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Genomes and GenesSpecies | Long-Circulating Polymer-Modified LiposomesSummaryPrincipal 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
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ATP-loaded liposomes effectively protect mechanical functions of the myocardium from global ischemia in an isolated rat heart modelD 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...
TAT peptide-modified liposomes provide enhanced gene delivery to intracranial human brain tumor xenografts in nude miceBhawna 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...- New ways of imaging uptake and intracellular fate of liposomal drug carrier systems inside individual cells, based on Raman microscopyChristian 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... - Tumor-specific antibody-mediated targeted delivery of Doxil reduces the manifestation of auricular erythema side effect in miceTamer 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... 
Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene deliveryVladimir P Torchilin
Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA 02115
Biopolymers 90:604-10. 2008....- Prostate cancer-specific monoclonal antibody 5D4 significantly enhances the cytotoxicity of doxorubicin-loaded liposomes against target cells in vitroRishikesh 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.... - Gene delivery into ischemic myocardium by double-targeted lipoplexes with anti-myosin antibody and TAT peptideY 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... - Self-assembling micelle-like nanoparticles based on phospholipid-polyethyleneimine conjugates for systemic gene deliveryYoung 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... - Tumor-specific anti-nucleosome antibody improves therapeutic efficacy of doxorubicin-loaded long-circulating liposomes against primary and metastatic tumor in miceTamer 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... - Tumor-targeted nanomedicines: enhanced antitumor efficacy in vivo of doxorubicin-loaded, long-circulating liposomes modified with cancer-specific monoclonal antibodyTamer 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... - Enhanced cytotoxicity of monoclonal anticancer antibody 2C5-modified doxorubicin-loaded PEGylated liposomes against various tumor cell linesTamer 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... - Enhanced transfection of tumor cells in vivo using "Smart" pH-sensitive TAT-modified pegylated liposomesAmit 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... - ATP-loaded liposomes effectively protect the myocardium in rabbits with an acute experimental myocardial infarctionDaya 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... - Monoclonal antibody 2C5-mediated binding of liposomes to brain tumor cells in vitro and in subcutaneous tumor model in vivoBhawna 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... - "SMART" drug delivery systems: double-targeted pH-responsive pharmaceutical nanocarriersR 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... - ATP-loaded immunoliposomes specific for cardiac myosin provide improved protection of the mechanical functions of myocardium from global ischemia in an isolated rat heart modelDaya 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... - Monoclonal antibody 2C5-modified doxorubicin-loaded liposomes with significantly enhanced therapeutic activity against intracranial human brain U-87 MG tumor xenografts in nude miceBhawna 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... - 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 conjugatesAmit 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.... - Antinucleosome antibody-modified liposomes and lipid-core micelles for tumor-targeted delivery of therapeutic and diagnostic agentsTamer 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... - Tatp-mediated intracellular delivery of pharmaceutical nanocarriersV 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.... - Protective effect of coenzyme Q10-loaded liposomes on the myocardium in rabbits with an acute experimental myocardial infarctionDaya 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.... - Environment-responsive multifunctional liposomesAmit 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...