Sulfur-containing ionizable lipids for the delivery of nucleic acids and other therapeutic agents

A lipid nanoparticle comprising an ionizable, cationic amino lipid or a pharmaceutically acceptable salt thereof and a nucleic acid,

• the ionizable, cationic amino lipid comprising:
• a protonatable amino head group;
• two lipophilic chains, wherein the protonatable amino head group has a central carbon atom to which each of the two lipophilic chains are directly bonded;
• at least one of the two lipophilic chains has a structure of Formula A.1:
• wherein the wavy line represents a bond to the central carbon atom;
• wherein m and n are independently 2 to 8;
• E is an ester group that is —(C═O)O— or —O (C═O)—;
• R1 is a linear, branched, monocyclic or polycyclic, optionally substituted, C3 to C20 alkyl group, comprising 0-2 carbon-carbon double bonds;
• R2 is a linear or branched, optionally substituted, C1 to C10 alkyl group, comprising 0-2 carbon-carbon double bonds, or R2 is bound to R3 to form a ring structure as indicated by the dashed curved line;
• R3 is H, or a linear or branched, optionally substituted, C1 to C10 alkyl group, comprising 0-2 carbon-carbon double bonds, or R3 is bound to R2 to form a ring structure as indicated by the dashed curved line;
• R4 and R5 are, independently, H, or a linear or branched, optionally substituted, C1 to C10 alkyl group, comprising 0-2 carbon-carbon double bonds, or R4 and R5 are bound to each other to form a ring structure;
• and
• each lipophilic chain has between 15 and 40 carbon atoms in total;
• and
• wherein (i) a nitrogen atom of the protonatable amino head group of the ionizable, cationic amino lipid is positively charged below its pKa;
• and (ii) the ionizable, cationic amino lipid has a ClogP of at least 11.

A method for treating a subject in need of a nucleic acid therapy, the method comprising preparing or providing a lipid nanoparticle comprising an ionizable, cationic amino lipid or a pharmaceutically acceptable salt thereof comprising:

• a protonatable amino head group;
• two lipophilic chains, wherein the protonatable amino head group has a central carbon atom to which each of the two lipophilic chains are directly bonded;
• at least one of the two lipophilic chains has a structure of Formula A.1:
• wherein the wavy line represents a bond to the central carbon atom;
• wherein m and n are independently 2 to 8;
• E is an ester group that is —(C═O)O— or —O (C═O)—;
• R1 is a linear, branched, monocyclic or polycyclic, optionally substituted, C3 to C20 alkyl group, comprising 0-2 carbon-carbon double bonds;
• R2 is a linear or branched, optionally substituted, C1 to C10 alkyl group, comprising 0-2 carbon-carbon double bonds, or R2 is bound to R3 to form a ring structure as indicated by the dashed curved line;
• R3 is H, or a linear or branched, optionally substituted, C1 to C10 alkyl group, comprising 0-2 carbon-carbon double bonds, or R3 is bound to R2 to form a ring structure as indicated by the dashed curved line;
• R4 and R5 are, independently, H, or a linear or branched, optionally substituted, C1 to C10 alkyl group, comprising 0-2 carbon-carbon double bonds, or R4 and R5 are bound to each other to form a ring structure;
• each lipophilic chain has between 15 and 40 carbon atoms in total;
• wherein (i) a nitrogen atom of the protonatable amino head group of the lipid is positively charged below its pKa;
• and (ii) the ionizable, cationic amino lipid has a ClogP of at least 11;
• and
• a nucleic acid,
• and administering the lipid nanoparticle to the subject.

A method for delivering a nucleic acid molecule to a cell, the method comprising contacting a lipid nanoparticle with the cell in vivo or in vitro, the lipid nanoparticle comprising:

• the nucleic acid molecule;
• and
• an ionizable, cationic amino lipid or a pharmaceutically acceptable salt thereof comprising:
• a protonatable amino head group;
• two lipophilic chains, wherein the protonatable amino head group has a central carbon atom to which each of the two lipophilic chains are directly bonded;
• at least one of the two lipophilic chains has a structure of Formula A.1:
• wherein the wavy line represents a bond to the central carbon atom;
• wherein m and n are independently 2 to 8;
• E is an ester group that is —(C═O)O— or —O (C═O)—;
• R1 is a linear, branched, monocyclic or polycyclic, optionally substituted, C3 to C20 alkyl group, comprising 0-2 carbon-carbon double bonds;
• R2 is a linear or branched, optionally substituted, C1 to C10 alkyl group, comprising 0-2 carbon-carbon double bonds, or R2 is bound to R3 to form a ring structure as indicated by the dashed curved line;
• R3 is H, or a linear or branched, optionally substituted, C1 to C10 alkyl group, comprising 0-2 carbon-carbon double bonds, or R3 is bound to R2 to form a ring structure as indicated by the dashed curved line;
• R4 and R5 are, independently, H, or a linear or branched, optionally substituted, C1 to C10 alkyl group, comprising 0-2 carbon-carbon double bonds, or R4 and R5 are bound to each other to form a ring structure;
• each lipophilic chain has between 15 and 40 carbon atoms in total;
• and
• wherein (i) a nitrogen atom of the protonatable amino head group of the lipid is positively charged below its pKa;
• and (ii) the ionizable, cationic amino lipid has a ClogP of at least 11.