Compositions and methods for targeted delivery to cells

Abstract

Described herein are compositions, kits, and methods for potent delivery to a cell of a subject. The cell can be of a particular cell type, such as a basal cell, a ciliated cell, or a secretory cell. In some cases, the cell can be a lung cell of a particular cell type. Also described herein are pharmaceutical compositions comprising a therapeutic or prophylactic agent assembled to a lipid composition. The lipid composition can comprise an ionizable cationic lipid, a phospholipid, and a selective organ targeting lipid. Further described herein are high-potency dosage forms of a therapeutic or prophylactic agent formulated with a lipid composition.

What is claimed is: 
     
         1 - 119 . (canceled) 
     
     
         120 . A lipid nanoparticle (LNP) composition for delivering a polynucleotide to a cell in the lung wherein the LNP comprises:
 (i) a polynucleotide;   (ii) an ionizable cationic lipid;   (iii) an 1,2-Dioleoyl-3-dimethylammonium-propane (DODAP) at a molar percentage from about 20% to about 65%;   (iv) a phospholipid;   (v) a cholesterol; and   (vi) a polyethylene glycol-conjugated lipid (PEG-lipid).   
     
     
         121 . The composition of  claim 120 , wherein the composition preferentially delivers the polynucleotide to lung cells in the subject. 
     
     
         122 . The composition of  claim 120 , wherein the ionizable cationic lipid is a compound of Formula (D-I):
 Core-Repeating Unit-Terminating Group (D-I),   or a pharmaceutically acceptable salt thereof, wherein the core is linked to four to six repeating units and each repeating unit is linked to a nitrogen of the core, wherein:
 the core has the formula:
                     
 wherein: 
 X 3  is —NR 6 —, wherein R 6  is hydrogen or alkyl (C≤8) ; 
 R 3  and R 4  are each independently amino, alkylamino (C≤12) , dialkylamino (C≤12) ,
                     
                     
                     
 wherein: 
 
 each e independently is 1, 2, or 3; 
 R c , R d , and R f  are each independently hydrogen or alkyl (C≤6) ; 
 c and d are each independently 1, 2, 3, 4, 5, or 6; 
 
   the repeating unit is a degradable diacyl group having the formula:
                     
 wherein: 
 A 1  and A 2  are each —O—; 
 Y 3  is alkanediyl (C≤12) ; and 
 R 9  is alkyl (C≤8) , and 
   the terminating group has the formula:
                     
 wherein: 
 Y 4  is alkanediyl (C≤18) ; and 
 R 10  is hydrogen. 
   
     
     
         123 . The composition of  claim 120 , wherein the ionizable cationic lipid is present in the composition at a molar percentage from about 5% to about 30%. 
     
     
         124 . The composition of  claim 122 , wherein in the compound of Formula (D-I) or the pharmaceutically acceptable salt thereof:
                       R 9  is —CH 3 ; and   the terminating group is selected from the group consisting of:
                     
                     
                     
                     
                     
                     
                     
 . 
   
     
     
         125 . The composition of  claim 124 , wherein in the compound of Formula (D-I) or the pharmaceutically acceptable salt thereof, the core is linked to four repeating units and the core has the following structure:
                       .   
     
     
         126 . The composition of  claim 124 , wherein in the compound of Formula (D-I) or the pharmaceutically acceptable salt thereof, the core is linked to four or five repeating units and the core has the following structure:
                                             .   
     
     
         127 . The composition of  claim 124 , wherein in the compound of Formula (D-I) or the pharmaceutically acceptable salt thereof, the core has the following structure:
                       .   
     
     
         128 . The composition of  claim 120 , wherein the dendrimer is
                       .   
     
     
         129 . The composition of  claim 120 , wherein the dendrimer is
                       .   
     
     
         130 . The composition of  claim 120 , wherein the dendrimer is
                       .   
     
     
         131 . The composition of  claim 120 , wherein the DODAP is present in the composition at a molar percentage from about 20% to about 40%. 
     
     
         132 . The composition of  claim 120 , wherein the phospholipid is present in the composition at a molar percentage from about 7.5% to about 60%. 
     
     
         133 . The composition of  claim 120 , wherein the cholesterol is present in the composition at a molar percentage from about 15% to about 46%. 
     
     
         134 . The composition of  claim 120 , wherein the PEG-lipid is present in the composition at a molar percentage from about 0.5% to about 10%. 
     
     
         135 . The composition of  claim 120 , wherein the polynucleotide comprises a small interfering RNA (siRNA), a short hairpin RNA (shRNA), or microRNA. 
     
     
         136 . The composition of  claim 135 , wherein the polynucleotide comprises a messenger RNA (mRNA). 
     
     
         137 . The composition of  claim 136 , wherein the mRNA encodes a gene-editing system or component thereof. 
     
     
         138 . The composition of  claim 136 , wherein the polynucleotide comprises modified mRNA by 5-uracil (pseudouracil) and/or capping reaction. 
     
     
         139 . The composition of  claim 136 , wherein the mRNA comprises a sequence encoding cystic fibrosis transmembrane conductance regulator (CFTR). 
     
     
         140 . The composition of  claim 136 , wherein the mRNA comprises a sequence encoding dynein axonemal intermediate chain 1 (DNAI). 
     
     
         141 . The composition of  claim 120 , wherein the composition is an aerosolized composition. 
     
     
         142 . A method for treating a lung disease in a subject in need thereof, comprises administering a lipid nanoparticle (LNP), wherein the LNP comprises:
 (i) a polynucleotide   (ii) an ionizable cationic lipid;   (iii) an DODAP at a molar percentage from about 20% to about 65%;   (iv) a phospholipid;   (v) a cholesterol; and   (vi) a polyethylene glycol-conjugated lipid (PEG-lipid), 
 wherein the ionizable cationic lipid is a compound of Formula (D-I):
 Core-Repeating Unit-Terminating Group (D-I), 
 or a pharmaceutically acceptable salt thereof, wherein the core is linked to four to six repeating units and each repeating unit is linked to a nitrogen of the core, wherein: 
 the core has the formula:
                     
 wherein: 
 X 3  is —NR 6 —, wherein R 6  is hydrogen or alkyl (C≤8) ; 
 R 3  and R 4  are each independently amino, alkylamino (C≤12) , dialkylamino (C≤12) ,
                     
                     
                     
 wherein: 
 each e independently is 1, 2, or 3; 
 R c , R d , and R f  are each independently hydrogen or alkyl (C≤6) ; 
 c and d are each independently 1, 2, 3, 4, 5, or 6; 
 
 
 the repeating unit is a degradable diacyl group having the formula:
                     
 wherein: A 1  and A 2  are each -O-; 
 Y 3  is alkanediyl (C≤12) ; and 
 R 9  is alkyl (C≤8) , and 
 
 the terminating group has the formula:
                     
 wherein: 
 Y 4  is alkanediyl (C≤18) ; and 
 R 10  is hydrogen. 
 
 
     
     
         143 . The method of  claim 142 , wherein the administering comprises administration by inhalation. 
     
     
         144 . The method of  claim 142 , wherein the administering comprises administration by intravenous injection. 
     
     
         145 . The composition of  claim 120 , wherein the DODAP is present in the composition at a molar percentage from about 20% to about 40%;
 wherein the phospholipid is present in the composition at a molar percentage from about 7.5% to about 60%;   wherein the cholesterol is present in the composition at a molar percentage from about 15% to about 46%;   wherein the PEG-lipid is present in the composition at a molar percentage from about 0.5% to about 10%; and   wherein the dendrimer is 4A3-SC7, 4A3-SC8, or 5A2-SC8.