Cancer Chemotherapy and Pharmacology

, Volume 32, Issue 3, pp 190–196 | Cite as

Organ distribution and tumor uptake of annamycin, a new anthracycline derivative with high affinity for lipid membranes, entrapped in multilamellar vesicles

  • Yiyu Zou
  • Waldemar Priebe
  • Yi-He Ling
  • Roman Perez-Soler
Original Articles Annamycin, Anthracycline Derivative, Multilamellar Vesicles


Annamycin (Ann) is a lipophilic, non-cross resistant anthracycline antibiotic that is easily amenable to formulation in a wide variety of liposomal carriers. We studied the organ distribution and tumor uptake of Ann entrapped in multilamellar vesicles (L-Ann), free annamycin (F-Ann), and doxorubicin (DOX) in C57BL/6 mice bearing advanced subcutaneous B16 melanoma tumors. L-Ann was composed of DMPC: DMPG: Ann at a molar ratio of 7:3:0.7. Mean particle size was 1.88±0.89 μm, and the entrapment efficiency was 93.08%±2.96%. F-Ann was prepared as a suspension (particle size ≤0.2 μm) in 10% DMSO. Drug levels were measured by fluorescence spectrometry after extraction with chloroform. The extraction ratio ranged between 60% and 90% for both drugs in most tissues. Compared with those of DOX, organ AUCs of L-Ann were threefold higher in plasma and brain, twofold higher in liver and kidney, six-fold higher in lung, ninefold higher in spleen, and tenfold higher in B16 tumors. Compared with F-Ann, organ AUCs of L-Ann were twofold higher in plasma, liver, and B16 tumors and were twofold lower in brain. Heart AUCs were similar with all three drugs. Higher tumor uptake was associated with a faster penetration and more prolonged retention of Ann in tumor tissue compared with those of DOX. The results obtained indicate significant differences in organ distribution between L-Ann and DOX as a result of the higher affinity of Ann for lipid membranes and the use of the liposomes as a delivery system. The potential clinical relevance of the increased uptake of L-Ann in B16 tumors, lung, and brain is being investigated.


Melanoma Doxorubicin Anthracycline Tumor Uptake Entrapment Efficiency 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Acton EM, Tong GL, Mosher CW, Wolgemuth RL (1984) Intensely potent morpholinyl anthracyclines. J Med Chem 27: 638Google Scholar
  2. 2.
    Ahlgren P, Panasci L, Skelton J, Gruner P, Major D, Leyland-Jones B, Saletan S, Pilkiewicz F, Haccoun L (1992) Phase II study of liposomal doxzorubicin (TLCD99) in metastatic breast cancer. Proc ASCO 11: 82Google Scholar
  3. 3.
    Allen TM, Mehra T, Hansen C, Chin YC (1992) Stealth liposomes: an improved sustained release for 1-b-arabinofuranosylcytosine. Cancer Res 52: 2431Google Scholar
  4. 4.
    Balazsovits JAE, Mayer LD, Bally MB, Cullis PR, McDonell M, Ginsberg RS, Falk RE (1989) Analysis of the effect of liposome encapsulation on the vesicant properties, acute and cardiac toxicities, and antitumor activity of doxorubicin. Cancer Chemother Pharmacol 23: 81Google Scholar
  5. 5.
    Coley HM, Twentyman PR, Workman P (1989) Identification of anthracyclines and related agents that retain preferential activity over Adriamycin in multidrugresistant cell lines, and further resistance modification by verapamil and cyclosporin A. Cancer Chemother Pharmacol 24: 284Google Scholar
  6. 6.
    Cordon-Cardo C, OBrien JP, Casals D, Rittman-Grauer L, Biedler JL, Melamed MR, Bertino JR (1989) Multidrug-resistant gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci USA 86: 695Google Scholar
  7. 7.
    DeVita VT, Hellman S, Rosenberg S (eds) (1985) Principles and practice of oncology, 3rd edn Lippincott, PhiladelphiaGoogle Scholar
  8. 8.
    Fan D, Bucana CD, O'Brian CA, Zwelling LA, Seid C, Fidler IJ (1990) Enhancement of murine tumor cell sensitivity to adriamycin by presentation of the drug in phosphatidylcholine-phosphatidylserine liposomes. Cancer Res 50: 3619Google Scholar
  9. 9.
    Forssen E, Tokes ZA (1981) Use of anionic liposomes for the reduction of chronic doxorubicin-induced cardiotoxicity. Proc Natl Acad Sci USA 78: 1873Google Scholar
  10. 10.
    Forssen EA, Coulter DM, Profitt RT (1992) Selective in vivo localization of daunorubicin small unilamellar vesicles in solid tumors. Cancer Res 52: 3255Google Scholar
  11. 11.
    Gabizon A (1992) Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes. Cancer Res 52: 891Google Scholar
  12. 12.
    Gabizon A, Papahadjopoulos D (1988) Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci USA 85: 6949Google Scholar
  13. 13.
    Gabizon A, Dagan A, Goren D, Barenholz Y, Fuks Z (1982) Liposomes as in vivo carriers of adriamycin: reduced cardiac uptake and preserved antitumor activity in mice. Cancer Res 42: 4734Google Scholar
  14. 14.
    Gabizon A, Goren D, Fuks Z, Meshorer A, Barenholz Y (1985) Superior therapeutic activity of liposome-associated Adriamycin in a murine metastatic tumor model. Br J Cancer 51: 681Google Scholar
  15. 15.
    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: 6371Google Scholar
  16. 16.
    Gabizon A, Catane R, Uziely B, Kaufman T, Safra Y, Barenholz Y, Huang A (1992) A pilot study of doxorubicin encapsulated in longcirculating (StealthR) liposomes (S-DOX) in cancer patients. Proc ASCO 11: 124Google Scholar
  17. 17.
    Geroni MC, Pesenti E, Broggini M, Amboldi N, D'Incalci M, Grandi M (1992) Cells resistant to methoxymorpholinyl-doxorubicin (FCE 23762) are specifically resistant only to the class of morpholinyl and methoxymorpholinyl anthracyclines. Proc AACR 33: 464Google Scholar
  18. 18.
    Herman EH, Rahman A, Ferrans VJ, Vick JA, Schein PS (1983) Prevention of chronic doxorubicin cardiotoxicity in beagles by liposome encapsulation. Cancer Res 43: 5427Google Scholar
  19. 19.
    Horichi N, Tapiero H, Sagimoto Y, Bungo M, Nishiyama M, Fourcade A, Lampidids TJ, Kasahara K, Sasaki Y, Takahashi T, Saijo N (1990) 3′-Deaminio-3′-morpholino-13-deoxo-10-hydroxycarminomycin conquers multidrug resistance by rapid influx following higher frequency of formation of DNA singel- and double-strand breaks. Cancer Res 50: 4698Google Scholar
  20. 20.
    Khokhar AR, Wright K, Siddik ZH, Perez-Soler R (1988) Organ distribution and tumor uptake of liposome-entrapped cis-bis-neode-canoato-trans-R,R-1,2-diaminocyclohexane-platinum (II) administered intravenously and into the hepatic artery. Cancer Chemother Pharmacol 22: 223Google Scholar
  21. 21.
    Lautersztain J, Perez-Soler R, Khokhar AR, Newman RA, Lopez-Berestein G (1986) Pharmacokinetics and tissue distribution of liposome-encapsulated cis-bis-N-decyliminodiacetato-1,2-diaminocyclohexane-platinum (II). Cancer Chemother Pharmacol 18: 93Google Scholar
  22. 22.
    Ling YH, Priebe W, Yang LY, Burke TG, Pommier Y, Perez-Soler R. In vitro cytotoxicity, cellular pharmacology, and DNA lesions induced by Arramycin, a non-cross resistant doxorubicin analogue with high affinity for lipid membranes. Cancer Res (in press)Google Scholar
  23. 23.
    Lothstein L, Sweatman TW, Dokter ME, Israel M (1992) Resistance to N-benzyladriamycin-14-valerate in mouse J774.2 cells: P-glyco-protein expression without reduced N-benzyladriamycin accumulation. Cancer Res 52: 3409Google Scholar
  24. 24.
    Mayer LD, Tai LCL, Ko DSC, Masin D, Ginsberg RS, Cullis PR, Bally MB (1989) Influence of vesicle size lipid composition, and drug-to-lipid ratio on the biological activity of liposomal doxorubicin in mice. Cancer Res 49: 5922Google Scholar
  25. 25.
    Mayhew E, Rustum Y, Vail WJ (1983) Inhibition of liver metastases of M5076 tumor by liposome-entrapped Adriamycin. Cancer Drug Delivery, 1: 43Google Scholar
  26. 26.
    Moscow JA, Cowan KH (1989) Multidrug resistance. J Natl Cancer Inst 8: 14Google Scholar
  27. 27.
    Oudard S, Thierry A, Jorgensen TJ, Rahman A (1991) Sensitization of multidrug-resistant colon cancer cells to doxorubicin encapsulated in liposomes. Cancer Chemother Pharmacol 28: 259Google Scholar
  28. 28.
    Perez-Soler R, Priebe W (1990) Anthracyline antibiotics with high liposome entrapment: structural features and biological activity. Cancer Res 50: 4260Google Scholar
  29. 29.
    Priebe W, Van NT, Burke TG, Perez-Soler R. Removal of the basic aminogroup at position 3′ of doxorubicin overcomes multidrug resistance and decreases cardiotoxicity. Anticancer Drugs (in press)Google Scholar
  30. 30.
    Rahman A, White G, More N, Schein PS (1985) Pharmacological, toxicological, and therapeutic evaluation in mice of doxorubicin entrapped in cardiolipin liposomes. Cancer Res 45: 796Google Scholar
  31. 31.
    Rahman A, Carmichael D, Harris M, Roh JK (1986) Comparative pharmacokinetics of free doxorubicin and doxorubicin entrapped in cardiolipin liposomes. Cancer Res 46: 2295Google Scholar
  32. 32.
    Szoka F, Papahadjopoulos D (1981) Liposomes: preparation and characterization. In: Knight (ed) Liposomes: from physical structure to therapeutic applications. Elsevier/North Holland Biomedical Press, pp 51–82Google Scholar
  33. 33.
    Warren L, Jardillier JC, Malarska A, Akeli MG (1992) Increased accumulation of drugs in multidrug-resistant cells induced by liposomes. Cancer Res 52: 3241Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • Yiyu Zou
    • 1
  • Waldemar Priebe
    • 1
  • Yi-He Ling
    • 1
  • Roman Perez-Soler
    • 1
  1. 1.Department of Medical OncologyM. D. Anderson CenterHoustonUSA

Personalised recommendations