Research Article

Preclinical studies for a cationic liposome formulation containing Il-2 Intended for the treatment of Human Tumors

Maria Teresa Corona-Ortega*, Arturo Valle-Mendiola, Leonor Aguilar-Santelises, Araceli Garcia del Valle, Rosalva Rangel-Corona and Benny Weiss-Steider

Published: 29 October, 2018 | Volume 2 - Issue 1 | Pages: 051-059

Human cervical cancer tumours expressing the IL-2 receptor (IL-2R) were induced in the peritoneal cavity of nude mice. The tumours were significantly reduced by the i.p. administration of either free IL-2 or liposomes containing this growth factor. No toxicity was observed in the mice even at the highest doses of IL-2 in liposomes. We did not detect any IL-2 in the blood plasma pointing to a strong retention of the liposomes on the cavity. We concluded that this preclinical study for the treatment of tumours expressing IL-2R in the peritoneal cavity is effective and safe. The liposomes were stable and their IL-2 active for up to one year when kept at -14oC in a cryopreservation media approved by the FDA for human use.

Read Full Article HTML DOI: 10.29328/journal.apps.1001010 Cite this Article Read Full Article PDF


  1. Spottswood SE, Lopatina OA, Fey GL, Boardman CH. Peritoneal carcinomatosis from cervical cancer detected by F-18 FDG positron emission tomography. Clin Nucl Med. 2005; 30: 56-59. Ref.: https://goo.gl/PehsiG
  2. Bekes I, Friedl TW, Köhler T, Möbus V, Janni W, et al. Does VEGF facilitate local tumor growth and spread into the abdominal cavity by suppressing endothelial cell adhesion, thus increasing vascular peritoneal permeability followed by ascites production in ovarian cancer? Mol Cancer. 2016; 15: 13. Ref.: https://goo.gl/wg6wjn
  3. Auer K, Bachmayr-Heyda A, Aust S, Sukhbaatar N, Reiner AT, et al. Peritoneal tumor spread in serous ovarian cancer-epithelial mesenchymal status and outcome. Oncotarget. 2015; 6: 17261-17275. Ref.: https://goo.gl/8ePYYe
  4. Kurihara H. Integrated 64Cu therapy for the peritoneal dissemination of gastrointestinal cancer. Oncotarget. 2018; 9: 31165-31166. Ref.: https://goo.gl/WTKXtq
  5. Sugarbaker PH. Peritoneal Metastases from Gastrointestinal Cancer. Curr Oncol Rep. 2018; 20: 62. Ref.: https://goo.gl/nr3oy2
  6. Mugerwa S, Lekharaju V, Kiire CF. Management of peritoneal carcinomatosis secondary to metastatic cancer of unknown primary in men. Eur J Cancer Care (Engl). 2009; 18: 22-27. Ref.: https://goo.gl/hztJmX
  7. Levy AD, Shaw JC, Sobin LH. Secondary tumors and tumorlike lesions of the peritoneal cavity: imaging features with pathologic correlation. Radiographics. 2009; 29: 347-373. Ref.: https://goo.gl/QeTQjA
  8. de Bree E, Witkamp AJ, Zoetmulder FA. Intraperitoneal chemotherapy for colorectal cancer. J Surg Oncol. 2002; 79: 46–61. Ref.: https://goo.gl/XksNuC
  9. Van der Speeten K, Stuart OA, Sugarbaker PH. Using pharmacologic data to plan clinical treatments for patients with peritoneal surface malignancy. Curr Drug Discov Technol. 2009; 6: 72–81. Ref.: https://goo.gl/1gKBxL
  10. Dadashzadeh S, Mirahmadi N, Babaei MH, Vali AM. Peritoneal retention of liposomes: Effects of lipid composition, PEG coating and liposome charge. J Control Release. 2010; 148: 177-186. Ref.: https://goo.gl/WHQefQ
  11. Mirahmadi N, Babaei MH, Vali AM, Dadashzadeh S. Effect of liposome size on peritoneal retention and organ distribution after intraperitoneal injection in mice. Int J Pharm. 2010; 383: 7-13. Ref.: https://goo.gl/HJBYpf
  12. Ulrich AS. Biophysical aspects of using liposomes as delivery vehicles. Bioscience Reports. 2002; 22: 129-150. Ref.: https://goo.gl/MhEH7w
  13. Fatima MT, Islam Z, Ahmad E, Barreto GE, Md Ashraf G. Ionic gradient liposomes: Recent advances in the stable entrapment and prolonged released of local anesthetics and anticancer drugs. Biomed Pharmacother. 2018; 107: 34-43. Ref.: https://goo.gl/uT2Wck
  14. Franco MS, Oliveira MC. Liposomes co-encapsulating anticancer drugs in synergistic ratios as an approach to promote increased efficacy and greater safety. Anticancer Agents Med Chem. 2018; Ref.: https://goo.gl/jQRzj2
  15. Zhang T, Zhou S, Hu L, Peng B, Liu Y, et al. Polysialic acidpolyethylene glycol conjugate-modified liposomes as a targeted drug delivery system for epirubicin to enhance anticancer efficiency. Drug Deliv Transl Res. 2018; 8: 602-616. Ref.: https://goo.gl/nD6mnK
  16. Jang EJ, Choi WR, Kim SY, Hong SS, Rhee I, et al. 2-Hydroxyoleic acid-inserted liposomes as a multifunctional carrier of anticancer drugs. Drug Deliv. 2017; 24: 1587-1597. Ref.: https://goo.gl/ZLHLG7
  17. Syrigos KN, Vile RG, Peters AM, Harrington KJ. Biodistribution and pharmacokinetics of 111In-DTPA-labelled pegylated liposomes after intraperitoneal injection. Acta Oncol. 2003; 42: 147–153. Ref.: https://goo.gl/HD54Sc
  18. Chen LC, Chang CH, Yu CY, Chang YJ, Hsu WC, et al. Biodistribution, pharmacokinetics and imaging of 188Re-BMEDA-labeled pegylated liposomes after intraperitoneal injection in a C26 colon carcinoma ascites mouse model. Nucl Med Biol. 2007; 34: 415–423. Ref.: https://goo.gl/cduMTb
  19. Zavaleta CL, Phillips WT, Soundararajan A, Goins BA. Use of avidin/biotin–liposome system for enhanced peritoneal drug delivery in an ovarian cancer model. Int J Pharm. 2007; 337: 316–328. Ref.: https://goo.gl/Z473Hd
  20. Schwartz RN, Stover L, Dutcher JP. Managing toxicities of high-dose interleukin-2. Oncology (Williston Park). 2002; 16(11 Suppl 13): 11-20. Ref.: https://goo.gl/4XLwLh
  21. Li Y, Strick-Marchand H, Lim AI, Ren J, Masse-Ranson G, et al. Regulatory T cells control toxicity in a humanized model of IL-2 therapy. Nat Commun. 2017; 8: 1762 Ref.: https://goo.gl/LMk6eb
  22. Donohue JH, Rosenberg SA. The fate of interleukin-2 after in vivo administration. J Immunol 1983; 130: 2203-2208. Ref.: https://goo.gl/Bm4KEo
  23. Rangel-Corona R, Corona-Ortega T, Soto-Cruz I, López-Labra A, Pablo-Arcos T, et al. Evidence that cervical cancer cells secrete IL-2, which becomes an autocrine growth factor. Cytokine. 2010; 50: 273–277. Ref.: https://goo.gl/sWVxeN
  24. Rangel-Corona R, Corona-Ortega T, del Río-Ortiz I, Nieves-Ramírez ME, Morán-Bañuelos H, et al. Cationic liposomes bearing IL-2 on their external surface induced mice leukocytes to kill human cervical cancer cells in vitro, and significantly reduced tumor burden in immunodepressed mice. J Drug Target. 2011; 19: 79–85. Ref.: https://goo.gl/N3EMLB
  25. Corona T, Rangel R, Hernández M, Baeza I, Ibáñez M, et al. Characterization of cationic liposomes having IL-2 expressed on the external surface, and their affinity to cervical cancer cells expressing the IL-2 receptor. J Drug Target. 2009; 17: 496-501. Ref.: https://goo.gl/RDBkVR
  26. O'Loughlin EV, Pang GP, Noltorp R, Koina C, Batey R, et al. Interleukin 2 modulates ion secretion and cell proliferation in cultured human small intestinal enterocytes. Gut. 2001; 49: 636-643. Ref.: https://goo.gl/PVY4Lt
  27. Du C, Guan Q, Yin Z, Zhong R, Jevnikar AM. IL-2-mediated apoptosis of kidney tubular epithelial cells is regulated by the caspase-8 inhibitor c-FLIP. Kidney Int. 2005; 67: 1397-1409. Ref.: https://goo.gl/Pevp3T
  28. Kawami H, Yoshida K, Yamaguchi Y, Saeki T, Toge T. The expression and biological activity of IL-2 receptor on a human pancreas cancer cell line. Biotherapy. 1993; 6: 33-39. Ref.: https://goo.gl/XQReZ5
  29. Barton DP, Blanchard DK, Wells AF, Nicosia SV, Roberts WS, et al. Expression of interleukin-2 receptor alpha (IL-2R alpha) mRNA and protein in advanced epithelial ovarian cancer. Anticancer Res. 1994; 14(3A): 761-772. Ref.: https://goo.gl/GmZai2
  30. Lorke D. A new approach to practical acute toxicity testing. Arch Toxicol. 1983; 54: 275-287. Ref.: https://goo.gl/LG245s
  31. Corona-Ortega MT, Soto-Vázquez R, Rangel-Corona R, Huante-García RM, AguilarSantelises L, et al. A Novel Nanocarrier System for Cancer Treatment. Current Nanomedicine. 2016; 6: 133-145. Ref.: https://goo.gl/ZrCCe2
  32. Fernández I, Peña A, Del Teso N, Pérez V, Rodríguez-Cuesta J. Clinical Biochemistry Parameters in C57BL/6J Mice after Blood Collection from the Submandibular Vein and Retroorbital Plexus. J Am Assoc Lab Anim Sci. 2010; 49: 202-206. Ref.: https://goo.gl/NDmvHi
  33. Kallerup RS, Madsen CM, Schiøth ML, Franzyk H, Rose F, et al. Influence of trehalose 6,60-diester (TDX) chain length on the physicochemical and immunopotentiating properties of DDA/TDX liposomes. Eur J Pharm and Biopharm. 2015; 90: 80– 89. Ref.: https://goo.gl/6TQMWK
  34. Sydykov B, Oldenhof H, de Oliveira Barros L, Sieme H, Wolkers WF. Membrane permeabilization of phosphatidylcholine liposomes induced by cryopreservation and vitrification solutions. BBA – Biomembranes. 1860, 2018; 467–474. Ref.: https://goo.gl/DHty55
  35. Corona-Ortega MT, Soto-Vázquez R, Weiss-Steider B, Rangel-Corona R. Inv.: PROCESO DE ESTABILIZACIÓN DE LIPOSOMAS QUE CONTIENEN IL-2 MEDIANTE CRIOPRESERVACIÓN, Patent request, Mx/a/2015/013539.
  36. Hansson J, Ericsson PO, Dohlsten M, Sjögren HO, Kalland T, et al. Locally superantigen-activated peritoneal cytolytic T lymphocytes belong to the CD8+ CD45RC- subset and lyse MHC class II+ tumor cells. Immunol Lett. 1992; 34: 229-236. Ref.: https://goo.gl/p3aLxf
  37. Berek JS, Bast RC Jr, Lichtenstein A, Hacker NF, Spina CA, et al. Lymphocyte cytotoxicity in the peritoneal cavity and blood of patients with ovarian cancer. Obstet Gynecol. 1984; 64: 08-14. Ref.: https://goo.gl/btzWMv
  38. Sakaguchi H, Ishida H, Nitanda H, Yamazaki N, Kaneko K, et al. Pharmacokinetic evaluation of intrapleural perfusion with hyperthermic chemotherapy using cisplatin in patients with malignant pleural effusion. Lung Cancer. 2017; 104: 70-74. Ref.: https://goo.gl/dXmM4Q
  39. Cao S, Jin S, Cao J, Shen J, Hu J, et al. Advances in malignant peritoneal mesothelioma. Int J Colorectal Dis. 2015; 30: 1-10. Ref.: https://goo.gl/UpMxhz


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