Long-Circulating Polymer-Modified Liposomes

Summary

Principal Investigator: Vladimir Torchilin
Affiliation: Northeastern University
Country: USA
Abstract: Long-circulating liposomes coated with amphiphilic derivatives of certain soluble polymers have high potential as drug carriers. They increase the duration of drug action, decrease toxicity of various drugs, and are able to accumulate non-specifically in tissues with leaky vasculature (infarcts and tumors). Targeted long- circulating liposomes can be made by simultaneous attachment of specific ligands (monoclonal antibodies) onto their surface or directly only distal termini of liposome-grafted protecting polymers. We have designed a set of polymers to be used as liposome steric protectors and developed a simple and fast method for the attachment of specific ligands, including monoclonal antibodies, to distal termini of polymeric chains via p- nitrophenylcarbonyl (pNP) group. Such sterically-protected targeted liposomes demonstrated superior properties including target accumulation compared with plain liposomes, immunoliposomes or long-circulating liposomes both in vitro and in vivo. We hypothesize that: i. Drug-loaded long-circulating targeted liposomes can provided higher therapeutic effects compared with other liposome-based drug delivery systems; ii. Experimental myocardial infarction and tumors represent convenient models for studies with drug-loaded long- circulating immunoliposomes; iii. Long-circulating infarct- specific anti-myosin immunoliposomes loaded with ATP or coenzyme Q10 can diminish heart damage upon induced ischemia in vitro and in vivo; iv. Long-circulating tumor-specific anti-nucleosome immunoliposomes loaded with doxorubicin can enhance tumor cell killing in vivo. The use of new general approaches a new polymers for the preparation of polymer- modified long-circulating (targeted) liposomes may increase the potential of liposomes as drug carriers as well as the therapeutic efficacy of liposome-entrapped drugs. To test our hypothesis, we plan: (1) To prepare a set of long- circulating immunoliposomes coated with protecting polymers and antimyosin or anti-nucleosome antibody attached to distal end of the liposome surface-grafted polymer via p-NP- group, and load liposomes with ATP or coenzyme Q10 (for infarct-related experiments) and with doxorubicin (for a few cancer-related experiments); (2) To study the ability of long-circulating anti-myosin immunoliposomes to deliver ATP or coenzyme Q10 to affected areas and decrease damage to the heart in a model of ischemia in perfused isolated rat and rabbit heart in vitro and in a model of experimental myocardial infarction in rabbits in vivo; (3) To study the ability of long-circulating anti-nucleosome liposomes to deliver higher quantities of anticancer drug doxorubicin to cancer cells and increase the level of cell death in growing murine tumor in C57BL mice and human tumor in nude mice. This study could bring to life new liposomal drugs with controlled in vivo stability and biodistribution. Specifically, liposomal drugs can be prepared for the treatment of the consequences of myocardial ischemia and for the inhibition of tumor growth.
Funding Period: 1997-04-01 - 2005-06-30
more information: NIH RePORT

Top Publications

  1. ncbi ATP-loaded liposomes effectively protect mechanical functions of the myocardium from global ischemia in an isolated rat heart model
    D D Verma
    Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA
    J Control Release 108:460-71. 2005
  2. ncbi TAT peptide-modified liposomes provide enhanced gene delivery to intracranial human brain tumor xenografts in nude mice
    Bhawna Gupta
    Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    Oncol Res 16:351-9. 2007
  3. ncbi New ways of imaging uptake and intracellular fate of liposomal drug carrier systems inside individual cells, based on Raman microscopy
    Christian Matthäus
    Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massacusetts 02115, USA
    Mol Pharm 5:287-93. 2008
  4. ncbi Tumor-specific antibody-mediated targeted delivery of Doxil reduces the manifestation of auricular erythema side effect in mice
    Tamer A Elbayoumi
    Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    Int J Pharm 357:272-9. 2008
  5. ncbi Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery
    Vladimir P Torchilin
    Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115
    Biopolymers 90:604-10. 2008
  6. ncbi Prostate cancer-specific monoclonal antibody 5D4 significantly enhances the cytotoxicity of doxorubicin-loaded liposomes against target cells in vitro
    Rishikesh M Sawant
    Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    J Drug Target 16:601-4. 2008
  7. ncbi Gene delivery into ischemic myocardium by double-targeted lipoplexes with anti-myosin antibody and TAT peptide
    Y T Ko
    Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    Gene Ther 16:52-9. 2009
  8. ncbi Self-assembling micelle-like nanoparticles based on phospholipid-polyethyleneimine conjugates for systemic gene delivery
    Young Tag Ko
    Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    J Control Release 133:132-8. 2009
  9. ncbi Tumor-specific anti-nucleosome antibody improves therapeutic efficacy of doxorubicin-loaded long-circulating liposomes against primary and metastatic tumor in mice
    Tamer A Elbayoumi
    Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, USA
    Mol Pharm 6:246-54. 2009
  10. ncbi Tumor-targeted nanomedicines: enhanced antitumor efficacy in vivo of doxorubicin-loaded, long-circulating liposomes modified with cancer-specific monoclonal antibody
    Tamer A Elbayoumi
    R and D Formulation Vascular Systems, Atrium Medical Corporation, Hudson, New Hampshire, USA
    Clin Cancer Res 15:1973-80. 2009

Scientific Experts

  • Vladimir Torchilin
  • Tamer A Elbayoumi
  • Amit A Kale
  • Bhawna Gupta
  • Daya D Verma
  • William C Hartner
  • Y T Ko
  • Young Tag Ko
  • Amit Kale
  • Rishikesh M Sawant
  • Christian Matthäus
  • A Kale
  • Tatyana S Levchenko
  • R M Sawant
  • Tatiana S Levchenko
  • T S Levchenko
  • Eugene A Bernstein
  • D D Verma
  • Brigitte Papahadjopoulos-Sternberg
  • W C Hartner
  • Tatyana Chernenko
  • Michael B Cohen
  • Max Diem
  • Oskar W Rokhlin
  • Vineet Thakkar
  • S Salmaso
  • J P Hurley
  • Dmitriy Mongayt
  • E Tolcheva
  • Tatayana S Levchenko
  • E A Bernstein
  • Dmitry A Mongayt

Detail Information

Publications22

  1. ncbi ATP-loaded liposomes effectively protect mechanical functions of the myocardium from global ischemia in an isolated rat heart model
    D D Verma
    Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA
    J Control Release 108:460-71. 2005
    ..Our results suggest that ATP-L can effectively protect myocardium from ischemic/reperfusion damage...
  2. ncbi TAT peptide-modified liposomes provide enhanced gene delivery to intracranial human brain tumor xenografts in nude mice
    Bhawna Gupta
    Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    Oncol Res 16:351-9. 2007
    ..No transfection (green fluorescence of the GFP) was noted in the normal brain adjacent to tumor...
  3. ncbi New ways of imaging uptake and intracellular fate of liposomal drug carrier systems inside individual cells, based on Raman microscopy
    Christian Matthäus
    Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massacusetts 02115, USA
    Mol Pharm 5:287-93. 2008
    ..Depending on the experimental setup, the technique may be applied to fixed or living cell organisms...
  4. ncbi Tumor-specific antibody-mediated targeted delivery of Doxil reduces the manifestation of auricular erythema side effect in mice
    Tamer A Elbayoumi
    Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    Int J Pharm 357:272-9. 2008
    ..Thus, targeting of Doxil with the anti-cancer mAb 2C5 not only can increase the tumor-specific accumulation of the drug, but also diminishes the cutaneous side effect of the original Doxil therapy...
  5. ncbi Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery
    Vladimir P Torchilin
    Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115
    Biopolymers 90:604-10. 2008
    ....
  6. ncbi Prostate cancer-specific monoclonal antibody 5D4 significantly enhances the cytotoxicity of doxorubicin-loaded liposomes against target cells in vitro
    Rishikesh M Sawant
    Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    J Drug Target 16:601-4. 2008
    ....
  7. ncbi Gene delivery into ischemic myocardium by double-targeted lipoplexes with anti-myosin antibody and TAT peptide
    Y T Ko
    Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    Gene Ther 16:52-9. 2009
    ..Such complexes also demonstrate an increased accumulation in the ischemic myocardium and effective transfection of hypoxic cardiomyocytes in vivo...
  8. ncbi Self-assembling micelle-like nanoparticles based on phospholipid-polyethyleneimine conjugates for systemic gene delivery
    Young Tag Ko
    Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    J Control Release 133:132-8. 2009
    ..Intravenous injection of MNP loaded with plasmid DNA encoding for the Green Fluorescence Protein (GFP) resulted in an effective transfection of a distal tumor. Thus, MNP provide a promising tool for systemic gene therapy...
  9. ncbi Tumor-specific anti-nucleosome antibody improves therapeutic efficacy of doxorubicin-loaded long-circulating liposomes against primary and metastatic tumor in mice
    Tamer A Elbayoumi
    Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, USA
    Mol Pharm 6:246-54. 2009
    ..Our results clearly show the remarkable capability of 2C5-targeted Doxil to specifically deliver its cargo into various tumor manifestations (solid and metastatic) significantly increasing the efficacy of therapy...
  10. ncbi Tumor-targeted nanomedicines: enhanced antitumor efficacy in vivo of doxorubicin-loaded, long-circulating liposomes modified with cancer-specific monoclonal antibody
    Tamer A Elbayoumi
    R and D Formulation Vascular Systems, Atrium Medical Corporation, Hudson, New Hampshire, USA
    Clin Cancer Res 15:1973-80. 2009
    ..Following earlier in vitro results with various cancer cell lines, the mAb 2C5 liposomes were studied in vivo versus plain and nonspecific-IgG liposomes...
  11. ncbi Enhanced cytotoxicity of monoclonal anticancer antibody 2C5-modified doxorubicin-loaded PEGylated liposomes against various tumor cell lines
    Tamer A Elbayoumi
    Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
    Eur J Pharm Sci 32:159-68. 2007
    ..The IC50 values of mAb 2C5-Doxil with various murine and human cancer cells were 5-8-fold lower than those of control doxorubicin-loaded liposomes, Doxil or Doxil modified with a nonspecific IgG...
  12. ncbi Enhanced transfection of tumor cells in vivo using "Smart" pH-sensitive TAT-modified pegylated liposomes
    Amit A Kale
    Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    J Drug Target 15:538-45. 2007
    ..This result can be considered as an important step in the development of tumor-specific stimuli-sensitive drug and gene delivery systems...
  13. ncbi ATP-loaded liposomes effectively protect the myocardium in rabbits with an acute experimental myocardial infarction
    Daya D Verma
    Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, USA
    Pharm Res 22:2115-20. 2005
    ..ATP-L may provide an effective exogenous source of the ATP in vivo to protect ischemically damaged cells...
  14. ncbi Monoclonal antibody 2C5-mediated binding of liposomes to brain tumor cells in vitro and in subcutaneous tumor model in vivo
    Bhawna Gupta
    Northeastern University, Department of Pharmaceutical Sciences, Bouve College of Health Sciences, Boston, MA 02115, USA
    J Drug Target 13:337-43. 2005
    ..mAb 2C5 specifically recognizes brain tumor cells and can serve as a ligand to target drug carriers such as liposomes to brain tumor cells in vivo...
  15. ncbi "SMART" drug delivery systems: double-targeted pH-responsive pharmaceutical nanocarriers
    R M Sawant
    Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, USA
    Bioconjug Chem 17:943-9. 2006
    ..We consider this result as the first step in the development of multifunctional stimuli-sensitive pharmaceutical nanocarriers...
  16. ncbi ATP-loaded immunoliposomes specific for cardiac myosin provide improved protection of the mechanical functions of myocardium from global ischemia in an isolated rat heart model
    Daya D Verma
    Department of Pharmaceutical Sciences, Bouve College of Health Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, USA
    J Drug Target 14:273-80. 2006
    ..The extent of preservation depended on the amount of the antibody present on the surface of the ATP-IL...
  17. ncbi Monoclonal antibody 2C5-modified doxorubicin-loaded liposomes with significantly enhanced therapeutic activity against intracranial human brain U-87 MG tumor xenografts in nude mice
    Bhawna Gupta
    Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    Cancer Immunol Immunother 56:1215-23. 2007
    ..Thus, monoclonal antibody 2C5-modified LCL can specifically target the anticancer drugs to brain tumors, leading to improved therapeutic treatment of brain tumor in an intracranial model, in vivo...
  18. ncbi Design, synthesis, and characterization of pH-sensitive PEG-PE conjugates for stimuli-sensitive pharmaceutical nanocarriers: the effect of substitutes at the hydrazone linkage on the ph stability of PEG-PE conjugates
    Amit A Kale
    Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts 02115, USA
    Bioconjug Chem 18:363-70. 2007
    ....
  19. ncbi Antinucleosome antibody-modified liposomes and lipid-core micelles for tumor-targeted delivery of therapeutic and diagnostic agents
    Tamer A Elbayoumi
    Department of Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
    J Liposome Res 17:1-14. 2007
    ..Pharmaceutical lipid-based nanoparticular carriers modified with mAb 2C5 could represent universal systems for tumor-specific delivery of various soluble and insoluble pharmaceuticals...
  20. ncbi Tatp-mediated intracellular delivery of pharmaceutical nanocarriers
    V P Torchilin
    Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115, USA
    Biochem Soc Trans 35:816-20. 2007
    ....
  21. ncbi Protective effect of coenzyme Q10-loaded liposomes on the myocardium in rabbits with an acute experimental myocardial infarction
    Daya D Verma
    Center for Pharmaceutical Biotechnology and Nanomedicine, Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, USA
    Pharm Res 24:2131-7. 2007
    ....
  22. ncbi Environment-responsive multifunctional liposomes
    Amit A Kale
    Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA
    Methods Mol Biol 605:213-42. 2010
    ..These results can be considered as an important step in the development of tumor-specific stimuli-sensitive drug and gene delivery systems...