The goal of this project is to develop a target specific drug delivery system to cells which have been infected with Human Immunodeficiency Virus. The specific delivery vehicles to be used in the project are immunoliposomes which contain covalently conjugated monoclonal antibody to specific antigenic sites on the surface of the infected cells. As an initial step, we will use two animal models to evaluate our approach. The first is T- lymphocytes which have been infected in vitro by recombinant murine leukemia virus containing the Herpes Simplex Virus glycoprotein gD gene. Since the virus will be so constructed that it is infectious but not replication competent, HSV-gD will be constitutively expressed on the surface of the infected T-cells. These cells will be injected inot syngenic mice to serve as a target for immunoliposomes containing anti-HSV-gD. Elimination of these cells in the circulation by cytotoxic drugs (such as ara C) encapsulated in the immunoliposomes is expected. Another animal model is cats which have been persistently infected with the Feline Leukemia Virus. Immunoliposomes containing anti- FLV-gp70 will be used to target cytotoxic or antiviral drugs to the infected cells. Two types of immunoliposomes will be used: the pH-sensitive immunoliposome which effectively delivers drugs to the cytoplasm of the target cells via the endocytosis pathway, and the target-sensitive immunoliposome which spontaneously releases drugs at the target cell surface. Liposome targeting and drug delivery will be studied first in vitro to obtain optimal conditions for liposome stability, drug entrapment, binding to cells, drug delivery and cell killing. Extensive animal work will then follow.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI025834-02
Application #
3139503
Study Section
(SRC)
Project Start
1987-09-30
Project End
1990-08-31
Budget Start
1988-09-01
Budget End
1989-08-31
Support Year
2
Fiscal Year
1988
Total Cost
Indirect Cost
Name
University of Tennessee Knoxville
Department
Type
Schools of Arts and Sciences
DUNS #
City
Knoxville
State
TN
Country
United States
Zip Code
37996
Park, Y S; Huang, L (1992) Cryoprotective activity of synthetic glycophospholipids and their interactions with trehalose. Biochim Biophys Acta 1124:241-8
Litzinger, D C; Huang, L (1992) Phosphatidylethanolamine liposomes: drug delivery, gene transfer and immunodiagnostic applications. Biochim Biophys Acta 1113:201-27
Wright, S E; Huang, L (1992) Bilayer stabilization of phosphatidylethanolamine by N-biotinylphosphatidylethanolamine. Biochim Biophys Acta 1103:172-8
Klibanov, A L; Maruyama, K; Beckerleg, A M et al. (1991) Activity of amphipathic poly(ethylene glycol) 5000 to prolong the circulation time of liposomes depends on the liposome size and is unfavorable for immunoliposome binding to target. Biochim Biophys Acta 1062:142-8
Maruyama, K; Kennel, S J; Huang, L (1990) Lipid composition is important for highly efficient target binding and retention of immunoliposomes. Proc Natl Acad Sci U S A 87:5744-8
Liu, D; Huang, L; Moore, M A et al. (1990) Interactions of serum proteins with small unilamellar liposomes composed of dioleoylphosphatidylethanolamine and oleic acid: high-density lipoprotein, apolipoprotein A1, and amphipathic peptides stabilize liposomes. Biochemistry 29:3637-43
Klibanov, A L; Maruyama, K; Torchilin, V P et al. (1990) Amphipathic polyethyleneglycols effectively prolong the circulation time of liposomes. FEBS Lett 268:235-7
Collins, D; Litzinger, D C; Huang, L (1990) Structural and functional comparisons of pH-sensitive liposomes composed of phosphatidylethanolamine and three different diacylsuccinylglycerols. Biochim Biophys Acta 1025:234-42
Liu, D; Huang, L (1990) pH-sensitive, plasma-stable liposomes with relatively prolonged residence in circulation. Biochim Biophys Acta 1022:348-54
Tari, A; Huang, L (1989) Structure and function relationship of phosphatidylglycerol in the stabilization of the phosphatidylethanolamine bilayer. Biochemistry 28:7708-12

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