Cationic lipid compositions for tissue-specific delivery
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 method of delivering a bioactive agent to a lung tissue in a subject, said method comprising:
intravenously administering a bioactive agent-lipid complex to the subject, thereby delivering said bioactive agent-lipid complex to the lung tissue,
wherein the bioactive agent-lipid complex comprises a bioactive agent and 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 method of claim 1 , wherein said first cationic lipid has the formula:
wherein
X a − is Cl − or CH 3 COO − .
3 . The method of claim 1 , wherein said second cationic lipid has the formula:
Wherein
X b − is Cl − or CH 3 COO − .
4 . The method of claim 1 , wherein said first helper lipid is dioleoylphosphatidylethanolamine (DOPE).
5 . The method of claim 1 , wherein said second helper lipid is cholesterol.
6 . The method of claim 1 , wherein said biostability enhancing agent is a polyether compound, a PEGylated phospholipid, or polyethylene glycol.
7 . The method of claim 1 , wherein said bioactive agent comprises a nucleic acid, a ribonucleoprotein or a small molecule.
8 . The method of claim 7 , wherein said nucleic acid is an mRNA, a siRNA, miRNA or guide RNA.
9 . The method of claim 1 , wherein said subject is a mammal, optionally wherein said mammal is a primate.
10 . The method of claim 1 , wherein said bioactive agent-lipid complex is delivered to an epithelial lung cell or an endothelial lung cell.
11 . The method of claim 1 , wherein the bioactive agent-lipid complex is delivered to lung tissue and spleen tissue in the subject.