TARGETING OF ANTIGEN-PRESENTING CELLS BY NANOPARTICLES CONTAINING POLYOXAZOLINE-LIPID CONJUGATES
A method of targeting antigen-presenting cells and delivering an encapsulated payload with lipid nanoparticles including a POZ-lipid conjugate. The encapsulated payload may include, but is not limited to, a nucleic acid payload such as mRNA or modified mRNA. These LNPs are not subject to accelerated blood clearance and they have a low or reduced immunogenicity profile in vivo.
1 . A method for preferentially delivering a payload to antigen-presenting cells in a subject comprising:
providing a lipid nanoparticle encapsulating the payload, wherein the lipid nanoparticle comprises:
a POZ-lipid of Formula I:
wherein R comprises an initiating group,
POZ comprises poly(ethyloxazoline),
L comprises a physiologically degradable linking group, and
Lipid comprises a non-charged lipid comprising at least one
hydrophobic moiety;
an ionizable or cationic lipid;
a helper lipid;
a sterol lipid; and
administering an effective amount of the lipid nanoparticle to the subject.
2 . The method of claim 1 , wherein the antigen-presenting cells comprise splenic macrophage cells, dendritic cells, or combinations thereof.
3 . The method of claim 1 , wherein POZ comprises [N(COR 2 )CH 2 CH 2 ] n , where R 2 is ethyl.
4 . The method of claim 1 , wherein R comprises a hydrogen, a substituted or unsubstituted alkyl, an alkyne-substituted alkyl, a triazole with attached carboxylic acid, or a substituted or unsubstituted aralkyl group.
5 . The method of claim 1 , wherein L comprises ethers, esters, carboxylate esters, carbonate esters, carbamates, amines, amides, urethanes, disulfides, and combinations thereof.
6 . The method of claim 1 , wherein Lipid comprises two hydrophobic moieties.
7 . The method of claim 1 , wherein Lipid comprises phospholipid, a glycerolipid, a di-alkyl acetamide, or a combination thereof.
8 . The method of claim 1 , wherein Lipid comprises 1,2-dimyristoyl-sn-glycerol, 1,2-dilauroyl-sn-glycerol, or a combination thereof.
9 . The method of claim 1 , wherein the payload comprises an oligonucleotide.
10 . A method of delivering a payload to target tissue of a subject, comprising:
providing a lipid nanoparticle encapsulating the payload, wherein the lipid nanoparticle comprises:
a POZ-lipid of Formula I:
wherein R comprises an initiating group,
POZ comprises poly(ethyloxazoline),
L comprises a physiologically degradable linking group, and
Lipid comprises a non-charged lipid comprising at least one hydrophobic moiety;
an ionizable or cationic lipid;
a helper lipid;
a sterol lipid; and
administering an effective amount of the lipid nanoparticle to the subject.
11 . The method of claim 10 , wherein the step of administering comprises intramuscularly injecting the subject.
12 . The method of claim 10 , wherein the step of administering comprises intramuscularly injecting the subject with a plurality of doses, wherein after a first dose is administered, each subsequent dose is administered after a predetermined amount of time.
13 . The method of claim 12 , wherein the predetermined amount of time is at least 30 days.
14 . The method of claim 10 , wherein the target tissue comprises liver, spleen, or a combination thereof.
15 . The method of claim 10 , wherein POZ comprises [N(COR 2 )CH 2 CH 2 ] n , where R 2 is ethyl.
16 . The method of claim 10 , wherein R comprises a hydrogen, a substituted or unsubstituted alkyl, an alkyne-substituted alkyl, a triazole with attached carboxylic acid, or a substituted or unsubstituted aralkyl group.
17 . The method of claim 10 , wherein L comprises ethers, esters, carboxylate esters, carbonate esters, carbamates, amines, amides, urethanes, disulfides, and combinations thereof.
18 . The method of claim 10 , wherein Lipid comprises phospholipid, a glycerolipid, a di-alkyl acetamide, or a combination thereof.
19 . The method of claim 10 , wherein Lipid comprises 1,2-dimyristoyl-sn-glycerol, 1,2-dilauroyl-sn-glycerol, or a combination thereof.
20 . The method of claim 10 , wherein the payload comprises mRNA.
21 . A method for delivering a therapeutic level of an immunogenic payload to target tissue of a subject, comprising:
administering a plurality of doses of a lipid nanoparticle to the subject, wherein the lipid nanoparticle encapsulates an mRNA encoding an antigen, wherein the lipid nanoparticle comprises an ionizable lipid, a helper lipid, a structural lipid, and a POZ-lipid of Formula I:
wherein R comprises an initiating group,
POZ comprises poly(ethyloxazoline),
L comprises a physiologically degradable linking group, and
Lipid comprises a non-charged lipid comprising at least one hydrophobic moiety, and
wherein the LNP induces an attenuated drug response associated with an LNP.
22 . The method of claim 21 , wherein the drug response comprises an attenuated induction of IgM, attenuated induction of IgG, an attenuated accelerated blood clearance, or a combination thereof.
23 . The method of claim 21 , wherein the target tissue comprises liver, spleen, or a combination thereof.
24 . The method of claim 21 , wherein POZ comprises [N(COR 2 )CH 2 CH 2 ] n , where R 2 is ethyl.
25 . The method of claim 21 , wherein R comprises a hydrogen, a substituted or unsubstituted alkyl, an alkyne-substituted alkyl, a triazole with attached carboxylic acid, or a substituted or unsubstituted aralkyl group.
26 . The method of claim 21 , wherein L comprises ethers, esters, carboxylate esters, carbonate esters, carbamates, amines, amides, urethanes, disulfides, and combinations thereof.