Methods, compositions, and systems for delivering therapeutic and diagnostic agents into cells
Disclosed are methods for delivering a therapeutic or diagnostic agent to the cytosol of a cell in a subject. The disclosed methods generally include administering to the subject an effective amount of a lipid nanoparticle comprising the therapeutic or diagnostic agent and an effective amount of a membrane-destabilizing polymer. Also disclosed are related compositions and delivery systems.
1. A pH-sensitive, membrane-destabilizing polymer of formula V:
T1-L-[PEGMA m -M2 n ] v -[DMAEMA q -PAA r -BMA s ] w V
wherein
PEGMA is polyethyleneglycol methacrylate residue with 2-20 ethylene glycol units;
M2 is butyl methacrylate residue or hexyl methacrylate residue;
BMA is butyl methacrylate residue;
PAA is propyl acrylic acid residue;
DMAEMA is dimethylaminoethyl methacrylate residue;
m and n are each a mole fraction greater than 0, wherein m is greater than n and m+n=1;
q is a mole fraction of 0.2 to 0.75;
r is a mole fraction of 0.05 to 0.6;
s is a mole fraction of 0.2 to 0.75;
q+r+s=1;
v is 1 to 25 kDa;
w is 1 to 25 kDa;
T1 is a first targeting ligand comprising an N-acetylgalactosamine (NAG) residue; and
L is a linking moiety comprising a polyethylene glycol (PEG) moiety.
2. The polymer of claim 1 , wherein M2 is hexyl methacrylate residue.
3. The polymer of claim 1 , wherein PEGMA is polyethyleneglycol methacrylate residue having 4-5 ethylene glycol units or 7-8 ethylene glycol units.
4. The polymer of claim 1 , wherein the linking moiety L comprises a polyethylene glycol (PEG) moiety having 2-20 ethylene glycol units.
5. The polymer of claim 1 , wherein the polymer of formula V is
NAG-PEG 12 -[PEGMA300 m -HMA n ] v -[D q -P r -B s ] w Vi,
wherein
PEG 12 is a linking moiety comprising a polyethylene glycol having 12 ethylene glycol units;
HMA is hexyl methacrylate residue;
B is a butyl methacrylate residue (BMA);
P is a propyl acrylic acid residue (PAA); and
D is a dimethylaminoethyl methacrylate residue (DMAEMA).
6. The polymer of claim 5 , wherein m is 0.7 to 0.85.
7. The polymer of claim 5 , wherein n is 0.15 to 0.3.
8. The polymer of claim 5 , wherein s is 0.5 to 0.65.
9. The polymer of claim 5 , wherein v is 2.5 to 7 kDa.
10. The polymer of claim 5 , wherein w is 4 to 7 kDa.
11. The polymer of claim 5 , wherein q is 0.25 to 0.4.
12. The polymer of claim 5 , wherein r is 0.07 to 0.15.