(12) United States Patent (10) Patent No.: US 9,655,847 B1 Halwani Et Al
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US0096.55847B1 (12) United States Patent (10) Patent No.: US 9,655,847 B1 Halwani et al. (45) Date of Patent: May 23, 2017 (54) THERAPEUTIC LIPOSOME AND METHOD (56) References Cited OF TREATING ASUBJECT HAVING CANCER U.S. PATENT DOCUMENTS 5,731,346 A * 3/1998 Egberg................... A61K 31, 20 (71) Applicants:National Guard Health Affairs, 514,458 Riyadh (SA); King Saud bin 2002/0146448 A1* 10, 2002 KOZbor .................. A61K 9,127 Abdulaziz University for Health 424/450 2007/0116753 A1* 5/2007 Hong ................... A61K9/0019 Sciences, Riyadh (SA); King Abdullah 424/450 International Medical Research 2011/0274746 A1* 11/2011 Schmidt ................. A61K 9,127 Center, Riyadh (SA) 424/450 2012/0076795 A1 3/2012 Debs (72) Inventors: Majed Abdulaziz Saleh Halwani, 2012/0288558 A1* 11/2012 Gabizon .............. A61K 31,337 Riyadh (SA); Moayad Abdulaziz 424/450 Alhariri, Riyadh (SA) (Continued) (73) Assignees: National Guard Health Affairs, FOREIGN PATENT DOCUMENTS Riyadh (SA); King Saud bin EP O 198765 A2 10, 1986 Abdulaziz University for Health EP O 198765 A3 10, 1986 Sciences, Riyadh (SA); King Abdullah WO WO 2011 (143271 A2 11/2011 International Medical Research Center, Riyadh (SA) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this PG Rose. “Pegylated Liposomal Doxorubicin: Optimizing the Dos patent is extended or adjusted under 35 ing Schedule in Ovarian Cancer.” The Oncologist, vol. 10, 2005, pp. U.S.C. 154(b) by 0 days. 205-214. (Continued) (21) Appl. No.: 15/212,389 Primary Examiner — Isaac Shomer (22) Filed: Jul. 18, 2016 (74) Attorney, Agent, or Firm — Oblon, McClelland, Maier & Neustadt, L.L.P. (51) Int. C. (57) ABSTRACT A 6LX 9/27 (2006.01) A6 IK3I/704 (2006.01) A therapeutic liposome including a bilayer comprising at (52) U.S. C. least one poly-unsaturated fatty acid (omega-3 fatty acid, CPC ............ A61K 9/127 (2013.01); A61 K3I/704 omega-6 fatty acid, and omega-9 fatty acid), a beta-glucan, (2013.01); Y10S 977/906 (2013.01); Y10S a cholesterol, and a doxorubicin. The liposome has a diam 977/907 (2013.01) eter of 100 nm to 1.5um. The beta-glucan and the doxoru (58) Field of Classification Search bicin are encapsulated in the liposome and the cholesterol is None integral to the bilayer of the liposome. See application file for complete search history. 13 Claims, 5 Drawing Sheets sa 838 -3. 8. 3 38: 3:3: 8: ex:ix: S. 8:3&sts: sr. ... : US 9,655,847 B1 Page 2 (56) References Cited U.S. PATENT DOCUMENTS 2013/0022663 A1 1/2013 Buckman OTHER PUBLICATIONS Janssen Inc. “Product Monograph CaelyX(R).” Janssen Inc., Revised Oct. 10, 2013, pp. 1-55.* DAkramiene, A Kondrotas, J Didziapetriene, E Kevelaitis. “Effects of b-glucans on the immune system.' Medicina (Kaunas), vol. 43(8), 2007, pp. 597-606.* Majed Halwani, et al., "Liposomal f-Glucan: Preparation, Charac terization and Anticancer Activities'. Journal of Nanomedicine & Nanotechnology, vol. 6, Issue 5. Oct. 2015. 7 pages. Godfrey Chi-Fung Chan., et al., “The effects of B-glucan on human immune and cancer cells'. Journal of Hematology & Oncology 2:25, pp. 1-11, (2009). * cited by examiner U.S. Patent May 23, 2017 Sheet 1 of 5 US 9,655,847 B1 U.S. Patent May 23, 2017 Sheet 2 of 5 US 9,655,847 B1 YYYYYYYYYYYYYY 2: YYYYY 2222222, s s Y2Ya. * . SS 8 & s & 3.: s & i. : & U.S. Patent May 23, 2017 Sheet 3 of 5 US 9,655,847 B1 Z Z s YY ce g E. -t s: (%) ill||Ely & s U.S. Patent May 23, 2017 Sheet 4 of 5 US 9,655,847 B1 c o e x ve 8. r g o &&. g: * s: W E. s (%) Alcel," a U.S. Patent May 23, 2017 Sheet S of 5 US 9,655,847 B1 -------------------------------------------------------------- s 8 f: s s x x %) kalice Alao US 9,655,847 B1 1. 2 THERAPEUTIC LIPOSOME AND METHOD Such, glucans have shown beneficial effects in the treatment OF TREATING ASUBJECT HAVING of infectious and autoimmune diseases, and in clinical CANCER management of cancer. Glucans target various cell types in the immune system, BACKGROUND OF THE INVENTION and more particularly macrophages. Previous research has shown that glucans display protective properties against Technical Field experimentally induced infections in mammalian model The present invention relates to a liposome for treating systems. Specifically, glucans exert their function on mac cancer by including doxorubicin, a polyunsaturated fatty rophages, monocytes, lymphocytes, and other immune cells 10 in the mammalian system that plays a significant role in acid, and beta glucan in combination. elicitation of the immune response. Description of the Related Art For example, administration of glucans has been shown to The “background description provided herein is for the significantly enhance the immune system in animals to a purpose of generally presenting the context of the disclo wide variety of experimentally induced bacterial, viral, sure. Work of the presently named inventors, to the extent it 15 fungal and parasitic infections. Glucans also show strong is described in this background section, as well as aspects of anti-tumor activity. Glucan carries out its biological function the description which may not otherwise qualify as prior art by binding to specific receptor molecules located on the at the time of filing, are neither expressly or impliedly Surface of macrophages. In in vitro studies, exposure of admitted as prior art against the present invention. these cells to beta-glucans stimulates the immune system. Doxorubicin (DOX) has been found to have a broad One representative glucan with Such immune-enhancing spectrum of application in cancer, which includes numerous characteristics is branched beta (1,3)-glucan. Solid tumors such as breast cancer, sarcomas and bladder Beta-glucans are naturally occurring polymers of Saccha cancers. See Weinstein D M, Mihm MJ, Bauer J.A. “Cardiac rides (polysaccharides) and are constituents of the cell wall peroxynitrite formation and left ventricular dysfunction fol of certain pathogenic bacteria, algae, fungi, and cereals (e.g. lowing doxorubicin treatment in mice. J Pharmacol Exp 25 oats, barley, rye, wheat). The healing and immunostimulat Ther 2000; 294: 396–401, incorporated herein by reference ing properties of mushrooms have been known for thou in its entirety. Despite its common use, the clinical utility of sands of years in the Eastern countries. These mushrooms DOX is compromised by dose-limiting cardiotoxicity due to contain biologically active polysaccharides that mostly its effects on mitochondria. The heart contains a large belong to group of beta-glucans. Beta-glucans can increase 30 host immune defense by enhancing macrophages and natural amount of energy producing mitochondria to function as a killer cell function. The induction of cellular responses by pump which requires a great amount of energy that circu beta-glucans is likely to involve their specific interaction lates blood throughout the body. See Angsutararux P. Luan with several cell Surface receptors, such as complement pitpong S. Issaragrisil S. "Chemotherapy-Induced Cardio receptor 3 (CR3: CD11b/CD18), lactosylceramide, selected toxicity: Overview of the Roles of Oxidative Stress.” Oxid 35 Scavenger receptors, and dectin-1 (betaGR). As an immu Med Cell Longev 2015; 2015: 795602, incorporated herein nostimulating agent, which acts through the activation of by reference in its entirety. A mitochondrion is the site of macrophages and NK cell cytotoxicity, beta-glucan can most reactive oxygen species (ROS) which are produced as inhibit tumor growth in promotion stage also. The interac a result of electrons escaping from electron transport chain tion between glucan and its receptor produce further stimu and captured by oxygen, rendering it as a main source of 40 latory effects such as enhanced phagocytosis, increased cell superoxide production. See Andreyev AY, Kushnareva Y E. size, enhanced cell proliferation, enhanced adherence and Murphy A N et al. “Mitochondrial ROS Metabolism: 10 chemotactic activity and production of a wide range of Years Later.” Biochemistry (Most) 2015; 80: 517-31, incor cytokines and leukotrienes. porated herein by reference in its entirety. However, DOX Cytokines are critical to a myriad of fundamental homeo can drive these ROS production to much higher levels. See 45 static and pathophysiological processes such as fever, Varin R, Mulder P. Richard V et al. “Exercise improves wound healing, inflammation, tissue repair and fibrosis. flow-mediated vasodilatation of skeletal muscle arteries in They play important roles in regulating cell function Such as rats with chronic heart failure. Role of nitric oxide, pros proliferation, migration, and matrix synthesis. It is the tanoids, and oxidant stress.” Circulation 1999; 99: 2951-7. balance or the net effect of the complex interplay between Recent research Suggests that nitric oxide (NO) may play 50 these mediators, which appears to play a major role in diverse roles in cardiac function and disease. High level of regulating the initiation, progression and resolution of NO production is associated with multiple forms of cardiac wounds. Wound healing involves a complex process includ disease, including dilated cardiomyopathy and congestive ing induction of acute inflammation by the initial injury, heart failure. See Fadillioglu E, Yilmaz HR, Erdogan Het followed by parenchymal and mesenchymal cell prolifera al. The activities of tissue Xanthine oxidase and adenosine 55 tion, migration, and activation with production and deposi deaminase and the levels of hydroxyproline and nitric oxide tion of extracellular matrix. in rat hearts subjected to doxorubicin: protective effect of A study reported that B-glucan has immunomodulation erdosteine. Toxicology 2003; 191: 153-8, incorporated effect on innate and adaptive immunity. See Thompson I J. herein by reference in its entirety. A mechanism to reduce Oyston PC, Williamson D. E. "Potential of the beta-glucans cardiotoxicity from DOX is of interest to the medical 60 to enhance innate resistance to biological agents.” Expert community.