Research in my group has been aimed at developing the use of “stealth” liposomes as targeted delivery vehicles, for the delivery of drugs, antigens and nucleic acids, for use as vaccines and/or therapeutic agents against infectious diseases and cancer.
Our work has shown that the chelator lipid 3(nitrilotriacetic acid)-ditetradecylamine (NTA3-DTDA) can be used to engraft onto stealth liposomes and membrane vesicles, histidine-tagged forms of recombinant targeting proteins by metal chelating linkage. Such engrafted liposomal membranes could potentially be used to deliver liposome-encapsulated agents to specific cells in vivo for therapeutic applications, including the development of novel vaccines. We have found that engrafted liposomal membranes containing encapsulated antigen and immunomodulatory factors can elicit marked immunological effects when targeted to dendritic cells (DCs) in vivo. For example, DC-targeted stealth liposomes encapsulating the model antigen ovalbumin (OVA), and tumour-derived modified plasma membrane vesicles, can induce dramatic anti-tumour responses when used as vaccines in a syngeneic tumour model. Immunisation with antigen-containing liposomal vaccines targeting dendritic cells can induce a strong CTL response, and elicit marked protection against tumour growth and metastasis, in mice subsequently challenged with the highly metastatic B16-OVA melanoma. Similarly, administration of the vaccine to mice after challenge with B16-OVA cells, induces a dramatic immunotherapeutic effect, promoting prolonged disease-free survival. The induction of effective immune responses was found to be dependent on the simultaneous delivery of both antigen and a dendritic cell maturation or “danger signal” such as interferon-γ and lipopolysaccharide. This suggests that the targeting of liposomal membranes in this way has potential for the development of tumour vaccines and immunotherapies.
Our current research goals are directed towards exploring whether the targeted stealth liposome technology we have developed can be used to effectively deliver nucleic acids (eg. DNA and siRNA) to specific cells in vivo, for the development of novel therapeutic/immunotherapeutic strategies for the treatment and prevention of cancer, as well as autoimmune and infectious diseases. |
Herringson TP, Patlolla, RR and Altin JG (2009) Targeting of plasmid DNA-lipoplexes to cells with molecules anchored via a metal chelator-lipid. Journal of Gene Medicine (In Press).
Faham A, Bennet D and Altin JG. (2009) Liposomal Ag engrafted with peptides of sequence derived from HMGB1 induce potent Ag-specific and anti-tumour immunity. Vaccine (In Press).
Herringson TP and Altin JG Convenient targeting of stealth siRNA-lipoplexes to cells with chelator lipid-anchored molecules. (2009)Journal of Controlled Release (In Press).
Hamzah J, Altin JG, Herringson T, Parish CR, Hammerling GJ, O'Donoghue H. and Ganss R. (2009) Targeted liposome delivery of TLR9 ligands activates spontaneous anti-tumour immunity in an autochthonous cancer model. Journal of Immunology (in Press).
Altin, J.G. and Parish, C.R. (2006) Liposomal vaccines - targeting the delivery of antigen. Methods (Science Direct) 40, 39-52.
Altin, J.G., Banwell, M.G., Coghlan, P.A., Easton, C.J., Nairn, M.R. and Offermann, D.A. (2006) Synthesis of NTA3-DTDA - A chelator-Lipid that Promotes Stable Binding of His-tagged Proteins to Membranes. Australian Journal of Chemistry 59, 302-306.
van Broekhoven, C.L. and Altin, J.G. (2005) The novel chelator lipid 3(nitrilotriacetic acid)-ditetradecylamine (3NTA-DTDA) promotes stable binding of His-tagged proteins to liposomal membranes: potent anti-tumour responses induced by simultaneously targeting antigen, cytokine and costimulatory signals to T cells. Biochimica et Biophysica Acta 1716, 104-116.
Altin, J.G., van Broekhoven, C.L. and Parish, C.R. (2004) Targeting
dendritic cells with antigen-containing liposomes:antitumour immunity. Expert Opinion in Biological Therapy, 4 (11): 1735-47.
Jones, A.L., Hulett, M.D., Altin, J.G., Hogg, P. and Parish, C.R. (2004)
Plasminogen is tethered with high affinity to the cell surface by the
plasma protein, histidine-rich glycoprotein. Journal of Biological
Chemistry, 279: 38267-38276.
van Broekhoven, C.L., Parish, C.R., Demangel, C., Britton, W.J. and
Altin, J.G. (2004) Targeting dendritic cells with antigen-containing
liposomes: a highly effective procedure for induction of anti-tumor
immunity and for tumor immunotherapy. Cancer Research, 64,
4357-4365. (Cover feature and research paper).
vanBroekhoven, C.L. and Altin, J.G. (2002) a novel approach for modifying
tumour cell-derived plasma membrane vesicles to contain encapsulated
IL-2 and egrafted contimulatory molecules for use in tumour immunotherapy. International Journal of Cancer 98: 63-72.
van Broekhoven, C.L. and Altin, J.G. (2001) A novel system for convenient
detection of low-affinity receptor-ligand interaction: chelator-lipid
liposomes engrafted with recombinant CD4 bind to cells expressing MHC
class II. Immunology and Cell Biology 79: 274-284.
Altin, J.G., White, F.A.J. and Easton, C.J. (2001) Synthesis of the
chelator lipid nitrilo-triacetic acid ditretradecylamine (NTA-DTDA)
and its use with the IAsys biosensor to study receptor-ligand interactions
on model membranes. Biochimica et Biophysica Acta 1513: 131-148.
van Broekhoven, C.L., Parish, C.R., Vassiliour, G. and Altin, J.G.
(2000). Engrafting Costimulator Molecules onto Tumor Cell Surfaces with
Chelator Lipids: A Potentially Convenient Approach in Cancer Vaccine
Development. Journal of Immunology 2000, 164: 2433-2443. |
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