Lipid nanoparticles comprising lipophilic anti-inflammatory agents and methods of use thereof

Abstract

Disclosed herein are lipid nanoparticles comprising a lipid phase and at least one lipophilic anti-inflammatory agent, and pharmaceutical compositions comprising lipid nanoparticles and methods for using lipid nanoparticles.

1 . An anti-inflammatory lipid nanoparticle comprising:
 a) a lipid phase; and   b) at least one lipophilic anti-inflammatory agent.   
     
     
         2 . The anti-inflammatory lipid nanoparticle according to  claim 1 , wherein the lipid phase comprises at least one ionizable lipid, at least one neutral lipid, at least one sterol, and at least one polymer-conjugated lipid. 
     
     
         3 . The anti-inflammatory lipid nanoparticle according to  claim 2 , wherein the at least one ionizable lipid is chosen from DLin-DMA, DLin-MC3-DMA, DLin-KC2-DMA, Merck-32, KL10, Acuitas-5, C12-200, and mixtures thereof. 
     
     
         4 . The anti-inflammatory lipid nanoparticle according to  claim 2 , wherein the at least one neutral lipid is chosen from distearoyl phosphatidylcholine (DSPC), dioleoyl phosphatidylethanolamine (DOPE), dipalmitoyl phosphatidylcholine (DPPC), dimyristoyl phosphatidylcholine (DMPC), and mixtures thereof. 
     
     
         5 . The anti-inflammatory lipid nanoparticle according to  claim 2 , wherein the at least one sterol is cholesterol. 
     
     
         6 . The anti-inflammatory lipid nanoparticle according to  claim 2 , wherein the at least one polymer-conjugated lipid is chosen from DMPE-PEG2000, DPPE-PEG2000, DMG-PEG2000, DPG-PEG2000, PEG2000-c-DOMG, PEG2000-c-DOPG, and mixtures thereof. 
     
     
         7 . The anti-inflammatory lipid nanoparticle according to  claim 1 , wherein the anti-inflammatory agent is a rofleponide prodrug. 
     
     
         8 . The anti-inflammatory lipid nanoparticle according to  claim 7 , wherein the rofleponide prodrug is chosen from rofleponide valerate (C5), rofleponide caproate (C6), rofleponide caprylate (C8), rofleponide caprate (C10), rofleponide laurate (C12), rofleponide myristate (C14), rofleponide palmitate (C16), or rofleponide stearate (C18). 
     
     
         9 . The anti-inflammatory lipid nanoparticle according to  claim 1 , wherein the anti-inflammatory agent is a budesonide prodrug. 
     
     
         10 . The anti-inflammatory lipid nanoparticle according to  claim 9 , wherein the anti-inflammatory agent prodrug is chosen from budesonide myristate (C14), budesonide palmitate (C16), budesonide stearate (C18), budesonide oleate (C18:1), and budesonide linoleate (C18:2). 
     
     
         11 . The anti-inflammatory lipid nanoparticle according to  claim 1 , further comprising a nucleic acid segment chosen from DNA, mRNAs, siRNAs, Cas9-guideRNA complex, and combinations thereof. 
     
     
         12 . The anti-inflammatory lipid nanoparticle according to  claim 8 , wherein the weight ratio of lipid phase to nucleic acid segment ranges from about 40:1 to 1:1. 
     
     
         13 . The anti-inflammatory lipid nanoparticle according to  claim 1 , wherein the weight ratio of lipophilic anti-inflammatory agent to nucleic acid segment ranges from about 10:1 to about 1:100. 
     
     
         14 . A pharmaceutical composition comprising a plurality of anti-inflammatory lipid nanoparticles according to  claim 1 . 
     
     
         15 . Use of a pharmaceutical composition according to  claim 14 , for increasing the expression of at least one peptide or protein in cells of a subject in need thereof as compared to a control level. 
     
     
         16 . The use of a pharmaceutical composition according to  claim 14 , wherein the composition is administered to the subject intradermally, intramuscularly, subcutaneously, intratumorally, intracardiac, by intratracheal instillation, bronchial instillation, and/or via inhalation. 
     
     
         17 . The use of a pharmaceutical composition according to  claim 14 , wherein the expression of at least one peptide or protein is increased by a factor of about 2 up to 24 hours, compared to control levels. 
     
     
         18 . The use of a pharmaceutical composition according to  claim 14 , wherein the expression of at least one peptide or protein is increased by a factor of about 3 up to 72 hours, compared to control levels. 
     
     
         19 . Use of a pharmaceutical composition according to  claim 14 , for inhibiting the immune response associated with non-anti-inflammatory LNP administration. 
     
     
         20 . The use of a pharmaceutical composition according to  claim 19 , for inhibiting the expression or activity of a pro-inflammatory marker as compared to a control level. 
     
     
         21 . The use of a pharmaceutical composition according to  claim 20 , wherein the production of IL-6, IL-8, KC, IP-10, and MCP-1 is reduced by a percentage of about 80% or greater, as compared to a control level. 
     
     
         22 . The use of a pharmaceutical composition according to  claim 19 , wherein the administration of the pharmaceutical composition produces substantially no edema at the injection site. 
     
     
         23 . The use of a pharmaceutical composition according to  claim 19 , for inhibiting the production of plasma haptoglobin as compared to a control level. 
     
     
         24 . The use of a pharmaceutical composition according to  claim 23 , wherein the production of plasma haptoglobin is inhibited by a percentage of about 60% or greater, as compared to a control level.