Drug delivery systems for treatment of infections
Lipid-based drug delivery vehicles (including liposomal nanoparticles) are described which include antibiotic(s) for the treatment of infections, such as Methicillin-Resistant Staphylococcus ( S .) aureus (MRSA) infections and Methicillin-Susceptible S. aureus (MSSA) infections. These drug delivery vehicles have high drug-loading, do not accumulate in the liver, and can optionally include one or more targeting ligands.
1 . A method of treating Staphylococcus ( S .) aureus infection in a subject in need thereof, comprising:
administering a therapeutically effective amount of a drug delivery system comprising vancomycin and cefazolin to the subject wherein the drug delivery system comprises a liposomal nanoparticle comprising:
a lipid component comprising:
a 1:0.5:0.07 ratio of hydro soy phosphatidylcholine (HSPC) to cholesterol to methoxyl polyethylene glycol (PEG)-ylated distearoyl-phosphatidyl-ethanolamine (DSPE-mPEG), or
a 1:0.05:0.007:0.007 ratio of HSPC to cholesterol to DSPE-mPEG to DSPE-PEG-Folate, or
a 1:0.5:0.07 ratio of N-(1-(2,3-dioleoyloxy) propyl)-N,N,N-trimethylammonium chloride (DOTAP) to cholesterol to DSPE-mPEG; and
wherein the liposomal nanoparticle encapsulates:
at least 10% vancomycin; and
cefazolin, and
wherein the nanoparticle comprises a 1:1 drug:lipid ratio,
thereby treating the S. aureus infection in the subject.
2 . The method of claim 1 , wherein the liposomal nanoparticle was made using a modified water in oil (reverse phase) evaporation method described herein.
3 . The method of claim 1 , wherein the S. aureus infection is a Methicillin-Resistant Staphylococcus aureus (MRSA) infection or a Methicillin-Susceptible S. aureus (MSSA) infection.
4 . The method of claim 1 , wherein the drug delivery system comprises a targeting ligand, wherein the targeting ligand is selected from a leucocyte targeting ligand, a fibroblast targeting ligand, a neutrophil targeting ligand, a lymphocyte targeting ligand, a targeting ligand specific to a bacterial cell, or a targeting ligand specific to the cell of a host cell associated with a bacterial cell.
5 . The method of claim 4 , wherein the targeting ligand is a folate receptor beta (FRβ), a toll-like receptor (TLR), a hyaluronan receptor, a T cell receptor (TCR) of immune cells, a protein A receptor on the surface of S. aureus , or an extracellular protein expressed by leukocytes.
6 . The method of claim 4 , wherein the drug delivery system comprises one or more of folic acid, methotrexate, aminopterin, an antibody, peptides for targeting folate receptor (FR), lipopeptides, lipoprotein, small oligonucleotide sequences for targeting toll-like receptor (TLR), hyaluronic acid (HA) for targeting cluster of differentiation (CD)44, linagliptin, and/or other xanthine scaffold for targeting fibroblast activation protein (FAP) of wound fibroblast cells.
7 . The method of claim 4 , wherein the leucocyte targeting ligand is folic acid or another folate receptor ligand.
8 . The method of claim 1 , wherein the drug delivery system comprises a carbonic anhydrase (CA) targeting ligand.
9 . The method of claim 8 , wherein the CA targeting ligand comprises imidazole, sulfoimidazole derivative, acetazolamide; methazolamide; ethoxzolamide; dichorophenamide; dorzolamide; brinzolamide; benzolamide; topiramate; zonisamide; sulpiride; indisulam; celecoxib; valdecoxib; antibody, or a peptide.
10 . The method of claim 8 , wherein the CA targeting ligand is acetazolamide.
11 . The method of claim 4 , wherein the targeting ligand, the vancomycin, and/or the cefazolin is chemically conjugated with lipid molecule(s) of the liposomes.
12 . The method of claim 1 , wherein the nanoparticle comprises at least 30% vancomycin.
13 . The method of claim 1 , wherein the nanoparticle is within a population of nanoparticles having a mean diameter of 192.9 nm, or having a mean diameter of 176.5 nm.
14 . The method of claim 5 , wherein the hyaluronan receptor is CD44.