Nanoparticle PEG modification with H-phosphonates
View Patent ↗The present invention provides phosphonate conjugates and methods of preparing the phosphonate conjugates so as to allow, for example, improved methods and compounds for modifying the surface of a nanoparticle to increase in vivo circulation times and targeted delivery performance.
1. A compound of the formula:
wherein
each L 1 , L 2 , L 3 and L 4 is independently selected from the group consisting of a bond and a linking group;
R 1 is selected from the group consisting of a nanoparticle, an attachment component, a targeting agent, a diagnostic agent, a stealth agent, and a tetrapodal presentation component;
each R 2 is independently selected from the group consisting of a stealth agent, C 1 -C 10 alkyl, a carboxylic acid or ester, a phosphonic acid or ester, a sulfonic acid or ester, and a hydroxy;
each R 3 and R 4 is independently selected from the group consisting of H, a nanoparticle, an attachment component, a targeting agent, a diagnostic agent, and a stealth agent, wherein at least one of R 3 or R 4 is other than H; and
n is an integer of from 0 to 2.
2. The compound of claim 1 , wherein at least one of L 1 , L 2 , L 3 , and L 4 is a hydrophilic, non-immunogenic, water soluble linking group.
3. The compound of claim 2 , wherein the hydrophilic, non-immunogenic, water soluble linking group is selected from the group consisting of polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polycarboxylate, polysaccharide and dextran.
4. The compound of claim 1 , wherein the targeting agent is an aptamer.
5. The compound of claim 1 , wherein the diagnostic agent is a radioactive agent, a fluorescent agent, or a contrast agent.
6. The compound of claim 1 , wherein the stealth agent is selected from the group consisting of a dendrimer, polyalkylene oxide, polyvinyl alcohol, polycarboxylate, a polysaccharide and hydroxyalkyl starch.
7. The compound of claim 6 , wherein the stealth agent is a polyalkylene oxide.
8. The compound of claim 7 , wherein the polyalkylene oxide is a polyethylene glycol (PEG) ranging from PEG 100 to PEG 10000 .
9. The compound of claim 6 , wherein the polyalkylene oxide is polyethylene glycol (PEG) selected from the group consisting of PEG 100 , PEG 500 , PEG 1000 , PEG 2000 , PEG 5000 and PEG 10000 .
10. The compound of claim 1 , wherein the stealth agent comprises at least two PEG molecules linked together with a linking group.
11. The compound of claim 1 , wherein R 1 is a tetrapodal presentation component having the formula:
wherein
each L 5 and L 6 is independently selected from the group consisting of a bond and a linking group; and
each R 5 and R 6 is independently selected from the group consisting of a targeting agent, a diagnostic agent, and a stealth agent.
12. The compound of claim 1 , wherein each of R 3 and R 4 is independently selected from the group consisting of a lipid and cholesterol.
13. The compound of claim 1 , wherein R 1 is a stealth agent; and each of R 3 and R 4 is an attachment component and independently selected from the group consisting of a lipid and cholesterol, wherein the attachment component is attached to a nanoparticle.
14. The compound of claim 13 , wherein the lipid is saturated or unsaturated C 10 -C 22 alkyl.
15. The compound of claim 14 , wherein n is 0.
16. The compound of claim 1 , wherein R 1 is an attachment component; and R 3 and R 4 are independently selected from the group consisting of a targeting agent, a diagnostic agent and a stealth agent.
17. The compound of claim 1 , wherein R 1 is a stealth agent selected from the group consisting of PEG 100 , PEG 500 , PEG 1000 , PEG 2000 , PEG 5000 and PEG 10000 .
18. The compound of claim 1 , wherein R 1 is an attachment component, and the attachment component is a phospholipid.
19. The compound of claim 18 , wherein the phospholipid has the formula:
wherein each of R 7 and R 8 is independently selected from the group consisting a saturated or unsaturated C 10-24 alkyl or alkanoyl group and a substituted saturated or unsaturated C 10-24 alkyl or alkanoyl group.
20. The compound of claim 1 , wherein each R 1 and R 2 is a stealth agent; each R 3 and R 4 is an attachment component independently selected from the group consisting of a lipid and cholesterol; and n is 1.