JPWO2021257262A5

JPWO2021257262A5 -

Info

Publication number: JPWO2021257262A5
Application number: JP2022578631A
Authority: JP
Publication date: 2024-06-04

Claims

A polyplex comprising:
(i) Formula I:

wherein n is an integer from 1 to 30; m, o, and p are independently integers from 1 to 20; x, y, and q are independently integers from 1 to 1000; Rx is hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, or substituted or unsubstituted C ₃ -C ₅₀ aryl, or substituted or unsubstituted C ₁ -C ₂₀ alkoxy; Z and Z' are independently O or NR', where R' is hydrogen, substituted or unsubstituted C ₁ -C ₂₀ alkyl, or substituted or unsubstituted C ₃ -C ₅₀ aryl;
_R1 and _R2 are chemical entities that contain a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or a combination thereof;
polymer ;
(ii) one or more nucleic acids encapsulated within the polyplex; and
(iii) (a) a polymer of formula I and a hydrophilic polymer, or (b) a conjugate of a poly(amine-co-ester) conjugated to a hydrophilic group, or a poly(amine-co-amide) conjugated to a hydrophilic group.
wherein said polymer of formula I is in a mixture containing (a1) said polymer of formula I conjugated to a hydrophilic polymer, or (a2) a poly(amine-co-ester) or a poly(amine-co-amine) conjugated to a hydrophilic polymer .

2. The polyplex of claim 1, wherein the hydrophilic polymer is polyethylene glycol (PEG).

The polymer conjugated to the hydrophilic polymer has the structure

wherein m, n, o, p, q, x, y, Rx, Z and Z' are as defined in claim 1;
m' and m" are independently 0 or 1, provided that m'+m" is 1 or 2; J in formula XI _１1 and J. _２2 is independently a linking moiety that is absent or that contains a moiety independently selected from -C(O)-, -C(O)NH-, -C(O)O-, -O-, and -NH-;
The polyplex of claim 1.

_R1 and/or _R2 are

The polyplex of claim 1 , which is not

The polymer of formula I has formula II:

wherein m, n, o, p, q, x, y, Rx, Z and Z' are as defined in claim 1;
_J1 and _J2 are independently a linking moiety that is absent or contains a moiety independently selected from -C(O)-, -C(O)NH-, -C(O)O-, -O-, and -NH- ;
R ₃ and R ₄ are independently a substituted C ₁ -C ₂₀ alkyl containing a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or a combination thereof;
The polyplex of claim 1.

The polymer of formula I has formula III:

wherein m, n, o, p, q, x, y, Rx, Z and Z' are as defined in claim 1;
R ₃ and R ₄ are independently a substituted C ₁ -C ₂₀ alkyl containing a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or a combination thereof;
The polyplex of claim 1 .

The polyplex of claim 1, wherein Z is the same as Z'.

2. The polyplex of claim 1, wherein n is 4, 10, 13, or 14.

2. The polyplex of claim 1, wherein m is 5, 6, or 7.

2. The polyplex of claim 1, wherein _Rx is a substituted or unsubstituted alkyl.

2. The polyplex of claim 1 , wherein the polymer of formula I has a weight average molecular weight of from 2,000 Daltons to 20,000 Daltons , from 2,000 Daltons to 10,000 Daltons , or from 2,000 Daltons to 7,000 Daltons, as measured by gel permeation chromatography using narrow polydispersity polystyrene standards.

The polyplex of claim 5 , wherein R ₃ is the same as R ₄ .

_R3 and/or _R4 are independently

The polyplex of claim 5 , selected from the group consisting of:

6. The polyplex of claim 5 , wherein J ₁ and J ₂ are independently selected from -C(O)-, -C(O)NH-, -C(O)O-, -O-, or -NH-.

6. The polyplex of claim 5 , wherein _R3 , _R4 , or both contain a primary amine group and optionally one or more secondary or tertiary amine groups .

6. The polyplex of claim 5 , wherein _R3 , _R4 , or both, contain a hydroxyl group and optionally one or more amine groups.

6. The polyplex of claim 5 , wherein _R3 , _R4 , or both contain hydroxyl groups and no amine groups.

The polyplex of claim 5 , wherein at least one of R ₃ and R ₄ does not contain a hydroxyl group.

6. The polyplex of claim 5, wherein R ₃ , R ₄ , or both are -unsubstituted C ₁ -C ₁₀ alkylene-Aq-unsubstituted C ₁ -C ₁₀ alkylene-Bq, -unsubstituted C ₁ -C ₁₀ alkylene-Aq-substituted C ₁ -C ₁₀ alkylene-Bq, -substituted C ₁ -C ₁₀ alkylene-Aq-unsubstituted C ₁ -C ₁₀ alkylene-Bq, or -substituted C ₁ -C ₁₀ alkylene-Aq-substituted C ₁ -C ₁₀ alkylene-Bq, where Aq is absent or -NR ₅ -, Bq is hydroxyl , primary amine, secondary amine, or tertiary amine, and R ₅ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.

2. The polyplex of claim 1, wherein Z' is O, n is an integer from 1 to 24, e.g., 4, 10, 13, or 14, m is an integer from 1 to 10, e.g., 4, 5, 6, 7, or 8, o and p are the same integer from 1 to 6, e.g., 2, 3, or 4, and optionally Z is also O.

2. The polyplex of claim 1, wherein Z' is O, n is an integer from 1 to 24 , e.g., 4, 10, 13, or 14 , m is an integer from 1 to 10 , e.g., 4, 5, 6, 7, or 8 , Rx is C ₁ -C ₂₀ alkyl, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, or homologs and isomers of, e.g., n-pentyl, n-hexyl, n-heptyl, and n-octyl, or aryl, e.g., phenyl, naphthalyl, anthracenyl, phenanthryl, chrysenyl, pyrenyl, tolyl, or xylyl, and optionally Z is also O.

2. The polyplex of claim 1, wherein n is 13, optionally pentadecalactone (PDL), m is 7, optionally sebacic acid, and o and p are 2, optionally N- methyldiethanolamine (MDEA).

22. The polyplex of any of claims 1 to 21 prepared from one or more lactones, one or more amine-diols (Z and Z' = O) or triamines (Z and Z' = NR'), and one or more diacids or diesters , wherein when two or more different lactones, diacids or diesters, and/or triamines or amine-diol monomers are used, the values of n, o, p, and/or m can be the same or different .

10. A composition comprising the polyplex of any one of claims 1 to 23 for use in a method of administering one or more therapeutic, diagnostic or prophylactic nucleic acid agents, or a combination thereof, in vivo or in vitro , said method comprising administering said polyplex to a cell or an individual in need thereof.

The composition of claim 24 , wherein the method comprises transfecting a cell by contacting the cell with the polyplex .

The composition of claim 24 , wherein the polyplex is administered to the lungs.

A particle,
(i) Formula I:

wherein n is an integer from 1 to 30; m, o, and p are independently integers from 1 to 20; x, y, and q are independently integers from 1 to 1000; and Rx is hydrogen, substituted or unsubstituted C _１1 ~C _２０20 Alkyl, or substituted or unsubstituted C _３3 ~C _５０50 Aryl, or substituted or unsubstituted C _１1 ~C _２０20 alkoxy, Z and Z' are independently O or NR', where R' is hydrogen, substituted or unsubstituted C _１1 ~C _２０20 Alkyl, or substituted or unsubstituted C _３3 ~C _５０50 is aryl,
R _１1 and R _２2 is a chemical entity that contains a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or a combination thereof;
polymer;
(ii) one or more nucleic acids encapsulated within the particle; and
(iii) (a) a conjugate of a polymer of formula I and a hydrophilic polymer, or (b) a poly(amine-co-ester) conjugated to a hydrophilic group, or a poly(amine-co-amide) conjugated to a hydrophilic group.
wherein said polymer of formula I is in a mixture containing (a1) said polymer of formula I conjugated to a hydrophilic polymer, or (a2) a poly(amine-co-ester) or a poly(amine-co-amine) conjugated to a hydrophilic polymer.