Skip to main content
Log in

Transfer of liposomal drug carriers from the blood to the peritoneal cavity of normal and ascitic tumor-bearing mice

  • Original Articles
  • Liposomes, Doxorubicin, Extravasation
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Summary

Previously we have demonstrated that the L1210 antitumor activity of liposomal doxorubicin increased significantly as the size of the liposomal carrier was reduced from 1.0 to 0.1 μm. It is demonstrated herein that empty and drug-loaded small (0.1-μm diameter) liposomes accumulate efficiently into the peritoneal cavity of normal and ascitic L1210 tumor-bearing animals following i.v. administration. In normal mice injected with 100 nm DSPC/chol liposomal doxorubicin (drug-to-lipid ratio of 0.2; wt/wt) approximately 2.8 μg drug could be recovered from the peritoneal cavity following peritoneal lavage at 24 h. Although this represents only 0.7% of the injected doxorubicin dose, this level of drug is 2 orders of magnitude greater than that achieved following administration of an equivalent dose of free drug (20 mg/kg). The drug levels achieved within the peritoneal cavity are dependent on the physical characteristics (size, drug-to-lipid ratio and lipid composition) of the liposomes employed. Optimal delivery is obtained employing 100 nm DSPC/chol liposomal doxorubicin, a vesicle system that is known to retain entrapped drug following i.v. administration and exhibits extended circulation lifetimes. Analysis of drug and liposome distribution within the peritoneal cavity of normal mice indicates that as much as 50% of the measured doxorubicin and liposomal lipid is cell-associated. Flow cytometric analysis of the peritoneal cells demonstrated that cell-associated doxorubicin resides almost exclusively within resident peritoneal macrophages. The increased delivery of doxorubicin to the peritoneal cavity of normal mice following i.v. administration of small (0.1-μm) liposomal doxorubicin is correlated with a pronounced (>90%) and prolonged (>14-day) suppression of resident peritoneal cells. Liposomal drug accumulation increased dramatically in animals with an established L1210 ascitic tumor. More than 5% of the injected dose was found in the peritoneal cavity of these animals 24 h after treatment with DSPC/chol liposomal doxorubicin as compared with a value of 0.03% of the injected dose achieved with free drug. It is proposed that accumulation of liposomes into the peritoneal cavity of normal and tumor-bearing mice may serve as a useful model for characterizing factors mediating the transfer of liposomes from the vascular compartment to extravascular sites.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Allen TM, Chonn A (1987) Large unilamellar liposomes with low uptake into the reticuloendothelial system. FEBS Lett 223: 42–46

    Google Scholar 

  2. Bakker-Woudenberg IAJM, Lakerse AF, Kate MT ten, Storm G (1992) Enhanced localization of liposomes with prolonged blood circulation time in infected lung tissue. Biochim Biophys Acta 1138: 318–326

    Google Scholar 

  3. Bally MB, Nayar R, Masin D, Hope MJ, Cullis PR, Mayer LD (1990) Liposomes with entrapped doxorubicin exhibit extended blood residence times. Biochim Biophys Acta 1023: 133–141

    Google Scholar 

  4. Bally MB, Mayer LD, Nayar R (1991) Peritoneal influx of intravenously administered liposomal doxorubicin: a model for extravasation of liposomal drug carriers. Proc Am Assoc Cancer Res 32: A2337

    Google Scholar 

  5. Dvorak HF, Nagy JA, Dvorak JT, Dvorak AM (1988) Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol 133: 95–109

    Google Scholar 

  6. Dvorak HF, Sioussat TM, Brown LF, Berse B, Nagy JA, Sotrel A, Manseau EJ, Water L, Senger DR (1991) Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med 174: 1275–1278

    Google Scholar 

  7. deleted

  8. deleted

  9. Finkelstein MC, Kuhn SH, Schieren H, Weissmann G, Hoffstein S (1981) Liposome uptake by human leukocytes: enhancement of entry mediated by human serum and aggregated immunoglobulins. Biochim Biophys Acta 673: 286–302

    Google Scholar 

  10. Flessner MF, Dedrick RL, Schultz JS (1985) Exchange of macromolecules between peritoneal cavity and plasma. Am J Physiol 248: 15–25

    Google Scholar 

  11. Forssen EA, Coulter DM, Proffitt RT (1992) Selective in vivo localization of daunorubicin small unilamellar vesicles in solid tumors. Cancer Res 52: 3255–3261

    Google Scholar 

  12. Frank MM (1989) The role of macrophages in blood stream clearance. In: Asherson GL, Zembaba M (eds) Human monocytes. Academic Press, San Diego, pp 337–334

    Google Scholar 

  13. Furth R van (1988) Phagocytic cells: development and distribution of mononuclear phagocytes in normal steady state and inflammation. In: Gallin JI, Goldstein IM, Snyderman R (eds) Inflammation: basic principles and clinical correlates. Raven, New York, pp 281–295

    Google Scholar 

  14. Gabizon A (1992) Selective tumor localization and improved therapeutic index of anthracyclines encapsulated in long-circulating liposomes. Cancer Res 52: 891–896

    Google Scholar 

  15. Gabizon A, Papahadjopoulos D (1988) Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. Proc Natl Acad Sci USA 85: 6949–6953

    Google Scholar 

  16. 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: 4734–4739

    Google Scholar 

  17. Gabizon A, Shiota R, Papahadjopoulos D (1989) Pharmacokinetics and tissue distribution of doxorubicin encapsulated in stable liposomes with long circulation times. J Natl Cancer Inst 81: 1484–1488

    Google Scholar 

  18. Gerlowski LE, Jain RK (1986) Microvascular permeability of normal and neoplastic tissues. Microvasc Res 31: 288–305

    Google Scholar 

  19. Heuser LS, Miller FN (1986) Differential macromolecular leakage from vasculature of tumors. Cancer 57: 461–464

    Google Scholar 

  20. Hope MJ, Bally MB, Webb G, Cullis PR (1985) Production of large unilamellar vesicles by a rapid extrusion procedure: characterization of size, trapped volume and ability to maintain a membrane potential. Biochim Biophys Acta 813: 55–65

    Google Scholar 

  21. Jain RK (1988) Determinants of tumor blood flow: a review. Cancer Res 48:2641–2658

    Google Scholar 

  22. Kohn S, Nagy JA, Dvorak HF, Dvorak AM (1992) Pathways of macromolecular tracer transport across venules and small veins. Lab Invest 67:596–607

    Google Scholar 

  23. Lasic DD, Martin FJ, Gabizon A, Huang SK, Papahadjopoulas D (1991) Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times. Biochim Biophys Acta 1070:187–192

    Google Scholar 

  24. Leypoldt JK, Parker HR, Frigon RP, Henderson LW (1987) Molecular size dependence of peritoneal transport. J Lab Clin Med 110:207–216

    Google Scholar 

  25. Malech HL (1988) Phagocytic cells: egress from marrow and diapedesis. In: Gallin JI, Goldstein IM, Snyderman R (eds) Inflammation: basic principles and clinical correlates. Raven, New York, pp 297–308

    Google Scholar 

  26. Mayer LD, Hope MJ, Cullis PR (1986) Vesicles of various sizes produced by a rapid extrusion precedure. Biochim Biophys Acta 858:161–168

    Google Scholar 

  27. 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 49:5922–5930

    Google Scholar 

  28. Mayer LD, Bally MB, Cullis PR (1990) Strategies for optimizing liposomal doxorubicin. J Liposome Res 1:463–480

    Google Scholar 

  29. Mayer LD, Bally MB, Cullis PR, Wilson SL, Emerman JT (1990) Comparison of free and liposomal encapsulated doxorubicin tumor drug uptake and antitumor efficacy in the SC115 murine mammar tumor. Cancer Lett 53:183–189

    Google Scholar 

  30. Mayer LD, Bally MB, Loughrey H, Masin D, Cullis PR (1990) Liposomal vincristine preparations which exhibit decreased drug toxicity and increased activity against murine L1210 and P388 tumors. Cancer Res 50:575–579

    Google Scholar 

  31. Mayer LD, Tai LCL, Bally MB, Mitilenes GN, Ginsberg RS, Cullis PR (1990) Characterization of liposomal systems containing doxorubicin entrapped in response to pH gradients. Biochim Biophys Acta 1025:143–151

    Google Scholar 

  32. Nagy JA, Henzberg KT, Masse EM, Zientara GP, Dvorak HF (1989) Exchange of macromolecules between plasma and peritoneal cavity in ascites tumor-bearing, normal and seratonin-injected mice. Cancer Res 49:5448–5458

    Google Scholar 

  33. Nayar R, Schroit AJ, Fidler IJ (1986) Liposome encapsulation of muramyl peptides for activation of macrophage cytotoxic properties. Methods Enzymol 132:594–603

    Google Scholar 

  34. Nayar R, Hope MJ, Cullis PR (1989) Generation of large unilamellar vesicles from long chain saturated phosphatidylcholines by extrusion technique. Biochim Biophys Acta 986:200–205

    Google Scholar 

  35. Oku N, Namba Y, Okada S (1992) Tumor accumulation of novel RES-avoiding liposomes. Biochim Biophys Acta 1126:255–260

    Google Scholar 

  36. O'Sullivan MM, Powell N, French AP, Williams KE, Morgan JR, Williams BD (1988) Inflammatory joint disease: a comparison of liposome scanning, bone scanning and radiography. Ann Rheum Dis 47:485–491

    Google Scholar 

  37. Papahadjopoulos D, Allen TM, Gabizon A, Mayhew E, Matthay K, Huang SK, Lee KD, Woodle MC, Lasic DD, Redemann C, Martin FJ (1991) Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. Proc Natl Acad Sci USA 88:11460–11464

    Google Scholar 

  38. deleted

  39. Proffitt RT, Williams LE, Presant CA, Tin GW, Uliana JA, Gamble RC, Baldeschwider JD (1983) Tumor-imaging potential of liposomes loaded with In-III-NTA: biodistribution in mice. J Nucl Med 24:45–51

    Google Scholar 

  40. Rahman A, White G, More N, Schein PS (1985) Pharmacological, toxicological and therapeutic evaluation in mice of doxorubicin entrapped liposomes. Cancer Res 45:796–803

    Google Scholar 

  41. Richardson VJ, Ryman BE, Jewkes RF, Jeyasingh K, Tattersall MNH, Newlands ES, Kaye SB (1979) Tissue distribution and tumor localization of 99m-technetium-labelled liposomes in cancer patients. Br J Cancer 40:35–43

    Google Scholar 

  42. Rubin P, Potchen J, Rubin P (1970) Microvasculature and microcirculation in tumor diagnosis and therapy. Microvasc Res 2: 341–349

    Google Scholar 

  43. Scherphof GL, Kuipers F, Denksen JTP, Spanyer HH, Wonk RJ (1987) Liposomes in vivo; conversion of liposomal cholesterol to bile salts. Biochem Soc Trans 15 [Suppl]:625–628

    Google Scholar 

  44. Syrjanen KJ (1978) Post-capillary venules in the lymphatic tissues of mice bearing experimental neoplasia. Exp Pathol 15:348–354

    Google Scholar 

  45. Vaage J, Mayhew E, Lasic D, Martin F (1992) Therapy of primary and metastatic mouse mammary carcinomas with doxorubicin encapsulated in long circulating liposomes. Int J Cancer 51: 942–948

    Google Scholar 

  46. Warren BA (1978) The vascular morphology of tumors. In: Peterson H (ed) Tumor blood circulation, CRC, Boca Raton, Florida, pp 1–47

    Google Scholar 

  47. Williams BD, O'Sullivan MM, Saggu GS, Williams KE, Williams LA, Morgan JR (1986) Imaging in rheumatoid arthritis using liposomes labelled with technetium. BMJ 293:1143–1144

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bally, M.B., Masin, D., Nayar, R. et al. Transfer of liposomal drug carriers from the blood to the peritoneal cavity of normal and ascitic tumor-bearing mice. Cancer Chemother. Pharmacol. 34, 137–146 (1994). https://doi.org/10.1007/BF00685931

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00685931

Key words

Navigation