IP Library › Granted Patent US 12,465,575
Granted Patent B2
US 12,465,575 · App. 18/653,164 · Granted Nov 11, 2025

Methods of treatment using cholestosome vesicles for incorporation of molecules into chylomicrons

Inventors: Jerome J. Schentag (Amherst, NY); Mary P. McCourt (Amherst, NY); Lawrence Mielnicki (Buffalo, NY); Julie Hughes (Williamsville, NY)
Assignee: THERASYN SENSORS, INC.
A61K9/51A61K9/127A61K9/1275A61K31/12A61K31/137A61K31/19A61K31/546A61K31/7034A61K31/713A61K38/14A61K38/28A61K39/29A61K39/3955A61K45/06
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Quick Facts
Patent No.
US 12,465,575
App. No.
18/653,164
Granted
Nov 11, 2025
Kind
B2
Abstract

The present invention is directed to a cargo-loaded cholesteryl ester nanoparticle with a hollow compartment (“cholestosome”) consisting essentially of at least one non-ionic cholesteryl ester and one or more encapsulated active molecules which cannot appreciably pass through an enterocyte membrane in the absence of said molecule being loaded into said cholestosome, the cholestosome having a neutral surface and having the ability to pass into enterocytes in the manner of orally absorbed nutrient lipids using cell pathways to reach the golgi apparatus. Pursuant to the present invention, the novel cargo loaded cholestosomes according to the present invention are capable of depositing active molecules within cells of a patient or subject and effecting therapy or diagnosis of the patient or subject.

Claims (19)

1 . A method of treating a patient or subject in need of treatment of a disease state or condition comprising administering to said patient or subject a composition comprising one or more active molecules encapsulated in a liquid vesicle to provide an intact loaded vesicle wherein the outer surface coating of said loaded vesicle comprises at least one cholesteryl ester obtained from cholesterol and a C6-C26 fatty acid, said molecules obtaining in an effective amount an intracellular concentration in target cells of said patient or subject which is at least 2-fold greater than the concentration obtained by said molecules in the absence of said coating, wherein said molecules are selected from the group consisting of small molecules, proteins, monoclonal antibodies, peptides, polynucleotides, oligonucleotides, nucleic acids and mixtures thereof, wherein said administration includes at least one oral, parenteral or topical dosage form and said outer surface coating of said loaded vesicle remains intact during passage of said loaded vesicle across a membrane of a cell in said patient or subject and wherein said vesicle optionally releases said one or more molecules inside target cells by the action of cholesteryl ester hydrolases on said vesicle, and said disease state or condition is cancer, or a condition requiring a cancer antigen therapeutic in said patient or subject.

2 . The method according to claim 1 wherein said disease state or condition is cancer and said composition is bevacizumab, wherein said administration is by oral or parenteral dosage form.

3 . The method according to claim 1 wherein said disease state or condition is cancer and said composition includes a molecule selected from the group consisting of nivolumab, ipilimumab, or a combination of nivolumab and ipilimumab, wherein said administration is by oral or parenteral dosage form.

4 . The method according to claim 1 wherein said disease state or condition is cancer and said composition includes a molecule selected from the group consisting of pembrolizumab, ipilimumab, tremelimumab or a combination of pembrolizumab and either ipilimumab or tremelimumab, wherein said administration is by oral or parenteral dosage form.

5 . The method according to claim 1 wherein said disease state or condition is cancer and said composition includes tremelimumab, wherein said administration is by oral or parenteral dosage form.

6 . The method according to claim 1 wherein said disease state or condition is cancer and said composition includes a molecule selected from the group consisting of alemtuzumab, ipilimumab, or a combination of alemtuzumab and ipilimumab, wherein said administration is by oral or parenteral dosage form.

7 . The method according to claim 1 wherein said disease state or condition is cancer and said composition includes a molecule selected from the group consisting of trastuzumab and T-DM1, wherein said T-DM1 is trastuzumab linked to emtansine, wherein said administration is by oral or parenteral dosage form.

8 . The method according to claim 1 wherein said composition is administered to said patient in pharmaceutical dosage form and includes one or more immunogenic polypeptides and/or oligopeptides encapsulated in lipid vesicles, each lipid vesicle comprising at least one non-ionic cholesteryl ester.

9 . The method according to claim 1 wherein said composition is in capsule form for oral administration, wherein said capsule is enterically coated to facilitate duodenal release of said molecules.

10 . The method according to claim 9 wherein said vesicles 1) enter duodenal enterocytes; 2) said enterocytes containing said vesicles transfer said vesicles in intact form into chylomicrons of said enterocytes; 3) said vesicles containing chylomicrons are released from said enterocytes into lymphatics; 4) said vesicles are transported into immune cells; and 5) said vesicles release their contents inside of said immune cells by the action of cholesteryl ester hydrolases.

11 . The method according to claim 1 wherein said composition is in capsule form for oral administration, wherein said capsule is enterically coated to enable ileum release, wherein said composition releases said vesicles from said capsule in the ileum and said vesicles enter the immune cells in the lumen of said patient's ileum.

12 . The method according to claim 1 , wherein said vesicles loaded with said composition are loaded into an enterically coated capsule targeted to release said composition in the ileum.

13 . The method according to claim 1 , wherein said vesicles loaded with said composition are loaded into an enterically coated capsule targeted to release said composition in the ileum and be taken into immune system cells.

14 . The method according to claim 1 wherein said immune system cells comprise one or more of dendritic cells, T-lymphocytes, or macrophages.

15 . The method according to claim 1 , wherein said composition additionally comprises one or more adjuvants.

16 . The method according to claim 1 , wherein said composition is released from said dosage form and enters dendritic cells of said patient.

17 . The method according to claim 1 , wherein said composition is released from said capsule, enters dendritic cells of said patient, and activates said patient's immune system cells against said patient's cancer.

18 . The method according to claim 1 , wherein said composition is released at dendritic cells in the ileum of said patient and enters said patient's dendritic cells.

19 . The method according to claim 1 , wherein said composition comprises an adjuvant.

Continuity (7)
Division 18126251 · Mar 24, 2023
Division 17337283 · Jun 2, 2021
Division 16527579 · Jul 31, 2019
Continuation 15603992 · May 24, 2017
Continuation 14776308
Provisional Application 61783003 · Mar 14, 2013
Related Publication 20240398719A1 · Dec 5, 2024
References Cited (71)
US 4544545A · Ryan et al. · 1985 [cited by applicant]
US 5013556A · Woodle et al. · 1991 [cited by applicant]
US 5049389A · Radhakrishnan · 1991 [cited by applicant]
US 5094854A · Ogawa et al. · 1992 [cited by applicant]
US 5288499A · Janoff et al. · 1994 [cited by applicant]
US 5844075A · Kawakami et al. · 1998 [cited by applicant]
US 9119782B2 · McCourt · 2015 [cited by applicant]
US 9693969B2 · Skigen · 2017 [cited by applicant]
US 10092516B2 · McCourt · 2018 [cited by applicant]
US 10369114B2 · Schentag et al. · 2019 [cited by applicant]
US 12005146B2 · Schentag et al. · 2024 [cited by applicant]
US 20040037874A1 · Hong · 2004 [cited by applicant]
US 20040052838A1 · Naeff et al. · 2004 [cited by applicant]
US 20040197393A1 · Smyth-Templeton et al. · 2004 [cited by applicant]
US 20060216255A1 · Lee et al. · 2006 [cited by applicant]
US 20060286161A1 · Panzner et al. · 2006 [cited by applicant]
US 20070014840A1 · Lee et al. · 2007 [cited by applicant]
US 20070225264A1 · McCourt · 2007 [cited by applicant]
US 20080241257A1 · Popescu et al. · 2008 [cited by applicant]
US 20110046053A1 · Kidron · 2011 [cited by applicant]
US 20130183270A1 · Geho · 2013 [cited by applicant]
US 20140199233A1 · Nagy · 2014 [cited by applicant]
US 20190060236A1 · McCourt · 2019 [cited by applicant]
US 20190175515A1 · Schentag et al. · 2019 [cited by applicant]
JP 2009143963A · 2009 [cited by applicant]
WO 9203123A1 · 1992 [cited by applicant]
WO 2004098564A2 · 2004 [cited by applicant]
WO 2013148258A1 · 2013 [cited by applicant]
WO 2014152795A2 · 2014 [cited by applicant]
WO 2016156398A1 · 2016 [cited by applicant]
Giguere S, et al. Role of the 85-Kilobase Plasmid and Plasmid-Encoded Virulence-Associated Protein A in Intracellular Survival and Virulence of Rhodococcus equi. Infection and Immunity, 1999;67(7):3548-3557. [cited by applicant]
Yoshida K, et al. Effect of Tumor Size on Monoclonal Antibody Uptake in a Metastatic Model. Journal of Surgical Oncology, 1992;49:249-252. [cited by applicant]
Bussiere JL, et al. 60-Day Repeated Dose Inhalation Toxicity Study of an Anti-IgE Antibody in Cynomolgus Monkeys. SOT Annual Meeting, 1997;271. [cited by applicant]
Sweeney TD, et al. Pulmonry Delivery of Anti-IgE Rationale for Topical Delivery to the Airway, 2001. [cited by applicant]
Bleavins MR, et al. Cynomolgus monkeys (Macaca fascicularis) in preclinical immune function safety testing: development of a delayed-type hypersensitivity procedure. Toxicology, 1995;95:103-112. [cited by applicant]
Ryffel B. Impact of Knockout Mice in Toxicology. Critical Reviews in Toxicology, 1997;27(2):135-154. [cited by applicant]
Congestive Heart Failure. American Heart Association (2006) http://www.americanheart.org/presenter.jhtml?identifier=4585. [cited by applicant]
Heart Attack, Stroke & Cariac Arrest Warning Sings. American Heart Association (2006) http://www.americanheart.org/presenter.jhtml?identifier=3053. [cited by applicant]
Bjorkhlem I, et al. Oxysterols: Friends, Foes or Just Fellow Passengers? Arteriosclerosis, Thrombosis, and Vascular Biology, 2002;22:734-742. [cited by applicant]
Christiansen Li. Preparation, Analysis and Cholesterol Lowering Effect of a Novel Microcrystalline . . . Suspension in Oil and Phase Behavior of Beta-sitosterol with Cholesterol. Academic Dissertation at the University … [cited by applicant]
Dorset DL, et al. Co-solubility in binary phospohlipid crystals. Biochimica et Biophysica Acta, 1987;903:319-332. [cited by applicant]
Dorset DL. Cholesteryl esters of saturated fatty acids: cosolubility and fractionation of binary mixtures. Journal of Lipid Research, 1987;28:993-1005. [cited by applicant]
Dorset DL. Co-solubility of saturated cholesteryl esters: a comparison of calculated and experimental binary phase diagrams. Biochimica et Biophysica Acta, 1988;963:88-98. [cited by applicant]
Dorset DL. Binary phase behavior of cholestryl oleate with cholesteryl linoleate. Biochimica et Biophysica Acta, 1990;1046:57-63. [cited by applicant]
Dorset DL. Eutectic interactions in binary systems containing cholesterol, cholesteryl esters and triacylgycerols. Biochimica et Biophysica Acta, 1990;1047:112-120. [cited by applicant]
Dorset DL. Binary phase behavior of angiotoxic oxidized cholesterols with cholesterol. Biochimica et Biophysica Acta, 1992;1127:293-297. [cited by applicant]
Garcia-Cruset S, et al. Oxysterols in cap and core oh human advanced atherosclerotic lesions. Free Radical Research, 1999;30:341-351. [cited by applicant]
Guo W, et al. Phase Behavior and Crystalline Structures of Cholesteryl Ester Mixtures: A C-13 MASNMR Study. Biophysical Journal, 1995;68:341-351. [cited by applicant]
Hulten LM, et al. Oxysterols persent in atherosclerotic tissue decrease the expression of lipoprotein fipase messenger RNA inhuman monocyte-derived macrophages. The Journal of Clinical Investigation, 1996;97:461-468. [cited by applicant]
Leoni V. On the possible use of oxysterols for the diagnosis and evaluation of patients with neurological and neurodegenerative diseases. Karolinska Institutel Thesis, Stockholm, Sweden, 2005. [cited by applicant]
Linseisen J, et al. Plasma 7beta-hydroxycholesterol as a possible predictor of lung cancer risk. Cancer Epidemoil Prev, 2002;11:1630-1637. [cited by applicant]
Lizard G, et al. Characterization and Comparison of the Mode of Cell Death . . . by 7beta-Hydroxycholesterol and 7-Ketocholesterol in the Cells of the Vascular Wall. Arteriosclerosis, Thrombosis and Vascular Biology, 19… [cited by applicant]
Mahadevan V, et al. Preparation of cholesterol esters of long-chain fatty acids and characterization of cholestryl arachidonate. Journal of Lipid Research, 1962;3:106-110. [cited by applicant]
Marcu L, et al. Arterial flourescent components involved in artherosclerotic plagque instability: differentiation by time-resolved flourescence spectroscopy, 2001. [cited by applicant]
McCourt MP, et al. X-ray crystal structure of cytotoxic oxidized cholesterols: 7-ketocholesterol and 25-hydroxycholesterol. Journal of Lipid Research, 1997;38:1014-1021. [cited by applicant]
Micheletta F, et al. Vitamin E Supplementation in Patients with Carotid Atherosclerosis. Arterioschlerosis, Thrombosis, and Vascular Biology, 2004;24:136. [cited by applicant]
Nelson DL, et al. Lehninger Principels of Biochemistry fourthedition. New York: WH Freeman and Company, 2005. [cited by applicant]
Raff LM. Principles of Physical Chemistry. Upper Sakkle River, NJ: Prentice Hall (2001). [cited by applicant]
Ringseis R, et al. Insufficient dietary vitamin e increases the concentration of 7beta-hydroxycholesterol in tissues of rats feed salmon oil. The Journal of Nutrition, 2002;132:2732-2735. [cited by applicant]
Rodriguez IR, et al. Cytotoxicity of Oxidized Low-Density Lipoprotein in Cultures RPE Cells is Dependent on the Formation of 7-Ketocholestrol. Investigative Ophthalmology and Visual Science, 2004;45:2830-2837. [cited by applicant]
Shands Health Care. Transcient ischemic attack (TIA). 2006. http://www.shands.org/health/information/article/000730.htm. [cited by applicant]
Sigma-Aldrich Corporation. Material Safety Data Sheet, 2006, http://www.sigma.com. [cited by applicant]
Tontonoz PA, et al. Regulation of macrophage gene expression by peroxisome-proliferator-activated receptor [gamme]: implications for cardiovascular disease. Current Opinion in Lipidology, 1999;10:485-490. [cited by applicant]
Wikipedia. Apoptosis (2006), http://en.wikipedia.org/wiki/Apoptosis. [cited by applicant]
Wohlfeil ER, et al. 25-Hydroxycholesterol Increases Eicosanoids and Alters Morphology in Cultures Pulmonary Artery Smooth Muscle and Endothelial Cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 1999;19:2901-29… [cited by applicant]
Funakoshi K, et al. Formation of Giant Lipid Vesiclelike Compartments from a Planar Lipid Membrane by a Pulsed Jet Flow. J Am Chem Soc, 2007;129:12608-12609. [cited by applicant]
Frankenburg S, et al. Recombinant hydrophilic human gp100: uptake by dendritic cells and stimulation of autologous CD8+ lymphocytes from melanoma patients. Immunology Letters, 2004;94:253-259. [cited by applicant]
Sahin NO. Niosomes as Nanocarrier Systems. IN: Nanomaterials and Nanosystems for Biomedical Applications. Edited by M. Mozafari Netherlands. Springer press, 2007, Chapter 4: p. 67-81. [cited by applicant]
Prasad S, et al. Polymer nanoparticles containing lysates as antigen delivery vehicles for dendritic cell-bases anti-tumor immunotherapy. Nanomedicine, 2011;7(1):1-10. [cited by applicant]
Lochmatter P, et al. Drug-specific in vitro release of IL-2, IL-5, IL-13, and IFN-gamma in patients with delayed-type drug hypersensitivity. Allergy, 2009;64(9):1269-1278. [cited by applicant]
Huan Xu, et al. Preparation and Characterization of pH-Sensitive Vesicles Made of Cholesteryl Hemisuccinate. Drug Development and Industrial Pharmacy, 2008;34(2):134-141. [cited by applicant]