Polar Lipids, Inc. Cat. #890890E, MW 698.55[0152]Concentration: 25 mg / mL ethanol solution[0153]Dilute lipid to 20 mg / ml with absolute ethanol before use

[0154]DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine)[0155]Obtained from Avanti Polar Lipids, Inc. Cat. #850725E, MW 744.04[0156]Concentration: 25 mg / mL ethanol solution.[0157]Dilute lipid to 20 mg / ml with absolute ethanol before use

[0158]Temozolomide (TMZ, M.W. 194.15), powder[0159]Obtained from Sigma, Cat. #T2577-100 mg[0160]Dissolve TMZ in pure DMSO to desired concentration. For example, 19.415 mg / ml=100 mM of TMZ; 28 mg / ml=144.218 mM of TMZ

[0161]Ultra-pure, endotoxin free LAL Reagent Water (e.g. BioWhittaker, Cat. #W50-500, endotoxin <0.005 EU / ml)

[0162]Injector: Hamilton Gastight Syringe, 1 ml (Hamilton #81230) with a 22 gauge needle, part #81365)

Procedure:

[0...

example 2

Preparation of scL-TMZ without Chemical Conjugation (by Simple Mixing)

[0193]Using the TMZ-comprising cationic liposomes prepared according to the procedure described in Example 1, the ligand targeted TMZ cationic liposome complex as described herein is prepared by simple mixing of the components and without chemical conjugation. The preparation of the complexes was in accordance with the following general procedure:

[0194]To the liposome-water (or buffer) the appropriate amount of targeting moiety is added to give the desired ratio and mixed by gentle inversion 5-10 seconds. The targeting moiety can be a ligand including but not limited to transferrin or folate, or other proteins. It can also be an antibody or an antibody fragment that targets a cell surface receptor including, but not limited to the transferrin or HER-2 receptor (e.g., TfRscFv). This mixture is kept at room temperature for 10-15 minutes (again inverted gently for 5-10 seconds after approximately 5 minutes). To yield...

example 3

Determination of the Percent Encapsulation of TMZ in the scL-TMZ Complex

[0200]To determine the percent of the TMZ encapsulated in the scL-TMZ complex, we prepared scL-TMZ as described in Example 1 with 2 mM stock Lip:TMZ. Various amounts of complex were prepared ranging from 126 to 560 ul scL-TMZ. The scL-TMZ complex was subsequently diluted to a Lip:TMZ concentration of 0.5 mM. The initial concentration of TMZ was checked by measuring the absorbance of the scL-TMZ complex at 320 nm using a Beckman spectrophotometer. A standard curve of TMZ concentrations spanning 0.001 to 0.1 mM TMZ was also generated by measuring absorbance at 320 nM using DMSO as the blank. Free TMZ was separated from complexed scL-TMZ by filtration through a Vivaspin® 500, 5 kDa MWCO (GE Healthcare, UK). 200 ul of the diluted scL-TMZ complex was loaded onto the filter and centrifuged at 14,000 g for 15 min at room temperature. The flow through was collected and the volume (175 ul), and optical density at 320 nm ...

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Abstract

The present invention is in the field of drug delivery, and specifically, cationic liposome-based drug delivery. In embodiments, this invention provides methods of making ligand-targeted (e.g., antibody- or antibody fragment-targeted) liposomes useful for the delivery of liposomes to tumors, including brain tumors. In embodiments, the liposomes deliver temozolomide across the blood-brain barrier for treatment of primary or metastatic brain tumors. Additional cancers that can be treated with the liposomes include neuroendocrine tumors, melanoma, prostate, head and neck, ovarian, lung, liver, kidney, breast, urogenital, gastric, colorectal, cervical, vaginal, angiosarcoma, liposarcoma, rhabdomyosarcoma, choriocarcinoma, pancreatic, retinoblastoma and other types of cancer. In another embodiment the liposomes deliver melphalan for the treatment of multiple myeloma, other tumors of the blood or other solid tumors. In still other embodiments the liposomes can deliver other drugs such as pemetrexed or irinotecan for treatment of cancer or drugs including atropine for treatment of organophosphate poisoning.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims the benefit of U.S. Provisional Patent Application Nos. 61 / 702,796, filed Sep. 19, 2012, and 61 / 767,453, filed Feb. 21, 2013, the disclosures of each of which are incorporated by reference herein in their entireties.BACKGROUND OF THE INVENTION[0002]1. Field of the Invention[0003]The present invention is in the field of drug delivery, and specifically, cationic liposome-based drug delivery. In embodiments, this invention provides methods of making ligand-targeted (e.g., antibody- or antibody fragment-targeted) liposomes useful for the delivery of liposomes to tumors, including brain tumors. In embodiments, the liposomes deliver temozolomide across the blood-brain barrier for treatment of primary or metastatic brain tumors. Additional cancers that can be treated with the liposomes include, but are not limited to, neuroendocrine tumors, melanoma, prostate, head and neck, ovarian, lung, liver, breast, kidney, ur...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K47/48A61K45/06
CPCA61K47/48823A61K45/06A61K9/0019A61K9/1271A61K9/1272
Inventor CHANG, ESTHER H.KIM, SANGSOORAIT, ANTONINA
Owner GEORGETOWN UNIV
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