In vivo distribution and antitumor activity of heparin-stabilized doxorubicin-loaded liposomes.

The purpose of this study was to investigate the effect of heparin conjugation to the surface of doxorubicin (DOX)-loaded liposomes on the circulation time, biodistribution and antitumor activity after intravenous injection in murine B16F10 melanoma tumor-bearing mice. The heparin-conjugated liposomes (heparin-liposomes) were prepared by fixation of the negatively charged heparin to the positively charged liposomes. The existence of heparin on the liposomal surface was confirmed by measuring the changes in the particle size, zeta potential and heparin amount of the liposomes. The stability of the heparin-liposomes in serum was higher than that of the control liposomes, due to the heparin-liposomes being better protected from the adsorption of serum proteins. The DOX-loaded heparin-liposomes showed high drug levels for up to 64 h after the intravenous injection and the half-life of DOX was approximately 8.4- or 1.5-fold higher than that of the control liposomes or polyethyleneglycol-fixed liposomes (PEG-liposomes), respectively. The heparin-liposomes accumulated to a greater extent in the tumor than the control or PEG-liposomes as a result of their lower uptake by the reticuloendothelial system cells in the liver and spleen. In addition, the DOX-loaded heparin-liposomes retarded the growth of the tumor effectively compared with the control or PEG-liposomes. These results indicate the promising potential of heparin-liposomes as a new sterically stabilized liposomal delivery system for the enhancement of the therapeutic efficacy of chemotherapeutic agents.

[1]  T M Allen,et al.  Liposomes containing synthetic lipid derivatives of poly(ethylene glycol) show prolonged circulation half-lives in vivo. , 1991, Biochimica et biophysica acta.

[2]  A. Gabizon,et al.  Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[3]  M C Garnett,et al.  Preparation of surface-modified albumin nanospheres. , 1997, Biomaterials.

[4]  Qiang Zhang,et al.  Enhanced Intracellular Uptake of Sterically Stabilized Liposomal Doxorubicin in Vitro Resulting in Improved Antitumor Activity in Vivo , 2005, Pharmaceutical Research.

[5]  W. Hennink,et al.  A novel family of L-amino acid-based biodegradable polymer-lipid conjugates for the development of long-circulating liposomes with effective drug-targeting capacity. , 2003, Bioconjugate chemistry.

[6]  R. Prud’homme,et al.  Association of hydrophobically-modified poly(ethylene glycol) with fusogenic liposomes. , 2003, Biochimica et biophysica acta.

[7]  Yechezkel Barenholz,et al.  Prolongation of the Circulation Time of Doxorubicin Encapsulated in Liposomes Containing a Polyethylene Glycol-Derivatized Phospholipid: Pharmacokinetic Studies in Rodents and Dogs , 1993, Pharmaceutical Research.

[8]  A. Albertsson,et al.  Bioactive heparin surfaces from derivatization of polyacrylamide-grafted LLDPE. , 1996, Biomaterials.

[9]  J. Petriz,et al.  A novel strategy affords high-yield coupling of antibody to extremities of liposomal surface-grafted PEG chains. , 1999, Biochimica et biophysica acta.

[10]  R Blumenthal,et al.  Design of liposomes for enhanced local release of drugs by hyperthermia. , 1978, Science.

[11]  Ho-Chul Shin,et al.  Conjugation of Low-Molecular-Weight Heparin and Deoxycholic Acid for the Development of a New Oral Anticoagulant Agent , 2001, Circulation.

[12]  S. Hirota,et al.  Effects of mixed polyethyleneglycol modification on fixed aqueous layer thickness and antitumor activity of doxorubicin containing liposome. , 2002, International journal of pharmaceutics.

[13]  Y. Kawashima,et al.  Polymer coating of liposomes with a modified polyvinyl alcohol and their systemic circulation and RES uptake in rats. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[14]  R. Rosenberg,et al.  Anticoagulant Action of Heparin , 1973, Nature.

[15]  F. Szoka,et al.  Determination and Modeling of Kinetics of Cancer Cell Killing by Doxorubicin and Doxorubicin Encapsulated in Targeted Liposomes , 2004, Cancer Research.

[16]  Y. Barenholz,et al.  Transmembrane ammonium sulfate gradients in liposomes produce efficient and stable entrapment of amphipathic weak bases. , 1993, Biochimica et biophysica acta.

[17]  T. Nagai,et al.  In vivo evaluation of doxorubicin carried with long circulating and remote loading proliposome. , 2000, International journal of pharmaceutics.

[18]  D. Papahadjopoulos,et al.  Optimizing liposomes for delivery of chemotherapeutic agents to solid tumors. , 1999, Pharmacological reviews.

[19]  Qiang Zhang,et al.  Intracellular delivery of doxorubicin with RGD-modified sterically stabilized liposomes for an improved antitumor efficacy: in vitro and in vivo. , 2005, Journal of pharmaceutical sciences.

[20]  Y. Kawashima,et al.  Passive targeting of doxorubicin with polymer coated liposomes in tumor bearing rats. , 2001, Biological & pharmaceutical bulletin.

[21]  D Needham,et al.  Increased microvascular permeability contributes to preferential accumulation of Stealth liposomes in tumor tissue. , 1993, Cancer research.

[22]  H. Maeda,et al.  Conjugates of anticancer agents and polymers: advantages of macromolecular therapeutics in vivo. , 1992, Bioconjugate chemistry.

[23]  M. Stuart,et al.  Transmembrane gradient driven phase transitions within vesicles: lessons for drug delivery. , 1995, Biochimica et biophysica acta.

[24]  Y. Kawashima,et al.  Prolonged circulation time of doxorubicin-loaded liposomes coated with a modified polyvinyl alcohol after intravenous injection in rats. , 1999, European journal of pharmaceutics and biopharmaceutics : official journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V.

[25]  D. Letourneur,et al.  The stability of heparin-coated liposomes in plasma and their effect on its coagulation , 1998 .

[26]  P. Sinko,et al.  The effect of physical barriers and properties on the oral absorption of particulates. , 1998, Advanced drug delivery reviews.

[27]  Theresa M Allen,et al.  Drug release rate influences the pharmacokinetics, biodistribution, therapeutic activity, and toxicity of pegylated liposomal doxorubicin formulations in murine breast cancer. , 2004, Biochimica et biophysica acta.

[28]  Qiang Zhang,et al.  A pegylated liposomal platform: pharmacokinetics, pharmacodynamics, and toxicity in mice using doxorubicin as a model drug. , 2004, Journal of pharmacological sciences.

[29]  A. Gabizon,et al.  Sterically stabilized liposomes: improvements in pharmacokinetics and antitumor therapeutic efficacy. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[30]  M. Dewhirst,et al.  The development and testing of a new temperature-sensitive drug delivery system for the treatment of solid tumors. , 2001, Advanced drug delivery reviews.

[31]  A. Monji,et al.  Identification of a heparin binding site and the biological activities of the laminin α1 chain carboxy‐terminal globular domain , 1999, Journal of cellular physiology.