Lipid nanoparticles
The present disclosure provides a lipid nanoparticle wherein the lipid ingredient comprises a compound of formula (IV). The present disclosure also provides a method of preparing the lipid nanoparticle, a pharmaceutical composition of the lipid nanoparticle, and use of the lipid nanoparticle and pharmaceutical compositions in the delivery of nucleic acids.
1 . A nanoparticle composition, comprising a lipid ingredient, and optionally comprising a load;
wherein the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 20 mol %-85 mol %;
Structure lipids 10 mol %-75 mol %;
Neutral lipids 1.0 mol %-30 mol %;
Polymer lipids 0.25 mol %-10 mol %;
wherein the ionizable cationic lipid is a compound of formula (IV), or a pharmaceutically acceptable salt, isotopic variant, tautomer or stereoisomer thereof,
wherein;
M 1 and M 2 are independently selected from —C(O)O—, —OC(O)O—, —OC(O)—, —SC(O)—, —C(O)S—, C(O)NR a —, and —NR a C(O)—, alternatively —C(O)O—, —OC(O)—, —SC(O)—, and —C(O)S—, alternatively —C(O)O— and —OC(O)—;
Q is C(O)O;
G 5 is a chemical bond;
G 6a and G 6b are independently a chemical bond or C 1-7 alkylene;
G 6a and G 6b have a total length of 0, 1, 2, 3, 4, 5, 6 or 7 carbon atoms;
R 9 , and R 10 are independently H, or C 1-8 alkyl;
G 1 , G 2 , G 3 and G 4 are independently a chemical bond, C 1-13 alkylene, C 2-13 alkenylene or C 2-13 alkynylene, which is optionally substituted with one or more R s ;
G 1 and G 2 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;
G 3 and G 4 have a total length of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms;
R 3 and R 4 are independently H, C 1-10 alkyl, C 1-10 haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, 3- to 14-membered cycloalkyl, 3- to 14-membered heterocyclyl, C 6-10 aryl or 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*:
or, R 3 and R 4 are taken together with the N atom to which they are attached to form 3- to 14-membered heterocyclyl, which is optionally substituted with one or more R*;
or, R 4 and R 9 are taken together with the atoms to which they are attached to form 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl, which is optionally substituted with one or more R*;
R* is independently H, halogen, cyano, C 1-10 alkyl, C 1-10 haloalkyl, -L b -OR b , -L b -SR b or -L b -NR b R′ b if present;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;
R 1 and R 2 are independently C 4-20 alkyl, C 4-20 alkenyl or C 4-20 alkynyl, which is optionally substituted with one or more R, and wherein one or more methylene units are optionally and independently replaced with —NR″—;
R s is independently H, C 1-14 alkyl, -L d -OR d , -L d -SR d or -L d -NR d R′ d if present;
R is independently H, C 1-20 alkyl, -L a -OR a , -L a -SR a or -L a -NR a R′ a if present;
R″ is independently H or C 1-20 alkyl if present;
L a and L e are independently a chemical bond or C 1-20 alkylene if present;
L b and L f are independently a chemical bond or C 1-10 alkylene if present;
L d is independently a chemical bond or C 1-14 alkylene if present;
R a and R′ a are independently H, C 1-20 alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl if present, which are optionally substituted with one or more of the following substituents: H, C 1-20 alkyl, -L e -OR e , -L e -SR e and -L e -NR e R′ e ;
R b and R′ b are independently H, C 1-10 alkyl, 3- to 14-membered cycloalkyl, and 3- to 14-membered heterocyclyl if present, which are optionally substituted with one or more of the following substituents: H, C 1-10 alkyl, -L f -OR f , -L f -SR f and -L f -NR f R′ f ,
R d and R′ d are independently H or C 1-14 alkyl if present;
R e and R′ e are independently H or C 1-20 alkyl if present;
R f and R′ f are independently H or C 1-10 alkyl if present.
2 . The nanoparticle composition of claim 1 , wherein the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 25 mol %-65 mol %;
Structure lipids 25 mol %-70 mol %;
Neutral lipids 1 mol %-25 mol %;
Polymer lipids 0.5 mol %-8 mol %;
alternatively, the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 30 mol %-60 mol %;
Structure lipids 27.5 mol %-66 mol %;
Neutral lipids 1.5 mol %-20 mol %;
Polymer lipids 1 mol %-5 mol %;
alternatively, the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 30 mol %-50 mol %;
Structure lipids 30.5 mol %-66 mol %;
Neutral lipids 1.5 mol %-20 mol %;
Polymer lipids 1 mol %-5 mol %.
3 . The nanoparticle composition of claim 1 , the compound of formula (IV) has a structure of formula (V):
wherein:
Q is C(O)O;
G 6 a and G 6b are independently a chemical bond or C 1-5 alkylene;
G 6a and G 6b have a total length of 0, 1, 2, 3, 4 or 5 carbon atoms;
R 9 is H, or C 1-6 alkyl;
one of L 3 and L 5 , or one of L 4 and L 6 is selected from —(CR s R s′ ) 2 —, —CH═CH— and —C≡C—, and the other is a chemical bond;
G 1a , G 1b , G 2a , G 2b , G 3a , G 3b , G 4a and G 4b are independently a chemical bond or C 1-7 alkylene, which is optionally substituted with 1, 2, 3, 4 or 5 R s ;
G 1a , G 1b , G 2a and G 2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms;
G 3a , G 3b , G 4a and G 4b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms;
R 3 and R 4 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;
or, R 3 and R 4 are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;
or, R 4 and R 9 are taken together with the atoms to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;
R* is independently H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L b -OR b or -L b -NR b R′ b , if present;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;
Y 1 and Y 2 are independently O, S or NR a ;
L 1 and L 2 are independently —(CRR′) 2 —, —CH═CH—, —C≡C— or —NR″—;
G 7 , G 8 , G 9 and G 10 are independently a chemical bond or C 1-12 alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or 6 R;
G 7 and G 8 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms;
G 9 and G 10 have a total length of 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms;
1, 2 or 3 methylenes in G 7 , G 8 , G 9 or G 10 are optionally and independently substituted with 1 R;
R s and R s′ are independently H, C 1-10 alkyl, -L d -OR d or -L d -NR d R′ d ;
R s and R s′ are independently H, C 1-14 alkyl, -L a -OR a or -L a -NR a R′ a ;
R″ is independently H or C 1-14 alkyl;
L a is independently a chemical bond or C 1-14 alkylene;
L b is independently a chemical bond or C 1-6 alkylene if present;
L d is independently a chemical bond or C 1-10 alkylene;
R a and R′ a are independently H, C 1-14 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl;
R b and R′ b are independently H, C 1-6 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl if present;
R d and R′ d are independently H or C 1-10 alkyl if present.
4 . The nanoparticle composition of claim 3 , wherein in the compound of formula (V),
Q is C(O)O;
G 6 a is a chemical bond or C 1-4 alkylene;
G 6b is a chemical bond or C 1-2 alkylene;
Goa and G 6b have a total length of 0, 1, 2, 3 or 4 carbon atoms;
R 9 is H or C 1-6 alkyl;
one of L 3 and L 5 , or one of L 4 and L 6 is selected from —(CHR s ) 2 —, —CH═CH— and —C≡C—, and
the other is a chemical bond;
G 1a and G 3a are independently a chemical bond or C 1-7 alkylene;
G 1b and G 3b are independently a chemical bond or C 1-3 alkylene;
G 2a and G 4a are independently a chemical bond or C 1-3 alkylene;
G 2b and G 4b are independently a chemical bond or C 1-4 alkylene;
G 1a , G 1b , G 2a and G 2b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms;
G 3a , G 3b , G 4a and G 4b have a total length of 1, 2, 3, 4, 5, 6 or 7 carbon atoms;
R 3 and R 4 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, 3- to 7-membered cycloalkyl or 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;
or, R 3 and R 4 are taken together with the N atom to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;
or, R 4 and R 9 are taken together with the atoms to which they are attached to form 3- to 7-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;
R* is independently H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L b -OR b or -L b -NR b R′ b if present;
R 5 , R 6 , R 7 and R 8 are independently C 1-6 alkyl;
Y 1 and Y 2 are independently O, S or NR a ;
L 1 and L 2 are independently —(CHR) 2 —, —CH═CH—, —C≡C— or —NR″—;
G 7 and G 9 are independently a chemical bond or C 1-6 alkylene;
G 8 and G 10 are independently C 1-10 alkylene;
G 7 and G 8 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms;
G 9 and G 10 have a total length of 4, 5, 6, 7, 8, 9 or 10 carbon atoms;
1, 2 or 3 methylenes in G 7 , G 8 , G 9 or G 10 are optionally and independently substituted with 1 R;
R s is independently H or C 1-6 alkyl;
R is independently H or C 1-10 alkyl;
R″ is independently H or C 1-10 alkyl;
L b is independently a chemical bond or C 1-6 alkylene;
R a is independently H or C 1-10 alkyl;
R b and R′ b are independently H or C 1-6 alkyl;
alternatively,
is independently selected from the following groups: —(CH 2 ) 3 —C(CH 3 ) 2 —, —(CH 2 ) 4 —C(CH 3 ) 2 —, —(CH 2 ) 5 —C(CH 3 ) 2 —, —(CH 2 ) 6 —C(CH 3 ) 2 —, —(CH 2 ) 7 —C(CH 3 ) 2 —, —(CH 2 ) 8 —C(CH 3 ) 2 —, —(CH 2 ) 3 —CH═CH—C(CH 3 ) 2 —, —(CH 2 ) 3 —C≡C—C(CH 3 ) 2 —, —(CH 2 ) 4 —C(CH 3 ) 2 —CH 2 —, —(CH 2 ) 3 —C(CH 3 ) 2 —(CH 2 ) 2 —, —(CH 2 ) 2 —C(CH 3 ) 2 —(CH 2 ) 3 —, —(CH 2 ) 2 —CH═CH—C(CH 3 ) 2 —CH 2 —, —(CH 2 ) 2 —C(CH 3 ) 2 —C≡C—CH 2 —, —(CH 2 ) 2 —C(CH 3 ) 2 —CH═CH—CH 2 —, —(CH 2 ) 2 —C≡C—C(CH 3 ) 2 —CH 2 — and —(CH 2 ) 3 —C(CH 3 ) 2 —C≡C—;
-G 7 -L 1 -G 8 -H or -G 9 -L 2 -G 10 -H is independently selected from the following groups: —(CH 2 ) 5 CH 3 , —(CH 2 ) 6 CH 3 , —(CH 2 ) 7 CH 3 , —(CH 2 ) 8 CH 3 , —(CH 2 ) 9 CH 3 , —(CH 2 ) 10 CH 3 , —(CH 2 ) 11 CH 3 , —CH 2 —C≡C—(CH 2 ) 5 CH 3 , —CH 2 —C≡C—(CH 2 ) 6 CH 3 , —(CH 2 ) 2 —C≡C—(CH 2 ) 5 CH 3 , —(CH 2 ) 4 —C≡C—(CH 2 ) 3 CH 3 , —CH 2 —CH═CH—(CH 2 ) 5 CH 3 , —CH 2 —CH═CH—(CH 2 ) 6 CH 3 , —(CH 2 ) 2 —CH═CH—(CH 2 ) 5 CH 3 , —(CH 2 ) 4 —CH═CH—(CH 2 ) 3 CH 3 , —(CH 2 ) 5 —CH═CH—CH 2 CH 3 ,
5 . The nanoparticle composition of claim 1 , wherein the compound of formula (IV) has a structure of formula (VI) or formula (VII):
wherein:
a, a′, b and g if present are independently 0, 1, 2, 3, 4 or 5, a′ and b if present are not 0 at the same time;
a′+g if present=0, 1, 2, 3, 4 or 5;
c and e are independently 3, 4, 5, 6, 7, 8 or 9;
d and f are independently 0, 1, 2, 3 or 4;
c+d=3, 4, 5, 6, 7, 8 or 9, e+f=3, 4, 5, 6, 7, 8 or 9;
methylenes in
if present are optionally and independently substituted with 1, 2, 3, 4, or 5 C 1-6 alkyl;
R 3 and R 4 if present are independently H, C 1-6 alkyl, C 1-6 haloalkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*; or, R 3 and R 4 if present are taken together with the N atom to which they are attached to form 3- to 10-membered heterocyclyl, which is optionally substituted with 1, 2, 3, 4 or 5 R*;
R* is independently H, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L b -OR b or -L b -NR b R′ b if present;
R 5 , R 6 , R 7 and R& are independently C1-2 alkyl;
Y 1 and Y 2 are independently O, S or NR 4 ;
L 1 ; and L 2 are independently —(CRR′) 2 —, —CH═CH—, —C≡C— or —NR″—;
G 7 , G 8 , G 9 and G 10 are independently a chemical bond or C 1-12 alkylene, which is optionally substituted with 1, 2, 3, 4, 5 or 6 R;
G 7 and G 8 have a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms;
G 9 and G 10 have a total length of 6, 7, 8, 9, 10, 11 or 12 carbon atoms;
1, 2 or 3 methylenes in G 7 , G 8 , G 9 or G 10 are optionally and independently substituted with 1 R;
R and R′ are independently H, C 1-14 alkyl, -L a -OR a or -L a -NR a R′ a if present;
L a is independently a chemical bond or C 1-14 alkylene if present;
L b is independently a chemical bond or C 1-6 alkylene if present;
R a and R′ a are independently H, C 1-14 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl if present;
R b and R′ b are independently H, C 1-6 alkyl, 3- to 10-membered cycloalkyl or 3- to 10-membered heterocyclyl if present;
R″ is independently H or C 1-14 alkyl.
6 . The nanoparticle composition of claim 5 , wherein in the compound of formula (VI) or formula (VII),
a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively 2, 3 or 4 if present;
a′ and b are independently 0, 1, 2, 3 or 4, alternatively 2 if present, provided that a′ and b are not 0 at the same time;
g is 0, 1 or 2, alternatively 0 or 1 if present;
a′+q=0, 1, 2, 3, 4 or 5, alternatively a′+g=2 or 3 if present;
c and e are independently 3, 4, 5 or 6;
d and f are independently 0, 1 or 2;
c+d=4, 5 or 6, e+f=4, 5 or 6;
methylenes in
if present are optionally and independently substituted with 1, 2, 3, 4 or 5 C 1-6 alkyl;
methylenes in
if present are optionally and independently substituted with 1 or 2 C 1-6 alkyl;
R 3 and R 4 if present are independently C 1-6 alkyl, which is optionally substituted with 1, 2 or 3 R*;
R* is independently H, C 1-6 alkyl, C 1-6 haloalkyl or —OR b if present;
or, R 3 and R 4 if present are taken together with the N atom to which they are attached to form 3- to 7-membered heterocyclyl, alternatively 5-membered heterocyclyl, which is optionally substituted with 1, 2 or 3 R*;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;
Y 1 and Y 2 are independently O, S or NR a , alternatively O or S;
L 1 and L 2 are independently —(CHR) 2 —, —CH═CH—, —C≡C— or —NR″—, alternatively —(CHR) 2 —, —CH═CH— or —C≡C—;
G 7 and Gg are independently a chemical bond or C 1-6 alkylene;
G 8 and G 10 are independently C 1-10 alkylene;
G 7 and G 9 have a total length of 6, 7, 8, 9 or 10 carbon atoms;
G 8 and G 10 have a total length of 6, 7, 8, 9 or 10 carbon atoms;
1, 2 or 3 methylenes in G 7 , G 8 , G 9 or G 10 are optionally and independently substituted with 1 R;
R is independently H or C 1-8 alkyl if present;
R″ is independently H or C 1-10 alkyl;
R a is independently H or C 1-10 alkyl;
R b is independently H or C 1-6 alkyl, alternatively H if present.
7 . The nanoparticle composition of claim 6 , wherein in the compound of formula (VI),
a is 0, 1, 2, 3 or 4, alternatively 1, 2, 3 or 4, alternatively 2, 3 or 4;
c and e are independently 3, 4, 5 or 6;
d and f are independently 0, 1 or 2;
c+d=4, 5 or 6, e+f=4, 5 or 6;
R 3 and R 4 are independently C 1-6 alkyl;
or, R 3 and R 4 are taken together with the N atom to which they are attached to form 4- to 6-membered heterocyclyl, alternatively 5-membered heterocyclyl, which is optionally substituted with 1, 2 or 3 R*;
R* is independently H, C 1-6 alkyl or C 1-6 haloalkyl if present;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;
Y 1 and Y 2 are independently O, S or NR a , alternatively O or S;
L 1 and L 2 are independently —(CHR) 2 —, —CH═CH—, —C≡C— or —NR″—, alternatively —(CHR) 2 —, —CH═CH— or —C≡C—;
G 7 and G 9 are independently a chemical bond or C 1-5 alkylene;
G 8 and G 10 are independently C 1-8 alkylene;
G 7 and G 8 have a total length of 6, 7, 8, 9 or 10 carbon atoms;
G 9 and G 10 have a total length of 6, 7, 8, 9 or 10 carbon atoms;
1, 2 or 3 methylenes in G 7 , G 8 , G 9 or G 10 are optionally and independently substituted with 1 R;
R is independently H or C 1-8 alkyl, alternatively H or C 1-7 alkyl, alternatively H or C 1-6 alkyl if present;
R″ is independently H or C 7-9 alkyl;
R a is independently H or C 8-10 alkyl.
8 . The nanoparticle composition of claim 7 , wherein in the compound of formula (VI),
a is 2, 3 or 4;
c and e are independently 3, 4, 5 or 6;
d and f are independently 0, 1 or 2;
c+d=4, 5 or 6, e+f=4, 5 or 6;
R 3 and R 4 are independently C 1-6 alkyl;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;
Y 1 and Y 2 are independently O or S;
L 1 and L 2 are independently —(CHR) 2 —, —CH═CH— or —C≡C—;
G 7 and G 9 are independently C 1-4 alkylene;
G 8 and G 10 are independently C 2-7 alkylene;
G 7 and G 8 have a total length of 6, 7 or 8 carbon atoms;
G 9 and G 10 have a total length of 6, 7 or 8 carbon atoms;
1, 2 or 3 methylenes in G 7 , G 8 , G 9 or G 10 are optionally and independently substituted with 1 R;
R is independently H or C 1-7 alkyl if present;
provided that, when L 1 is —C≡C—, then G 7 is C 1-2 alkylene, or when L 2 is —C≡C—, then G 9 is C 1-2 alkylene.
9 . The nanoparticle composition of claim 7 , wherein in the compound of formula (VI),
a is 2, 3 or 4, alternatively 2 or 3;
c and e are independently 4, 5 or 6;
d and f are 0;
R 3 and R 4 are independently C 1-6 alkyl;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;
Y 1 and Y 2 are O;
L 1 and L 2 are independently —(CHR) 2 — or —CH═CH—;
G 7 and G 9 are independently —CH 2 — or —CH 2 CHR—;
G 8 and G 10 are independently —(CH 2 ) 6 — or —(CH 2 ) 7 —;
G 7 and G 8 have a total length of 7 or 8 carbon atoms;
G 9 and G 10 have a total length of 7 or 8 carbon atoms;
1, 2 or 3 methylenes in G 8 or G 10 are optionally and independently substituted with 1 R;
R is independently H or C 4-6 alkyl, alternatively H or C 5 alkyl if present;
alternatively -G 7 -L 1 -G 8 -H and -G 9 -L 2 -G 10 -H are not —(CH 2 ) 9 CH 3 at the same time.
10 . The nanoparticle composition of claim 7 , wherein in the compound of formula (VI),
a is 2;
c and e are independently 4, 5 or 6, alternatively 5;
d and f are 0;
R 3 and R 4 are independently C 1-6 alkyl;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;
Y 1 and Y 2 are independently O or S;
one of L 1 and L 2 is —C≡C—, the other is —(CHR) 2 —, or both of L 1 and L 2 are —C≡C—; alternatively one of L 1 and L 2 is —C≡C—, the other is —(CHR) 2 —;
G 7 and G 9 are —CH 2 —;
G 8 and G 10 are independently —(CH 2 ) 6 — or —(CH 2 ) 7 —;
1 methylene in G 8 or G 10 is optionally and independently substituted with 1 R, alternatively G 8 and G 10 are independently —CHR—(CH 2 ) 5 —, —CHR—(CH 2 ) 6 —, —CH 2 —CHR—(CH 2 ) 4 — or —(CH 2 ) 2 —CHR—(CH 2 ) 4 —;
R is independently H or C 4-6 alkyl, alternatively H or C 5 alkyl if present;
provided that, only one of the -G 7 -L 1 -G 8 -H and -G 9 -L 2 -G 10 -H is substituted with one non-hydrogen R substituent and the other is unsubstituted.
11 . The nanoparticle composition of claim 7 , wherein in the compound of formula (VI),
a is 2;
c and e are independently 4, 5 or 6, alternatively 5;
d and f are 0;
R 3 and R 4 are independently C 1-3 alkyl, alternatively Me;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl, alternatively Me;
Y 1 and Y 2 are independently O or S, alternatively O;
both of L 1 and L 2 are —C≡C—;
G 7 and G 9 are —CH 2 —;
G 8 and G 10 are independently —(CH 2 ) 6 — or —(CH 2 ) 7 —, alternatively —(CH 2 ) 7 —.
12 . The nanoparticle composition of claim 7 , wherein in the compound of formula (VI),
a is 2;
c and e are 3;
d and f are 2;
R 3 and R 4 are independently C 1-3 alkyl, alternatively Me;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;
Y 1 and Y 2 are independently O or S, alternatively O;
L 1 and L 2 are —(CHR) 2 —;
G 7 and G 9 are independently —CH 2 — or —CH 2 CHR—;
G 8 and G 10 are independently —(CH 2 ) 5 —, —(CH 2 ) 6 — or —(CH 2 ) 7 —;
G 7 and G 8 have a total length of 6, 7 or 8 carbon atoms, alternatively 7 carbon atoms;
G 9 and G 10 have a total length of 6, 7 or 8 carbon atoms, alternatively 7 carbon atoms;
1, 2 or 3 methylenes in G 8 or G 10 are optionally and independently substituted with 1 R;
R is independently H or C 1-7 alkyl, alternatively H or C 1-6 alkyl, alternatively Me if present.
13 . The nanoparticle composition of claim 7 , wherein in the compound of formula (VI),
a is 2;
c and e are 4, 5, or 6, alternatively 5;
d and f are 0;
R 3 and R 4 are independently C 1-6 alkyl;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;
Y 1 and Y 2 are S;
L 1 and L 2 are —(CHR) 2 —;
G 7 and G 9 are independently —CH 2 — or —CH 2 CHR—;
G 8 and G 10 are independently —(CH 2 ) 5 —, —(CH 2 ) 6 — or —(CH 2 ) 7 —;
G 7 and G 8 have a total length of 7 or 8 carbon atoms, alternatively 8 carbon atoms;
G 9 and G 10 have a total length of 7 or 8 carbon atoms, alternatively 8 carbon atoms;
1, 2 or 3 methylenes in G 8 or G 10 are optionally and independently substituted with 1 R;
R is independently H or C 4-6 alkyl, alternatively H or C 5 alkyl if present.
14 . The nanoparticle composition of claim 6 , wherein in the compound of formula (VII),
a′ and b are 2;
g is 0 or 1;
c and e are 5;
d and f are 0;
R 3 is C 1-6 alkyl, which is optionally substituted with 1, 2 or 3 R*;
R* is independently H, C 1-6 alkyl, C 1-6 haloalkyl or —OR b , alternatively H, C 1-6 alkyl or C 1-6 haloalkyl if present;
R 5 , R 6 , R 7 and R 8 are independently C 1-2 alkyl;
Y 1 and Y 2 are independently O or S;
L 1 and L 2 are —(CHR) 2 —;
G 7 and G 9 are independently —CH 2 — or —CH 2 CHR—;
G 8 and G 10 are independently —(CH 2 ) 5 —, —(CH 2 ) 6 — or —(CH 2 ) 7 —;
G 7 and G 8 have a total length of 6, 7 or 8 carbon atoms;
G 9 and G 10 have a total length of 6, 7 or 8 carbon atoms;
1, 2 or 3 methylenes in G 8 or G 10 are optionally and independently substituted with 1 R;
R is independently H or C 4-6 alkyl if present;
R b is independently H or C 1-6 alkyl, alternatively H if present.
15 . The nanoparticle composition of claim 14 , wherein in the compound of formula (VII),
R 3 is Me or —CH 2 CH 3 , alternatively Me;
both of Y 1 and Y 2 are O;
G 7 and G 8 have a total length of 6 or 7 carbon atoms, alternatively 7 carbon atoms;
G 9 and G 10 have a total length of 6 or 7 carbon atoms, alternatively 7 carbon atoms.
16 . The nanoparticle composition of claim 14 , wherein in the compound of formula (VII),
R 3 is Me or —CH 2 CH 3 ;
Y 1 and Y 2 are independently O or S, where Y 1 and Y 2 are not O at the same time;
G 7 and G 8 have a total length of 6, 7 or 8 carbon atoms;
G 9 and G 10 have a total length of 6, 7 or 8 carbon atoms.
17 . The nanoparticle composition of claim 16 , wherein in the compound of formula (VII),
g is 0 or 1, alternatively 1;
R 3 is Me or —CH 2 CH 3 , alternatively Me;
one of Y 1 and Y 2 is O, and the other is S;
G 7 and G 8 have a total length of 7 carbon atoms;
G 9 and G 10 have a total length of 7 carbon atoms.
18 . The nanoparticle composition of claim 16 , wherein in the compound of formula (VII),
g is 0 or 1, alternatively 0;
R 3 is Me or —CH 2 CH 3 ;
both of Y 1 and Y 2 are S;
G 7 and G 8 have a total length of 7 or 8 carbon atoms;
G 9 and G 10 have a total length of 7 or 8 carbon atoms.
19 . The nanoparticle composition of claim 1 , wherein the ionizable cationic lipid is selected from the following:
20 . The nanoparticle composition of claim 1 , wherein the load is present and comprises phosphorus atoms, and the N:P molar ratio of nitrogen (N) atoms in the ionizable cationic lipids to phosphorus (P) atoms in the load molecules is 1-15:1, alternatively 1-10:1 alternatively 3-12:1, alternatively 3-7:1, alternatively 3-6:1, alternatively 3-5:1, alternatively 6-12:1, alternatively 3-6:1, and alternatively 5:1.
21 . The nanoparticle composition of claim 1 , wherein the particle size of the nanoparticle is 65-200 nm, alternatively 65-180 nm, alternatively 70-170 nm, alternatively 70-130 nm, alternatively 70-180 nm, alternatively 80-180 nm, alternatively 90-180 nm, alternatively 100-135 nm, alternatively 65-160 nm, alternatively 65-150 nm, alternatively 65-140 nm, alternatively 65-130 nm alternatively 70-150 nm, alternatively 70-130 nm, alternatively 90-130 nm, alternatively 90-115 nm, and alternatively 65-75 nm.
22 . The nanoparticle composition of claim 1 , wherein the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 30 mol %-55 mol %, alternatively 32.5 mol %-50 mol %;
Structure lipids 28 mol %-64 mol %, alternatively 30.6 mol %-61 mol %;
Neutral lipids 5 mol %-20 mol %;
Polymer lipids 1 mol %-3 mol %, alternatively 1 mol %-2 mol %;
the ionizable cationic lipid is
alternatively is:
alternatively, the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 40 mol %-52.5 mol %, alternatively 42.5 mol %-50 mol %;
Structure lipids 28 mol %-54 mol %, alternatively 30.6 mol %-51 mol %;
Neutral lipids 5 mol %-20 mol %;
Polymer lipids 1 mol %-3 mol %, alternatively 1 mol %-2 mol %.
23 . The nanoparticle composition of claim 1 , wherein the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 30 mol %-60 mol %;
Structure lipids 27.5 mol %-66 mol %;
Neutral lipids 1.5 mol %-20 mol %;
Polymer lipids 1.5 mol %-5 mol %;
The ionizable cationic
alternatively is:
alternatively is:
alternatively, the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 30 mol %-50 mol %;
Structure lipids 35 mol %-66 mol %;
Neutral lipids 1.5 mol %-20 mol %;
Polymer lipids 1.5 mol %-5 mol %;
alternatively, the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 30 mol %-50 mol %;
Structure lipids 38.5 mol %-63.5 mol %;
Neutral lipids 1.5 mol %-10 mol %;
Polymer lipids 1.5 mol %-4 mol %, alternatively 1.5 mol %-3.5 mol %;
alternatively, the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 30 mol %-50 mol %, alternatively 30 mol %-48.5 mol %;
Structure lipids 43 mol %-60 mol %, alternatively 45.5 mol %-57.5 mol %;
Neutral lipids 1.5 mol %-10 mol %;
Polymer lipids 1.5 mol %-4 mol %, alternatively 1.5 mol %-3.5 mol %.
24 . The nanoparticle composition of claim 1 , wherein the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 27.5 mol %-55 mol %, alternatively 30 mol %-50 mol %;
Structure lipids 35 mol %-68.5 mol %, alternatively 38.5 mol %-66 mol %;
Neutral lipids 1.5 mol %-20 mol %, alternatively 2.5 mol %-15 mol %;
Polymer lipids 1 mol %-5 mol %, alternatively 1.5 mol %-3.5 mol %;
the ionizable cationic lipid is
alternatively is:
alternatively, the lipid ingredient comprises the following components in the molar percentages:
Ionizable cationic lipids 27.5 mol %-42.5 mol %, alternatively 30 mol %-40 mol %;
Structure lipids 41 mol %-68.5 mol %, alternatively 43.5 mol %-66 mol %;
Neutral lipids 2 mol %-18 mol %, alternatively 2.5 mol %-15 mol %;
Polymer lipids 1 mol %-4 mol %, alternatively 1.5 mol %-3.5 mol %.
25 . The nanoparticle composition of claim 1 , wherein the neutral lipids are selected from one or more of DSPC, DMPC, DOPC, DPPC, POPC, DOPE, DMPE, POPE and DPPE, alternatively DSPC and/or DOPE.
26 . The nanoparticle composition of claim 1 , wherein the structure lipids are selected from one or more of cholesterol, sitosterol, coprosterol, fucosterol, brassicasterol, ergosterol, tomatine, ursolic acid, α-tocopherol, stigmasterol, avenasterol, ergocalciferol and campesterol, alternatively cholesterol and/or β-sitosterol.
27 . The nanoparticle composition of claim 1 , wherein the polymer lipids are polyethylene glycolated lipids.
28 . The nanoparticle composition of claim 1 , wherein the load is present and is selected from one or more of therapeutic, prophylactic and diagnostic agents.
29 . The nanoparticle composition of claim 27 , wherein the polyethylene glycolated lipids are selected from one or more of DMPE-PEG1000, DPPE-PEG1000, DSPE-PEG1000, DOPE-PEG1000, DMG-PEG2000, Ceramide-PEG2000, DMPE-PEG2000, DPPE-PEG2000, DSPE-PEG2000, Azido-PEG2000, DSPE-PEG2000-Mannose, Ceramide-PEG5000, and DSPE-PEG5000.
30 . The nanoparticle composition of claim 28 , wherein the therapeutic, prophylactic or diagnostic agent is a nucleic acid.
31 . A method for preparing the nanoparticle composition of claim 1 , comprising: mixing the ionizable cationic lipids, the structure lipids, the neutral lipids, and the polymer lipids, and subsequently optionally mixing with a load.
32 . A pharmaceutical composition, comprising the nanoparticle composition of claim 1 , and pharmaceutically acceptable excipient(s).
33 . The method of claim 31 , wherein the mixing with a load occurs and the load is present, and the load is a nucleic acid, which is dissolved with a 20-30 mmol/L sodium acetate solution.
34 . A method of treating, diagnosing, or preventing a disease in a subject, comprising administering to the subject the pharmaceutical composition of claim 32 , wherein the load is present and is capable of treating, diagnosing, or preventing said disease.
35 . A method of delivering a load in a subject, comprising administering to the subject the pharmaceutical composition of claim 32 ; wherein the load is present and is one or more of therapeutic, prophylactic or diagnostic agents.