Compositions and methods for organ specific delivery of nucleic acids

A composition comprising a SORT lipid composition assembled with a therapeutic agent, which SORT lipid composition comprises:

• (1) An ionizable cationic lipid;
• and
• (2) A permanently cationic selective organ targeting (SORT) lipid,
• wherein said SORT lipid composition comprises said permanently cationic SORT lipid at a molar percentage of about 5% or more, wherein the molar percentage is determined based on total mols of lipids present in the SORT lipid composition;
• wherein said SORT lipid composition is characterized by an apparent pKa of about 8 or higher as determined by a 2-(p-toluidino)-6-naphthalenesulfonic acid titration assay;
• and
• wherein said composition delivers said therapeutic agent to a lung or a lung cell following intravenous administration or inhalation;
• wherein (1) the ionizable cationic lipid is a compound having the structure of Formula (I)
• Core-Repeating Unit-Terminating Group (I)
• or a pharmaceutically acceptable salt thereof,
• wherein the compound of Formula (I) or the pharmaceutically acceptable salt is a dendron or dendrimer, wherein
• the Core is made from the structure of Formula (II) which has been linked to one or more Repeating Unit(s) by removing one or more hydrogen atoms from the structure of Formula (II) and replacing the one or more hydrogen atoms with the Repeating Unit(s) to form the Core, wherein Formula (II) is
• wherein, in Formula (II):
• X1 is amino, optionally substituted alkylamino(C≤12), optionally substituted dialkylamino(C≤12), optionally substituted heterocycloalkyl(C≤12), or optionally substituted heteroaryl(C≤12);
• R1 is amino, hydroxy, mercapto, optionally substituted alkylamino(C≤12), or optionally substituted dialkylamino(C≤12);
• and
• a is 1, 2, 3, 4, 5, or 6;
• or
• alternatively, the Core is made from a compound with the structure of Formula (III) which has been linked to one or more Repeating Unit(s) by removing one or more hydrogen atoms from the structure of Formula (III) and replacing the one or more hydrogen atoms with the Repeating Unit(s) to form the Core, wherein Formula (III) is:
• wherein, in Formula (III):
• X2 is N(R5)y, wherein:
• R5 is hydrogen or optionally substituted alkyl(C≤18);
• and
• y is 0, 1, or 2, provided that the sum of y and z is 3;
• R2 is amino, hydroxy, mercapto, optionally substituted alkylamino(C≤12), or optionally substituted dialkylamino(C≤12);
• b is 1, 2, 3, 4, 5, or 6;
• and
• z is 1, 2, 3;
• provided that the sum of z and y is 3;
• or
• alternatively, the Core is made from a compound with the structure of Formula (IV) which has been linked to one or more Repeating Unit(s) by removing one or more hydrogen atoms from the structure of Formula (IV) and replacing the one or more hydrogen atoms with the Repeating Unit(s) to form the Core, wherein Formula (IV) is:
• wherein, in Formula (IV):
• X3 is selected from —NR6—, —O—, optionally substituted alkylaminodiyl(C≤8), optionally substituted alkoxydiyl(C≤8), optionally substituted arenediyl(C≤8), optionally substituted heteroarenediyl(C≤8), and optionally substituted heterocycloalkanediyl(C≤8),
• wherein R6 is hydrogen, alkyl(C≤8), or substituted alkyl(C≤8);
• R3 and R4 are each independently selected from amino, hydroxy, mercapto, optionally substituted alkylamino(C≤12), and optionally substituted dialkylamino(C≤12);
• and
• c and d are each independently 1, 2, 3, 4, 5, or 6;
• or
• alternatively, the Core is made from an optionally substituted alkylamine(C≤18), an optionally substituted dialkylamine(C≤36), or an optionally substituted heterocycloalkane(C≤12) which has been linked to one or more Repeating Unit(s) by removing one or more hydrogen atom and replacing the one or more hydrogen atoms with the Repeating Unit(s) to form the Core;
• the Repeating Unit(s) comprises a degradable diacyl and optionally a linker;
• wherein:
• the degradable diacyl group has the formula:
• wherein, in Formula (VII):
• A1 and A2 are each independently —O— or —NRa— wherein Ra is hydrogen or optionally substituted alkyl(C≤6);
• Y3 is selected from optionally substituted alkanediyl(C≤12), optionally substituted alkenediyl(C≤12), optionally substituted arenediyl(C≤12), and a group of the formula:
• X3A and X4 are each independently selected from optionally substituted alkanediyl(C≤12), optionally substituted alkenediyl(C≤12), and optionally substituted arenediyl(C≤12);
• and
• Y5 is selected from a covalent bond, optionally substituted alkanediyl(C≤12), optionally substituted alkenediyl(C≤12), and optionally substituted arenediyl(C≤12);
• and
• R9 is optionally substituted alkyl(C≤8);
• and
• the linker group has the formula:
• Y1 is selected from optionally substituted alkanediyl(C≤12), optionally substituted alkenediyl(C≤12), and optionally substituted arenediyl(C≤12);
• and
• wherein when the repeating unit comprises the linker group, then the linker group is attached to the degradable diacyl group on both the nitrogen and the sulfur atoms of the linker group, wherein the first group in the repeating unit is the degradable diacyl group, wherein for each linker group, the next group comprises two degradable diacyl groups attached to the nitrogen atom of the linker group;
• and
• wherein n is the number of linker groups present in the repeating unit;
• wherein n is 0, 1, 2, 3, 4, 5, or 6;
• and
• the Terminating Group has the formula:
• wherein, in Formula (VIII):
• Y4 is alkanediyl(C≤8) optionally substituted with one or more substituents independently selected from —OH, —F, —Cl, —Br, —I, —SH, —OCH3, —OCH2CH3, —SCH3, and —OC(O)CH3;
• R10 is selected from hydrogen, carboxy, hydroxy, aryl(C≤12), alkylamino(C≤12), dialkylamino(C≤12), N-heterocycloalkyl(C≤12), —C(O)N(R11)-alkanediyl(C≤6)-heterocycloalkyl(C≤12), —C(O)-alkylamino(C≤12), —C(O)-dialkylamino(C≤12), and —C(O)—N-heterocycloalkyl(C≤12), wherein:
• R11 is hydrogen or optionally substituted alkyl(C≤6);
• and
• wherein the final degradable diacyl in the chain of repeating unit(s) is attached to the Terminating Group;
• and
• wherein (2) the permanently cationic SORT lipid comprises (i) a cationic headgroup and (ii) a plurality of hydrophobic tails, wherein:
• (i) the cationic headgroup comprises a quaternary ammonium moiety;
• and
• (ii) the plurality of hydrophobic tails comprises from 2 to 6 hydrophobic tails, wherein a hydrophobic tail in the plurality of hydrophobic tails is independently C6-C24 alkyl or C6-C24 alkenyl.