Lipid-coated particles for treating viral infections

Abstract

The present invention relates to lipid-coated particles for treating viral infections, including viral encephalitis infections. In particular, an antiviral compound can be disposed within the lipid-coated particle, thereby providing an antiviral carrier. Methods of making and using such carriers are described herein.

1 . A method of reducing brain viral load within a subject, the method comprising:
 administering an effective amount of a lipid-coated particle to the subject, wherein the lipid-coated particle comprises a porous core and an antiviral compound disposed within at least one pore of the porous core.   
     
     
         2 . The method of  claim 1 , wherein the antiviral compound has an aqueous solubility of from about 20 μg/mL to about 150 μg/mL in phosphate-buffered saline at a pH of 7.4 and/or a stability of about 80% or less of a remaining amount of the compound after incubating in plasma for about 3 hours. 
     
     
         3 . The method of  claim 1 , wherein the administering is performed via intravenous, intramuscular, intraperitoneal, retro-orbital, or subcutaneous injection. 
     
     
         4 . The method of  claim 1 , wherein a lipid layer of the lipid-coated particle includes about 10 to about 50 mol. % DOTAP, about 40 to 50 mol. % cholesterol, about 0 to 40 mol. % DOPE, and about 1 to 5 mol. % of a PEGylated lipid. 
     
     
         5 . The method of  claim 1 , wherein the lipid-coated particle has a (diameter) ranging from about 0.5 to about 30 nm, about 1 nm to about 30 nm. 
     
     
         6 . The method of  claim 1 , wherein the lipid-coated particle is monodisperse and colloidally stable. 
     
     
         7 . The method of  claim 1 , wherein the brain viral load includes an encephalitic alphavirus infection. 
     
     
         8 . The method of  claim 7 , wherein the encephalitic alphavirus is Venezuelan Equine Encephalitis Virus. 
     
     
         9 . The method of  claim 1 , wherein the antiviral compound has a structure of formula (I) or (II) or (III): 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 each R 1  is, independently, H or optionally substituted alkyl; 
 each R 2  is, independently, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkaryl, or optionally substituted alkheterocyclyl; 
 each R 4 , R 5 , R 7 , and R 8  is, independently, H, optionally substituted alkyl, halo, nitro, amino, azido, cyano, hydroxyl, optionally substituted hydroxyalkyl, optionally substituted haloalkyl, optionally substituted perfluoroalkyl, or optionally substituted cycloalkyl, or in which R 4  and R 5 , taken together, or R 7  and R 8 , taken together, form an optionally substituted spirocyclyl; and 
 each R 3  and R 6  is, independently, H, optionally substituted alkyl, halo, nitro, nitroso, amino, azido, carboxyl, cyano, hydroxyl, optionally substituted hydroxyalkyl, optionally substituted haloalkyl, optionally substituted perfluoroalkyl, or optionally substituted cycloalkyl. 
 
     
     
         10 . The method of  claim 1 , wherein the antiviral compound is present in an amount of from about 10 μg/mg to 50 μg/mg (μg of the compound per mg of the lipid-coated particle). 
     
     
         11 . The method of  claim 1 , wherein the antiviral compound is released at a rate of from about 3 μg/mg to about 20 μg/mg (μg of the compound per mg of the lipid-coated particle) over a period of about 24 hours in vitro. 
     
     
         12 . A method of treating cancer within a subject, the method comprising:
 administering an effective amount of a lipid-coated particle to the subject, wherein the lipid-coated particle comprises a porous core and an anticancer compound disposed within at least one pore of the porous core.   
     
     
         13 . A method of increasing a stability and/or a solubility of an antiviral compound within an aqueous solution, the method comprising:
 incubating the antiviral compound with a core comprising a plurality of pores, thereby providing a loaded core; and   coating the loaded core with a lipid layer, thereby provided a lipid-coated particle,   wherein the stability and/or the solubility of the lipid-coated particle within the aqueous solution is greater than the stability and/or the solubility of the antiviral compound within the aqueous solution.   
     
     
         14 . The method of  claim 13 , wherein the antiviral compound has an aqueous solubility of from about 20 μg/mL to about 150 μg/mL in phosphate-buffered saline at a pH of 7.4 and/or a stability of about 80% or less of a remaining amount of the antiviral compound after incubating in plasma for about 3 hours. 
     
     
         15 . The method of  claim 13 , wherein the compound has a structure of formula (I) or (II) or (III): 
       
         
           
           
               
               
           
         
       
       or a salt thereof, wherein:
 each R 1  is, independently, H or optionally substituted alkyl; 
 each R 2  is, independently, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkaryl, or optionally substituted alkheterocyclyl; 
 each R 4 , R 5 , R 7 , and R 8  is, independently, H, optionally substituted alkyl, halo, nitro, amino, azido, cyano, hydroxyl, optionally substituted hydroxyalkyl, optionally substituted haloalkyl, optionally substituted perfluoroalkyl, or optionally substituted cycloalkyl, or in which R 4  and R 5 , taken together, or R 7  and R 8 , taken together, form an optionally substituted spirocyclyl; and 
 each R 3  and R 6  is, independently, H, optionally substituted alkyl, halo, nitro, nitroso, amino, azido, carboxyl, cyano, hydroxyl, optionally substituted hydroxyalkyl, optionally substituted haloalkyl, optionally substituted perfluoroalkyl, or optionally substituted cycloalkyl. 
 
     
     
         16 . The method of  claim 13 , wherein the antiviral compound has a release rate of from about 3 μg/mg to about 20 μg/mg (μg of the antiviral compound per mg of the lipid-coated particle) over a period of about 24 hours in vitro. 
     
     
         17 . The method of  claim 13 , wherein the lipid layer comprises a zwitterionic lipid, a cholesterol or a derivative thereof, and a pegylated lipid. 
     
     
         18 . The method of  claim 13 , wherein the antiviral compound has an EC 50  value of from about 0.01 μM to about 1 μM as determined in a cellular assay. 
     
     
         19 . The method of  claim 18 , wherein the antiviral compound has an EC 90  value of from about 100 nM to about 300 nM as determined in a cellular assay. 
     
     
         20 . The method of  claim 13 , wherein the antiviral compound is hydrophobic or lipophilic.