Stealth® liposomes: from theory to product

Abstract The development of an effective anti-cancer liposomal formulation — doxorubicin in sterically stabilized liposomes — will be discussed. We shall argue that for many tumors the necessary condition for an effective anti-cancer activity of systemically administered liposomal doxorubicin formulation is the long circulation life of liposomes in blood and stable drug encapsulation. Theoretical basis for stabilization of liposomes in biological environments and for the stabilization of drug encapsulation will be shown. When a formulation with acceptable stability was obtained it was tested in pre-clinical models and simultaneously scaled-up and it entered into clinical studies. After successfully passing all these tests, doxorubicin in sterically stabilized liposomes (Doxil ™ by Sequus Pharmaceuticals, Inc., Menlo Park, CA) was approved by Food and Drug Administration and is commercially available since late 1995.

[1]  G. J. Fleer,et al.  Polymers at Interfaces , 1993 .

[2]  G. Storm,et al.  Specific targeting with poly(ethylene glycol)-modified liposomes: coupling of homing devices to the ends of the polymeric chains combines effective target binding with long circulation times. , 1993, Biochimica et biophysica acta.

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

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

[5]  J. Cohen,et al.  Sterically stabilized liposomes: physical and biological properties. , 1994, Journal of drug targeting.

[6]  Reinhard Lipowsky,et al.  Structure and dynamics of membranes , 1995 .

[7]  Samuel Zalipsky,et al.  Liposomes with detachable polymer coating: destabilization and fusion of dioleoylphosphatidylethanolamine vesicles triggered by cleavage of surface‐grafted poly(ethylene glycol) , 1996, FEBS letters.

[8]  F M Muggia,et al.  Liposomal doxorubicin: antitumor activity and unique toxicities during two complementary phase I studies. , 1995, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  D. Tirrell,et al.  Polyelectrolyte-sensitized phospholipid vesicles , 1992 .

[10]  A. Gabizon,et al.  Sterically stabilized liposomes: a hypothesis on the molecular origin of the extended circulation times. , 1991, Biochimica et biophysica acta.

[11]  V. Torchilin,et al.  Amphiphilic vinyl polymers effectively prolong liposome circulation time in vivo. , 1994, Biochimica et biophysica acta.

[12]  D. Leckband,et al.  Modulation of interaction forces between bilayers exposing short-chained ethylene oxide headgroups. , 1994, Biophysical journal.

[13]  D. Brooks,et al.  Interfacial thickness of liposomes containing poly(ethylene glycol)-cholesterol from electrophoresis. , 1996, Biophysical journal.

[14]  E. Sackmann,et al.  Conformational Transitions of Mixed Monolayers of Phospholipids and Poly(ethylene oxide) Lipopolymers and Interaction Forces with Solid Surfaces , 1995 .

[15]  F. Martin,et al.  Sterically stabilized liposomes. Reduction in electrophoretic mobility but not electrostatic surface potential. , 1992, Biophysical journal.

[16]  J. Silvius,et al.  Interbilayer transfer of phospholipid-anchored macromolecules via monomer diffusion. , 1993, Biochemistry.

[17]  D. Lasič,et al.  Liposomes: From Physics to Applications , 1993 .

[18]  F. Frézard.  Fluorometric determination in biological fluids of the release kinetics of liposome-entrapped doxorubicin , 1994 .

[19]  Léger,et al.  Characterization of the brush regime for grafted polymer layers at the solid-liquid interface. , 1991, Physical review letters.

[20]  K. Hristova,et al.  Effect of Bilayer Composition on the Phase Behavior of Liposomal Suspensions Containing Poly(ethylene glycol)-Lipids , 1995 .

[21]  G. Gregoriadis,et al.  The phospholipid component of small unilamellar liposomes controls the rate of clearance of entrapped solutes from the circulation , 1980, FEBS letters.

[22]  H. Ohshima,et al.  Determination of the thickness of the fixed aqueous layer around polyethyleneglycol-coated liposomes. , 1995, Journal of drug targeting.

[23]  E. Moase,et al.  Attachment of antibodies to sterically stabilized liposomes: evaluation, comparison and optimization of coupling procedures. , 1995, Biochimica et biophysica acta.

[24]  A. Henderson‐sellers,et al.  Cloud Feedback: A Stabilizing Effect for the Early Earth? , 1982, Science.

[25]  T. Allen,et al.  Insertion of poly(ethylene glycol) derivatized phospholipid into pre‐formed liposomes results in prolonged in vivo circulation time , 1996, FEBS letters.

[26]  John W. Park,et al.  Development of anti-p185HER2 immunoliposomes for cancer therapy. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[27]  M. Woodle,et al.  New amphipatic polymer-lipid conjugates forming long-circulating reticuloendothelial system-evading liposomes. , 1994, Bioconjugate chemistry.

[28]  D. Lasič.  Sterically Stabilized Vesicles , 1994 .

[29]  D. Lasič,et al.  Doxorubicin in sterically stabilized liposomes , 1996, Nature.

[30]  R. Benz,et al.  Surface Potential of Lipid Monolayers with Grafted Polyethylene Glycols , 1994 .

[31]  Y. Barenholz,et al.  Gelation of liposome interior A novel method for drug encapsulation , 1992, FEBS letters.

[32]  D. Papahadjopoulos,et al.  Permeability properties of phospholipid membranes: effect of cholesterol and temperature. , 1972, Biochimica et biophysica acta.

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

[34]  M. Newman,et al.  Pharmacokinetics, Biodistribution and Therapeutic Efficacy of Doxorubicin Encapsulated in Stealth® Liposomes (Doxil®) , 1994 .

[35]  N. Oku,et al.  Long-circulating liposomes. , 1994, Critical reviews in therapeutic drug carrier systems.

[36]  F. Martin,et al.  Pharmacokinetics and therapeutics of sterically stabilized liposomes in mice bearing C-26 colon carcinoma. , 1992, Cancer research.

[37]  D Needham,et al.  Repulsive interactions and mechanical stability of polymer-grafted lipid membranes. , 1992, Biochimica et biophysica acta.

[38]  F. Szoka,et al.  Mechanism of leakage of phospholipid vesicle contents induced by the peptide GALA. , 1990, Biochemistry.

[39]  M. Winterhalter,et al.  Polymer induced fusion and leakage of small unilamellar phospholipid vesicles: effect of surface grafted polyethylene-glycol in the presence of free PEG , 1997 .

[40]  L. Huang,et al.  Targetability of novel immunoliposomes modified with amphipathic poly(ethylene glycol)s conjugated at their distal terminals to monoclonal antibodies. , 1995, Biochimica et biophysica acta.

[41]  D. Lasič,et al.  Therapy of primary and metastatic mouse mammary carcinomas with doxorubicin encapsulated in long circulating liposomes , 1992, International journal of cancer.

[42]  F. Martin,et al.  Pharmacokinetics and antitumor activity of epirubicin encapsulated in long‐circulating liposomes incorporating a polyethylene glycol‐derivatized phospholipid , 1992, International journal of cancer.

[43]  P. Vierling,et al.  Fluorinated phosphatidylcholine-based liposomes: H+/Na+ permeability, active doxorubicin encapsulation and stability, in human serum. , 1994, Biochimica et biophysica acta.

[44]  M. Dewhirst,et al.  Polymer-Grafted Liposomes: Physical Basis for the “Stealth” Property , 1992 .

[45]  P. G. de Gennes,et al.  Polymers at an interface; a simplified view , 1987 .

[46]  T. McIntosh,et al.  Structure and phase behavior of lipid suspensions containing phospholipids with covalently attached poly(ethylene glycol). , 1995, Biophysical journal.

[47]  D. Needham,et al.  The "Stealth" Liposome: A Prototypical Biomaterial , 1995 .

[48]  Joseph D. Andrade,et al.  Protein—surface interactions in the presence of polyethylene oxide , 1991 .

[49]  D. Papahadjopoulos,et al.  Liposomes and biopolymers in drug and gene delivery , 1996 .

[50]  R. Benz,et al.  Electric field-induced breakdown in lipid membranes , 1995 .

[51]  R. Benz,et al.  Interaction of poly(ethylene-glycols) with air-water interfaces and lipid monolayers: investigations on surface pressure and surface potential. , 1995, Biophysical journal.

[52]  A A Bogdanov,et al.  Poly(ethylene glycol) on the liposome surface: on the mechanism of polymer-coated liposome longevity. , 1994, Biochimica et biophysica acta.

[53]  Y. Barenholz,et al.  Ammonium Sulfate Gradients for Efficient and Stable Remote Loading of Amphipathic Weak Bases into Liposomes and Ligandoliposomes. , 1994 .

[54]  D. Needham,et al.  Range and magnitude of the steric pressure between bilayers containing phospholipids with covalently attached poly(ethylene glycol). , 1995, Biophysical journal.

[55]  D. Papahadjopoulos.  Surface properties of acidic phospholipids: interaction of monolayers and hydrated liquid crystals with uni- and bi-valent metal ions. , 1968, Biochimica et biophysica acta.