Cationic lipid compositions for tissue-specific delivery

Abstract

Provided herein are, inter alia, compositions and methods useful for the in vivo delivery of bioactive agents (e.g., therapeutic or diagnostic agents). The compositions provided herein include cationic lipids, helper lipids and a biostability enhancing agent, which together form a lipid aggregate with the bioactive agent and allow for the systemic delivery of the bioactive agent to, for example, lung tissue without the requirement for biomolecular targeting.

1 . A composition comprising:
 (i) a first cationic lipid at a compositional molar ratio from about 0.18 to about 0.32 and of formula:   
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 3  and R 4  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         m is an integer from 1 to 6; 
         X a   −  is an anion; 
         (ii) a second cationic lipid at a compositional molar ratio from about 0.24 to about 0.51 and of formula: 
       
       
         
           
           
               
               
           
         
         wherein 
         R 5  and R 8  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         R 6  and R 7  are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; 
         n is an integer from 1 to 6; and 
         X b   −  is an anion; 
         (iii) a first helper lipid at a compositional molar ratio from about 0.20 to about 0.32; 
         (iv) a second helper lipid at a compositional molar ratio from about 0.01 to about 0.14; and 
         (v) a biostability enhancing agent at a compositional molar ratio from about 0.01 to about 0.02. 
       
     
     
         2 . The composition of  claim 1 , wherein m is an integer from about 1 to 5, about 1 to 4, about 1 to 3, or where m is 1, 2, 3, 4, 5, or 6. 
     
     
         3 - 10 . (canceled) 
     
     
         11 . The composition of  claim 1 , wherein n is an integer from about 1 to 5, about 1 to 4, about 1 to 3, or where n is 1, 2, 3, 4, 5, or 6. 
     
     
         12 - 19 . (canceled) 
     
     
         20 . The composition of  claim 1 , wherein said first cationic lipid is present at a compositional molar ratio of about 0.18 about 0.23, about 0.24, about 0.25, about 0.27, about 0.28, or about 0.32. 
     
     
         21 - 26 . (canceled) 
     
     
         27 . The composition of  claim 1 , wherein said first cationic lipid has the formula: 
       
         
           
           
               
               
           
         
         wherein 
         X a   −  is Cl −  or CH 3 COO − . 
       
     
     
         28 . The composition of  claim 27 , wherein X a   −  is CH 3 COO − . 
     
     
         29 . The composition of  claim 1 , wherein said first cationic lipid is dihydroxy dimyristyl spermidine. 
     
     
         30 . The composition of  claim 1 , wherein said second cationic lipid is present at a compositional molar ratio of about 0.24, about 0.38 about 0.39 about 0.40 about 0.45 about 0.47 about 0.51. 
     
     
         31 - 36 . (canceled) 
     
     
         37 . The composition of  claim 1 , wherein said second cationic lipid has the formula: 
       
         
           
           
               
               
           
         
         wherein 
         X b   −  is Cl −  or CH 3 COO − . 
       
     
     
         38 . The composition of any one of  claim 37 , wherein X b   −  is CH 3 COO − . 
     
     
         39 . The composition of  claim 1 , wherein said second cationic lipid is hydroxy dimyristyl spermidine. 
     
     
         40 . The composition of  claim 1 , wherein said first helper lipid is present at a compositional molar ratio of about 0.20, about 0.24, about 0.26, or about 0.32. 
     
     
         41 - 43 . (canceled) 
     
     
         44 . The composition of  claim 1 , wherein said first helper lipid is dioleoylphosphatidylethanolamine (DOPE). 
     
     
         45 . The composition of  claim 1 , wherein said second helper lipid is present at a compositional molar ratio of about 0.01, about 0.05, about 0.08, about 0.10, about 0.14. 
     
     
         46 - 49 . (canceled) 
     
     
         50 . The composition of  claim 1 , wherein said second helper lipid is cholesterol. 
     
     
         51 . The composition of  claim 1 , wherein said biostability enhancing agent is present at a compositional molar ratio of about 0.01 or about 0.02. 
     
     
         52 . (canceled) 
     
     
         53 . The composition of  claim 1 , wherein said biostability enhancing agent is a polyether compound, a PEGylated phospholipid, or polyethylene glycol. 
     
     
         54 . (canceled) 
     
     
         55 . (canceled) 
     
     
         56 . The composition of  claim 1 , wherein said biostability enhancing agent has a molecular weight of about 750 g/mol, about 2000 g/mol, or about 5000/mol. 
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . The composition of  claim 1 , wherein said biostability enhancing agent is C14 polyethylene glycol 750, C14 polyethylene glycol 2000, or C14 polyethylene glycol 5000. 
     
     
         60 - 72 . (canceled) 
     
     
         73 . The composition of  claim 1 , further comprising a bioactive agent. 
     
     
         74 . The composition of  claim 73 , wherein said bioactive agent is a therapeutic agent or a diagnostic agent. 
     
     
         75 . The composition of  claim 73 , wherein said bioactive agent comprises a nucleic acid, a ribonucleoprotein or a small molecule. 
     
     
         76 . The composition of  claim 75 , wherein said nucleic acid is an mRNA, a siRNA, a miRNA or a guide RNA. 
     
     
         77 . The composition of  claim 76 , wherein said bioactive agent comprises a nucleic acid and a ribonucleoprotein. 
     
     
         78 . The composition of  claim 77 , wherein said ribonucleoprotein is CRISPR associated protein 9 (Cas9). 
     
     
         79 . A pharmaceutical composition comprising a composition of  claim 76  and a pharmaceutically acceptable excipient. 
     
     
         80 . A cell comprising a composition of  claim 76 . 
     
     
         81 - 87 . (canceled) 
     
     
         88 . The cell of  claim 80 , wherein said cell is an epithelial cell, an epithelial lung cell, an endothelial cell, or an endothelial lung cell. 
     
     
         89 - 92 . (canceled) 
     
     
         93 . The cell of  claim 80 , wherein said cell is in the lung tissue of a mammal, optionally wherein said mammal is a primate, optionally wherein said primate is a human patient. 
     
     
         94 . A method of delivering a bioactive agent to a cell, said method comprising:
 (i) admixing an bioactive agent with a composition of one of  claim 1 , thereby forming a bioactive agent-lipid complex;   (ii) contacting a cell with said bioactive agent-lipid complex, thereby delivering said bioactive agent-lipid complex to said cell.   
     
     
         95 . (canceled) 
     
     
         96 . The method of  claim 94 , wherein said bioactive agent is a therapeutic agent or a diagnostic agent selected from a nucleic acid, a ribonucleoprotein a small molecule, or combinations thereof,
 wherein said nucleic acid is an mRNA, a siRNA, miRNA or guide RNA,   wherein said bioactive agent comprises a guide RNA and a ribonucleoprotein,   wherein said ribonucleoprotein is CRISPR associated protein, optionally wherein said CRISPR associated protein is bound to said guide RNA.   
     
     
         97 - 101 . (canceled) 
     
     
         102 . The method of  claim 94 , wherein said cell is a mammalian cell, optionally wherein said mammalian cell is a primate cell. 
     
     
         103 - 108 . (canceled) 
     
     
         109 . The method of  claim 94 , wherein said cell is an epithelial cell, an epithelial lung cell, an endothelial, or cell an endothelial lung cell. 
     
     
         110 - 112 . (canceled) 
     
     
         113 . A method of delivering a bioactive agent to lung tissue in a subject, said method comprising:
 (i) admixing an bioactive agent with a composition of  claim 1 , thereby forming a bioactive agent-lipid complex;   (ii) systemically administering an effective amount of said bioactive agent-lipid complex to a subject, thereby delivering said bioactive agent-lipid complex to a lung tissue in a subject.   
     
     
         114 . (canceled) 
     
     
         115 . A method of treating a pulmonary disease in a subject in need thereof, said method comprising administering to a subject a therapeutically effective amount of a bioactive agent and a composition of  claim 1 , thereby treating said pulmonary disease in said subject. 
     
     
         116 . The method of  claim 113 , wherein said composition and said bioactive agent are admixed prior to said administering. 
     
     
         117 . The method of  claim 113 , wherein said bioactive agent comprises a nucleic acid, a ribonucleoprotein or a small molecule. 
     
     
         118 . The method of  claim 117 , wherein said nucleic acid is an mRNA, a siRNA, a miRNA or a guide RNA. 
     
     
         119 . The method of one of  claim 115 , wherein said pulmonary disease is asthma, chronic obstructive pulmonary disease (COPD), lung cancer or cystic fibrosis.