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Liposome formulation of a novel hydrophobic aryl-imidazole compound for anti-cancer therapy

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Abstract

Purpose: A cholesterol-free liposome formulation formed from mixtures of egg phosphatidylcholine (ePC) and poly (ethylene glycol) conjugated distearoylphosphatidylethanolamine (DSPE-PEG 2000) was optimized and evaluated for delivery of a novel anti-cancer agent ML220 (2-(5-bromo-1H-indol-3-yl)-1H-phenanthro [9,10-d] imidazole). Results and Discussion: ML220 is highly lipophilic with a water solubility of 0.14 μg/ml and calculated log P of 5.69. The ML220-loaded liposomes had a unimodal size-distribution and a mean diameter of 89 nm. The drug to lipid ratio in the formulation was 1:3.5 (mol:mol) and the drug loading efficiency was 83% providing a more than 50,000-fold increase in the water solubility of ML220. The formulation was demonstrated to be stable in vitro at 37°C for over 2 weeks with a delayed drug release profile. Evaluation of the subacute toxicity of the liposome formulated drug in C3H mice revealed no overt signs of toxicity. Also, a biexponential drug plasma concentration pattern was found upon evaluation of the pharmacokinetics in Balb/C mice. The in vivo evaluation of the anti-cancer activity in a human colon HT29 carcinoma model revealed a significant delay in tumor growth. Conclusion: Overall, the ePC/DSPE-PEG liposomes were demonstrated to be a suitable delivery system for ML220. These studies also highlight the potential of cholesterol-free liposomes as a formulation strategy for highly lipophilic drugs.

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References

  1. Patel HM, Moghimi SM (1998) Serum-mediated recognition of liposomes by phagocytic cells of the reticuloendothelial system—the concept of tissue specificity. Adv Drug Deliv Rev 32(1–2):45–60

    Article  PubMed  Google Scholar 

  2. Allen C, Dos Santos N, Gallagher R, Chiu GNC, Shu Y, Li WM, Johnstone SA, Janoff AS, Mayer LD, Webb MS, Bally MB (2002) Controlling the physical behavior and biological performance of liposome formulations through use of surface grafted poly(ethylene glycol). Biosci Rep 22(2):225–250

    Article  PubMed  CAS  Google Scholar 

  3. Alakhov V, Klinski E, Li SM, Pietrzynski G, Venne A, Batrakova E, Bronitch T, Kabanov A (1999) Block copolymer-based formulation of doxorubicin. From cell screen to clinical trials. Colloids Surf B Biointerfaces 16(1–4):113–134

    Article  CAS  Google Scholar 

  4. Nakanishi T, Fukushima S, Okamoto K, Suzuki M, Matsumura Y, Yokoyama M, Okano T, Sakurai Y, Kataoka K (2001) Development of the polymer micelle carrier system for doxorubicin. J Control Release 74(1–3):295–302

    Article  PubMed  CAS  Google Scholar 

  5. Moghimi SM, Pavey KD, Hunter AC (2003) Real-time evidence of surface modification at polystyrene lattices by poloxamine 908 in the presence of serum: in vivo conversion of macrophage-prone nanoparticles to stealth entities by poloxamine 908. FEBS Lett 547(1–3):177–182

    Article  PubMed  CAS  Google Scholar 

  6. Janoff AS (1999) Liposomes: rational design. Marcel Dekker Inc, New York

    Google Scholar 

  7. Allen TM, Mehra T, Hansen C, Chin YC (1992) Stealth liposomes: an improved sustained release system for 1-beta-d-arabinofuranosylcytosine. Cancer Res 52(9):2431–2439

    PubMed  CAS  Google Scholar 

  8. Tardi PG, Boman NL, Cullis PR (1996) Liposomal doxorubicin. J Drug Target 4(3):129–140

    Article  PubMed  CAS  Google Scholar 

  9. Hanai T, Koizumi K, Kinoshita T (2000) Prediction of retention factors of phenolic and nitrogen-containing compounds in reversed-phase liquid chromatography based on logP and pKa obtained by computational chemical calculation. J Liquid Chromatogr Related Technol 23(3):363–385

    Article  CAS  Google Scholar 

  10. Drummond DC, Meyer O, Hong KL, Kirpotin DB, Papahadjopoulos D (1999) Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. Pharmacol Rev 51(4):691–743

    PubMed  CAS  Google Scholar 

  11. Maurer-Spurej E, Wong KF, Maurer N, Fenske DB, Cullis PR (1999) Factors influencing uptake and retention of amino-containing drugs in large unilamellar vesicles exhibiting transmembrane pH gradients. Biochim Biophys Acta-Biomembr 1416(1–2):1–10

    Article  CAS  Google Scholar 

  12. Crosasso P, Ceruti M, Brusa P, Arpicco S, Dosio F, Cattel L (2000) Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes. J Control Release 63(1–2):19–30

    Article  PubMed  CAS  Google Scholar 

  13. Sharma A, Mayhew E, Bolcsak L, Cavanaugh C, Harmon P, Janoff A, Bernacki RJ (1997) Activity of paclitaxel liposome formulations against human ovarian tumor xenografts. Int J Cancer 71(1):103–107

    Article  PubMed  CAS  Google Scholar 

  14. Zhang JA, Anyarambhatla G, Ma L, Ugwu S, Xuan T, Sardone T, Ahmad I (2005) Development and characterization of a novel Cremophor EL free liposome-based paclitaxel (LEP-ETU) formulation. Eur J Pharm Biopharm 59(1):177–187

    Article  PubMed  CAS  Google Scholar 

  15. Scialli AR, Waterhouse TB, Desesso JM, Rahman A, Goeringer GC (1997) Protective effect of liposome encapsulation on paclitaxel developmental toxicity in the rat. Teratology 56(5):305–310

    Article  PubMed  CAS  Google Scholar 

  16. Zhang JA, Anyarambhatla G, Ma L, Ugwu S, Xuan T, Sardone T, Ahmad I (2005) Development and characterization of a novel Cremophor (R) EL free liposome-based paclitaxel (LEP-ETU) formulation. Eur J Pharm Biopharm 59(1):177–187

    Article  PubMed  CAS  Google Scholar 

  17. Crosasso P, Ceruti M, Brusa P, Arpicco S, Dosio F, Cattel L (2000) Preparation, characterization and properties of sterically stabilized paclitaxel-containing liposomes. J Control Release 63(1–2):19–30

    Article  PubMed  CAS  Google Scholar 

  18. Moribe K, Maruyama K, Iwatsuru M (1999) Encapsulation characteristics of nystatin in liposomes: effects of cholesterol and polyethylene glycol derivatives. Int J Pharm 188(2):193–202

    Article  PubMed  CAS  Google Scholar 

  19. Huesca M, AL-Qawasmeh R, Young A, Lee Y (2005) Aryl imidazoles and their use as anti-cancer agents, in patent application no. PCT/WQ2005/047266. WO

  20. Lock L, Huesca M, Al-Qawasmeh R, Viau S, Cammisa E, Mikaylo V, Lee Y, Young A (2004) Molecular mechanisms of growth inhibition induced by novel aryl-imidazole compounds in human cancer cells. Drug Discovery Technology, Boston

    Google Scholar 

  21. Liu J, Xiao Y, Allen C (2004) Polymer-drug compatibility: a guide to the development of delivery systems for the anticancer agent, ellipticine. J Pharm Sci 93(1):132–143

    Article  PubMed  CAS  Google Scholar 

  22. Li YG, Liu H, Wang ZT (2005) A validated stability-indicating HPLC with photodiode array detector (PDA) method for the stress tests of Monascus purpureus—fermented rice, red yeast rice. J Pharm Biomed Anal 39(1–2):82–90

    Article  PubMed  CAS  Google Scholar 

  23. Liggins RT, Hunter WL, Burt HM (1997) Solid-state characterization of paclitaxel. J Pharm Sci 86(12):1458–1463

    Article  PubMed  CAS  Google Scholar 

  24. Semple SC, Chonn A, Cullis PR (1998) Interactions of liposomes and lipid-based carrier systems with blood proteins: relation to clearance behaviour in vivo. Adv Drug Deliv Rev 32(1–2):3–17

    Article  PubMed  CAS  Google Scholar 

  25. Gabizon A, Price DC, Huberty J, Bresalier RS, Papahadjopoulos D (1990) Effect of liposome composition and other factors on the targeting of liposomes to experimental tumors: biodistribution and imaging studies. Cancer Res 50(19):6371–6378

    PubMed  CAS  Google Scholar 

  26. Siegal T, Horowitz A, Gabizon A (1995) Doxorubicin encapsulated in sterically stabilized liposomes for the treatment of a brain tumor model: biodistribution and therapeutic efficacy. J Neurosurg 83(6):1029–1037

    Article  PubMed  CAS  Google Scholar 

  27. Mizumura Y, Matsumura Y, Hamaguchi T, Nishiyama N, Kataoka K, Kawaguchi T, Hrushesky WJM, Moriyasu F, Kakizoe T (2001) Cisplatin-incorporated polymeric micelles eliminate nephrotoxicity, while maintaining antitumor activity. Japan J Cancer Res 92(3):328–336

    CAS  Google Scholar 

  28. Yokoyama M, Fukushima S, Uehara R, Okamoto K, Kataoka K, Sakurai Y, Okano T (1998) Characterization of physical entrapment and chemical conjugation of adriamycin in polymeric micelles and their design for in vivo delivery to a solid tumor. J Control Release 50(1–3):79–92

    Article  PubMed  CAS  Google Scholar 

  29. King FG, Dedrick RL (1992) Physiological pharmacokinetic parameters for cis-dichlorodiammineplatinum(II) (DDP) in the mouse. J Pharm Biopharm 20(1):95–9

    Article  CAS  Google Scholar 

  30. Yamamoto Y, Nagasaki Y, Kato Y, Sugiyama Y, Kataoka K (2001) Long-circulating poly(ethylene glycol)-poly(d,l-lactide) block copolymer micelles with modulated surface charge. J Control Release 77(1–2):27–38

    Article  PubMed  CAS  Google Scholar 

  31. Torchilin VP, Lukyanov AN, Gao Z, Papahadjopoulos-Sternberg B (2003) Immunomicelles: targeted pharmaceutical carriers for poorly soluble drugs. Proc Natl Acad Sci USA 100(10):6039–44

    Article  PubMed  CAS  Google Scholar 

  32. Lukyanov AN, Gao Z, Mazzola L, Torchilin VP (2002) Polyethylene glycol-diacyllipid micelles demonstrate increased accumulation in subcutaneous tumors in mice. Pharm Res 19(10):1424–1429

    Article  PubMed  CAS  Google Scholar 

  33. Liu JB, Zeng FQ, Allen C (2005) Influence of serum protein on polycarbonate-based copolymer micelles as a delivery system for a hydrophobic anti-cancer agent. J Control Release 103(2):481–497

    Article  PubMed  CAS  Google Scholar 

  34. Weissig V, Whiteman KR, Torchilin VP (1998) Accumulation of protein-loaded long-circulating micelles and liposomes in subcutaneous Lewis lung carcinoma in mice. Pharm Res 15(10):1552–1556

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to NSERC and Lorus Therapeutics Inc. for funding this research. Dr. Ningping Feng and Ming Wang are acknowledged for their assistance with the in vivo evaluation of toxicity and efficacy. Dr. Gerald Guerin is acknowledged for his assistance with the multi-angle light scattering measurements.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Toronto, 19 Russell St, M5S 2S2, Toronto, ON, Canada

    Jubo Liu, Helen Lee & Christine Allen

  2. Lorus Therapeutics Inc., 2 Meridian Road, M9W 4Z7, Toronto, ON, Canada

    Mario Huesca & Aiping Young

Authors
  1. Jubo Liu
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  2. Helen Lee
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  3. Mario Huesca
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  4. Aiping Young
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  5. Christine Allen
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Correspondence to Christine Allen.

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Liu, J., Lee, H., Huesca, M. et al. Liposome formulation of a novel hydrophobic aryl-imidazole compound for anti-cancer therapy. Cancer Chemother Pharmacol 58, 306–318 (2006). https://doi.org/10.1007/s00280-005-0161-x

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  • DOI: https://doi.org/10.1007/s00280-005-0161-x

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