Method of delivering therapeutics and imaging agents to the brain by nanoparticles that cross the blood brain barrier
Described herein are methods of delivering a nanoparticle across the blood brain barrier to the brain of a subject by administering to the subject a nanoparticle having a nanoparticle core and a targeting agent. A variety of targeting agents may serve to promote delivery of the described nanoparticle.
1. A method of delivering a therapeutic agent or imaging agent to a patient, the method comprising administering to the patient a nanoparticle comprising a nanoparticle core having a surface; wherein
the nanoparticle further comprises (a) the therapeutic agent or the imaging agent and (b) a targeting agent, the targeting agent comprising a linker and a targeting ligand attached to the surface of the nanoparticle core by the linker;
the targeting ligand having an affinity for binding to a receptor expressed by endothelial cells of the blood brain barrier;
the surface of the nanoparticle core comprises a cationic mucic acid polymer (cMAP), poly(lactic-co-glycolic acid) (PLGA), chitosan, or a polyethyleneimine; and
the linker comprising a polyethylene glycol (PEG) moiety conjugated to the surface of the nanoparticle core by a pH sensitive linkage selected from the group consisting of diamino ketal or imine linkage, wherein the linker is dissociable at a pH in a range of from about 6.8 to about 2.0.
2. The method of claim 1 , wherein
the targeting ligand comprises transferrin, an antibody specific for the transferrin receptor, a polypeptide that specifically binds to the transferrin receptor, insulin, an antibody specific for the insulin receptor, a polypeptide that specifically binds to the insulin receptor, insulin-like growth factor 1, an antibody specific for the insulin-like growth factor receptor 1, a polypeptide that specifically binds to the insulin-like growth factor receptor 1, apolipoprotein E, angiopep-2, an antibody specific for low density lipoprotein receptor or lipoprotein receptor-related protein, a polypeptide that specifically binds to low density lipoprotein receptor or lipoprotein receptor-related protein; an antibody specific for diphtheria toxin receptor, or a polypeptide that specifically binds to diphtheria toxin receptor.
3. The method of claim 2 , wherein the surface of the nanoparticle core comprises a cationic mucic acid polymer (cMAP).
4. The method of claim 3 , wherein the nanoparticle core comprises cationic mucic acid polymer (cMAP) having the structure:
wherein m is any whole number between 5 and 50.
5. The method of claim 2 , wherein the nanoparticle comprises the therapeutic agent, the therapeutic agent comprising serotonin or dopamine.
6. The method of claim 2 , wherein the surface of the nanoparticle core comprises poly(lactic-co-glycolic acid) (PLGA) polymers.
7. The method of claim 2 , wherein the linker comprises a diamino ketal conjugated to the PEG.
8. The method of claim 1 , wherein the linker further comprises a disulfide bond.
9. The method of claim 1 , wherein the linker further comprises a polypeptide bond.
10. The method of claim 1 , wherein the pH sensitive linkage dissociates at a pH in a range of from about 5.5 to about 2.5.
11. The method of claim 1 , wherein the pH sensitive linkage dissociates at a pH in a range of from about 5.5 to about 4.0.
12. The method of claim 1 , wherein the linker comprises an imine linkage conjugated to the PEG.
13. The method of claim 1 , wherein the nanoparticle comprises up to 200 targeting agents conjugated to its surface.
14. The method of claim 1 , wherein the nanoparticle comprises less than 5 targeting agents conjugated to its surface.
15. The method of claim 1 , wherein the nanoparticle comprises a single targeting agent conjugated to its surface.
16. The method of claim 1 , wherein the nanoparticle has:
(a) an average particle size of from about 40 nm to about 100 nm as measured by dynamic light scattering (DLS);
(b) an average zeta potential of from about −0.5 mV to about −15.0 mV as measured by phase analysis light scattering; or
(c) both (a) and (b).
17. The method of claim 1 , wherein the nanoparticle comprises the therapeutic agent.
18. The method of claim 17 , wherein the therapeutic agent is effective against a neurological disorder.
19. The method of claim 17 , wherein the therapeutic agent is serotonin or dopamine.
20. The method of claim 1 , wherein the nanoparticle further comprises the imaging agent.
21. The method of claim 20 , wherein the imaging agent is Cu-64.
22. The method of claim 1 , wherein systemically administering comprises administering parenterally, intravenously, or intraperitoneally.
23. The method of claim 1 , wherein the patient suffers from a neurodegenerative disease.
24. The method of claim 1 , wherein the patient suffers from Alzheimer's disease, Huntington's disease, Parkinson's disease, and multiple sclerosis.