Granted Patent B2

US 12,558,429 · App. 18/002,241 · Granted Feb 24, 2026

Inventors: W. Mark Saltzman (New Haven, CT); Yuhang Jiang (New Haven, CT); Molly Grun (New Haven, CT); Alexandra Suberi (New Haven, CT)

Assignee: Yale University

A61K47/593C08G63/6856C08G63/916

Abstract

Claims (31)

1 . A method of administering one or more therapeutic, diagnostic, or prophylactic nucleic acid agents, or combinations thereof in vivo, comprising administering to the pulmonary system polyplexes or particles to cells of an individual in need thereof, wherein the polyplexes or particles comprise:

(i) a polymer having the structure of Formula I:

wherein n is an integer from 1-30, m, o, and p are independently integers from 1-20, x, y, and q are independently integers from 1-1000, Rx is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, or substituted or unsubstituted alkoxy, Z and Z′ are independently O or NR′, wherein R′ is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl,

wherein R 1 and R 2 are chemical entities containing a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or combinations thereof;

(ii) one or more nucleic acids encapsulated therein; and

(iii) a conjugate of (a) a polymer of Formula I and a hydrophilic polymer, or (b) poly(amine-co-ester)s conjugated to a hydrophilic group or poly(amine-co-amide)s conjugated to a hydrophilic group.

2 . The method of claim 1 wherein the polyplex or particles are administered to the lung.

3 . The method of claim 1 , wherein R 1 and/or R 2 are not

4 . The method of claim 1 , wherein polyplexes or particles formed from the polymer show improved loading, improved cellular transfection, improved intracellular endosomal release, or a combination thereof of an mRNA, relative to corresponding polyplexes or particles wherein R1 and/or R2 consist of

5 . The method of claim 1 , wherein the polymer of Formula I has a structure of Formula II:

wherein J 1 and J 2 are independently linking moieties or absent, wherein the linking moieties are optionally selected from —C(O)—, —C(O)NH—, —C(O)O—, —O—, and —NH—, and

R 3 and R 4 are independently substituted alkyl containing a hydroxyl group, a primary amine group, a secondary amine group, a tertiary amine group, or combinations thereof.

6 . The method of claim 5 , wherein the polymer of Formula II has a structure of Formula III:

7 . The polymer of claim 5 , wherein R3 and/or R4 are independently selected from the group consisting of

8 . The method of claim 5 , wherein:

(i) R 3 , R 4 , or both contain a primary amine group, and optionally one or more secondary or tertiary amine groups,

(ii) R 3 , R 4 , or both contain a hydroxyl group, and optionally one or more amine groups, or

(iii) R 3 , R 4 , or both contain a hydroxyl group and no amine group.

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

10 . The method 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, wherein Aq is absent or —NR 5 —, and Bq is hydroxyl, primary amine, secondary amine, or tertiary amine, wherein R 5 is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl.

11 . The method of claim 1 , wherein:

(i) Z is the same as Z′,

(ii) n is 4, 10, 13, or 14,

(iii) m is 5, 6, or 7, or

(iv) R x is substituted or unsubstituted alkyl.

12 . The method of claim 1 , wherein the weight average molecular weight, as measured by gel permeation chromatography using narrow polydispersity polystyrene standards, is between about 2,000 Daltons and 20,000 Daltons, between about 2,000 Daltons and about 10,000 Daltons, or between about 2000 Daltons and about 7,000 Daltons.

13 . The method 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).

14 . The method of claim 1 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 lactone, diacid or diester, and/or triamine or amine-diol monomers are used, the values of n, o, p, and/or m can be the same or different.

15 . The method of claim 1 wherein the poly(amine-co-ester)s conjugated to a hydrophilic group or the poly(amine-co-amide)s conjugated to a hydrophilic group contain a structure

wherein m′ and m″ are independently 0 or 1, with the proviso that m′+m″ is 1 or 2,

J 1 and J 2 in Formulae XI are independently absent or linking moieties optionally selected from —C(O)—, —C(O)NH—, —C(O)O—, —O—, and —NH—.

Assignments (3)

Continuity (2)

References Cited (158)