Self-assembling nanoparticle drug delivery system

Abstract

A self-assembling nanoparticle drug delivery system for the delivery of drugs including peptides, proteins, nucleic acids or synthetic chemical drugs is provided. The self-assembling nanoparticle drug delivery system described herein includes viral capsid proteins, such as Hepatitis B Virus core protein, encapsulating the drug, a lipid bi-layer envelope and targeting or facilitating molecules anchored in the lipid bilayer. A method for construction of the self-assembling nanoparticle drug delivery system is also provided.

We claim: 
     
         1 . A self-assembling nanoparticle drug delivery system comprising:
 a capsid comprised of viral capsid proteins;   a drug captured in said capsid; and   a lipid bi-layer enveloping said capsid.   
     
     
         2 . The self-assembling nanoparticle drug delivery system of  claim 1  wherein said viral capsid protein is Hepatitis B Virus (HBV) core protein. 
     
     
         3 . The self-assembling nanoparticle drug delivery system of  claim 1  wherein said HBV core protein has the amino acid sequence of SEQ ID NO. 1 or SEQ ID NO. 2. 
     
     
         4 . The self-assembling nanoparticle drug delivery system of  claim 1  wherein said viral capsid protein is mutated. 
     
     
         5 . The self-assembling nanoparticle drug delivery system of  claim 4  wherein said viral capsid protein includes a protease recognition site replacing amino acids 79 and 80 of said HBV core protein. 
     
     
         6 . The self-assembling nanoparticle drug delivery system of  claim 5  wherein said protease recognition site is a thrombin recognition site or a factor Xa recognition site. 
     
     
         7 . The self-assembling nanoparticle drug delivery system of  claim 4  wherein said HBV core protein is mutated such that at least one amino acid of SEQ ID NO. 1 or SEQ ID NO. 2 selected from the group consisting of phenylalanine 23, aspartic acid 29, threonine 33, leucine 37, valine 120, valine 124, arginine 127 and tyrosine 132 is changed to a cysteine. 
     
     
         8 . The self-assembling nanoparticle drug delivery system of  claim 1  wherein said drug is selected from the group consisting of peptides, proteins, nucleic acids and small molecule synthetic chemical drugs. 
     
     
         9 . The self-assembling nanoparticle drug delivery system of  claim 1  wherein said lipid bi-layer is comprised of phospholipids. 
     
     
         10 . The self-assembling nanoparticle drug delivery system of  claim 9  wherein said phospholipid is phosphotidyl ethanolamine. 
     
     
         11 . The self-assembling nanoparticle drug delivery system of  claim 1  further comprising either or both of cholesterol-tagged polyethylene glycol and cholesterol-tagged protein transduction domains. 
     
     
         12 . The self-assembling nanoparticle drug delivery system of  claim 11  wherein said protein transduction domains comprises the Human Immunodeficiency Virus transactivator of transcription or poly-arginine. 
     
     
         13 . The self-assembling nanoparticle drug delivery system of  claim 1  further comprising an antibody targeting molecule. 
     
     
         14 . A method for constructing a self-assembling nanoparticle drug delivery system comprising:
 mixing a drug with HBV core protein to form a cage solution;   encapsulating said drug in the core protein cage by raising the ionic strength of said cage solution;   adding phospholipids to said cage solution;   adding cholesterol-tagged polyethylene glycol to said cage solution;   adding cholesterol-tagged protein transduction domain to said cage solution;   purifying said nanoparticles by centrifugation or size exclusion chromatography.   
     
     
         15 . The method of  claim 14  wherein said drug is selected from the group consisting of peptides, proteins, nucleic acids and small molecule synthetic chemical drugs. 
     
     
         16 . The method of  claim 14  wherein said HBV core protein includes a protease recognition site replacing amino acids 79 and 80 of said HBV core protein. 
     
     
         17 . The method of  claim 16  wherein said protease recognition site is a thrombin recognition site or a factor Xa recognition site. 
     
     
         18 . The method of  claim 14  wherein said HBV core protein is mutated such that at least one amino acid of SEQ ID NO. 1 or SEQ ID NO. 2 selected from the group consisting of phenylalanine 23, aspartic acid 29, threonine 33, leucine 37, valine 120, valine 124, arginine 127 and tyrosine 132 is changed to a cysteine. 
     
     
         19 . The method of  claim 14  further comprising the step of adding an envelopment guiding protein or peptide after said encapsulating step. 
     
     
         20 . The method of  claim 19  wherein said envelopment guiding protein is Hepatitis B Virus S-protein or the transmembrane engineered peptide of SEQ ID NO. 5. 
     
     
         21 . The method of  claim 14  wherein said phospholipid is phophatidyl ethanolamine. 
     
     
         22 . The method of  claim 14  wherein said protein transduction domain comprises the Human Immunodeficiency Virus transactivator of transcription or poly-arginine. 
     
     
         23 . The method of  claim 14  further comprising the step of inserting targeting antibodies into said lipid bi-layer. 
     
     
         24 . A method of treating disease with a self-assembling nanoparticle drug delivery system comprising delivering said nanoparticles across a mucosal surface.